|
1
|
Liu Y, Peng J, Zhao Y, Wang W. Emerging pathological diagnostic strategies for solid pseudopapillary neoplasm of the pancreas: insights from omics and innovative techniques. J Pathol Clin Res 2025; 11:e70029. [PMID: 40312910 PMCID: PMC12046068 DOI: 10.1002/2056-4538.70029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/21/2025] [Accepted: 03/31/2025] [Indexed: 05/03/2025]
Abstract
Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare, low-grade malignant tumor, representing 0.9-2.7% of all exocrine pancreatic tumors. SPN patients generally have a favorable prognosis with a 5-year survival rate exceeding 95% following complete surgical resection. Accurate diagnosis is crucial to avoid unnecessary treatments. Currently, SPN diagnosis relies on imaging techniques such as CT and MRI, along with immunohistochemical analysis of biopsy and resection samples. The main challenge in diagnosis is the potential inability to accurately identify recurrent or metastatic SPN, as well as 'malignant' SPN, due to the lack of specific biomarkers. Advances in high-throughput omics technologies, including genomics, transcriptomics, proteomics and metabolomics, have opened new avenues for identifying novel biomarkers for SPN. Additional, liquid biopsy techniques have enabled more comprehensive analysis of biosamples such as pancreatic cyst fluid, offering promising prospects for preoperative diagnosis. This review highlights recent research on SPN diagnosis, focusing on immunohistochemical markers, tissue sampling methods and the potential of omics approaches. It also discusses the challenges and opportunities in improving diagnostic accuracy, particularly for high-grade and metastatic SPNs.
Collapse
Affiliation(s)
- Yuanhao Liu
- Department of PathologyPeking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical CollegeBeijingPR China
| | - Junya Peng
- Institute of Clinical MedicinePeking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical CollegeBeijingPR China
- State Key Laboratory of Complex, Severe, and Rare DiseasesPeking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical CollegeBeijingPR China
| | - Yupei Zhao
- State Key Laboratory of Complex, Severe, and Rare DiseasesPeking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical CollegeBeijingPR China
- Department of General SurgeryPeking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical CollegeBeijingPR China
- Department of Basic Medical SciencesSchool of Medicine, Tsinghua UniversityBeijingPR China
- Peking University‐Tsinghua Center for Life SciencesBeijingPR China
| | - Wenze Wang
- Department of PathologyPeking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical CollegeBeijingPR China
- Molecular Pathology Research Center, Department of PathologyPeking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingPR China
| |
Collapse
|
|
2
|
Zebene ED, Lombardi R, Pucci B, Medhin HT, Seife E, Di Gennaro E, Budillon A, Woldemichael GB. Proteomic Analysis of Biomarkers Predicting Treatment Response in Patients with Head and Neck Cancers. Int J Mol Sci 2024; 25:12513. [PMID: 39684225 DOI: 10.3390/ijms252312513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024] Open
Abstract
Head and neck cancers (HNCs) are the sixth most commonly diagnosed cancer and the eighth leading cause of cancer-related mortality worldwide, with squamous cell carcinoma being the most prevalent type. The global incidence of HNCs is steadily increasing, projected to rise by approximately 30% per year by 2030, a trend observed in both developed and undeveloped countries. This study involved serum proteomic profiling to identify predictive clinical biomarkers in cancer patients undergoing chemoradiotherapy (CRT). Fifteen HNC patients at Tikur Anbessa Specialized Hospital, Radiotherapy (RT) center in Addis Ababa were enrolled. Serum samples were collected before and after RT, and patients were classified as responders (R) or non-responders (NR). Protein concentrations in the serum were determined using the Bradford assay, followed by nano-HPLC-MS/MS for protein profiling. Progenesis QI for proteomics identified 55 differentially expressed proteins (DEPs) between R and NR, with a significance of p < 0.05 and a fold-change (FC) ≥ 1.5. The top five-up-regulated proteins included MAD1L1, PSMC2, TRIM29, C5, and SERPING1, while the top five-down-regulated proteins were RYR1, HEY2, HIF1A, TF, and CNN3. Notably, about 16.4% of the DEPs were involved in cellular responses to DNA damage from cancer treatments, encompassing proteins related to deoxyribonucleic acid (DNA) damage sensing, checkpoint activation, DNA repair, and apoptosis/cell cycle regulation. The analysis of the relative abundance of ten proteins with high confidence scores identified three DEPs: ADIPOQ, HEY2, and FUT10 as potential predictive biomarkers for treatment response. This study highlighted the identification of three potential predictive biomarkers-ADIPOQ, HEY2, and FUT10-through serum proteomic profiling in HNC patients undergoing RT, emphasizing their significance in predicting treatment response.
Collapse
Affiliation(s)
- Emeshaw Damtew Zebene
- Nuclear Medicine Unit, Department of Internal Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa 9086, Ethiopia
- Department of Microbial Cellular and Molecular Biology, College of Natural and Computational Sciences, Addis Ababa University, Addis Ababa 9086, Ethiopia
| | - Rita Lombardi
- Experimental Animal Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Biagio Pucci
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Hagos Tesfay Medhin
- Nuclear Medicine Unit, Department of Internal Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa 9086, Ethiopia
| | - Edom Seife
- Radiotherapy Center, College of Health Sciences, Addis Ababa University, Addis Ababa 9086, Ethiopia
| | - Elena Di Gennaro
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Alfredo Budillon
- Scientific Directorate, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131 Naples, Italy
| | - Gurja Belay Woldemichael
- Department of Microbial Cellular and Molecular Biology, College of Natural and Computational Sciences, Addis Ababa University, Addis Ababa 9086, Ethiopia
| |
Collapse
|
|
3
|
Fu C, Li X, Wang Y, Wang C, Jin H, Liu K, Xu H. Solid pseudopapillary neoplasm of the pancreas: a retrospective study of 195 cases. Front Oncol 2024; 14:1349282. [PMID: 38469229 PMCID: PMC10925641 DOI: 10.3389/fonc.2024.1349282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 02/12/2024] [Indexed: 03/13/2024] Open
Abstract
Objective Solid pseudopapillary neoplasm of the pancreas (SPN) is a rare exocrine tumor of the pancreas. The aim of our study is to summarize the clinical features of SPN and to analyze the risk factors for malignant SPN. Methods From May 2013 to September 2022, patients who were pathologically confirmed to have SPN were retrospectively reviewed. Demographic data, clinical and pathological features, follow-up data were collected and analyzed. To investigate the factors influencing the benign or malignant nature of SPN, we employed logistic regression. Additionally, we utilized Kaplan-Meier curves to depict and analyze the overall prognosis. Results A total of 195 patients were included, 163 of whom were female and the average age of all patients was 31.7 years old. Among 195 patients, 101 patients (51.8%) had no obvious clinical symptoms and their pancreatic lesions were detected during routine examination. The primary symptom was abdominal pain and distension in 64 cases (32.8%). The maximum diameter of SPN tumors ranged from 1-17 cm (mean 6.19 cm). Forty-eight postoperative complications developed in 43 (22.1%) patients. After a median follow-up duration of 44.5 months, the overall 5-year survival rate was 98.8% and the recurrence rate was 1.5%. Furthermore, we observed a statistically significant difference in the completeness of the tumor capsule between benign and malignant SPN. Conclusion SPN is associated with a favorable long-term survival after surgery in our large sample size cohort. For malignant SPN, tumor capsule incompleteness is an independent risk factor.
Collapse
Affiliation(s)
- Chang Fu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Xiaocong Li
- Medical Research and Biometrics Center, National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongxin Wang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Chuangshi Wang
- Medical Research and Biometrics Center, National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hengwei Jin
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Kai Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Hongji Xu
- Department of Abdominal Surgery, Guiqian International General Hospital, Guiyang, Guizhou, China
| |
Collapse
|
|
4
|
Papadopoulos N, Hruban RH. Molecular Mechanisms of Cystic Neoplasia‐. THE PANCREAS 2023:630-637. [DOI: 10.1002/9781119876007.ch82] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
5
|
Sun G, Fang K, Fu X, Peng L, Shu J, Tu Y, Li Y, Xiao W. Solid Pseudopapillary Neoplasm of the Pancreas: A Multi-Institution Study of 118 Cases. Pancreas 2023; 52:e121-e126. [PMID: 37523603 DOI: 10.1097/mpa.0000000000002219] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/02/2023]
Abstract
OBJECTIVES The aim of the study is to summary the clinicopathological characteristics and surgical outcomes of solid pseudopapillary neoplasm (SPN) of the pancreas. METHODS In this retrospective study, the information of 118 patients with SPN from 3 hospitals were analyzed. RESULTS A total of 118 patients. The mean age was 30.8 (standard deviation, 14.7) years and the majority were female (n = 95, 80.5%). Sixty-seven patients (56.8%) had clinical symptoms, of which the most common symptom was abdominal pain (49.6%). The mean tumor size was 5.9 (standard deviation, 2.9) cm. Pseudopapillary architecture was the commonest histologic feature, and β-catenin, CD56, vimentin, neuron-specific enolase, CD10, a1-antitrypsin, cytokeratins showed different degrees of positive expression in immunohistochemical staining. Fourteen patients (11.9%) presented aggressive pathologic behavior, which was correlated to the incomplete tumor capsule. At a median follow-up of 59.2 months, the recurrence rate was 1.8% and the overall 5-year survival rate was 97.7%. CONCLUSIONS Solid pseudopapillary neoplasm of the pancreas is a potentially low-grade malignant tumor that most frequently found in young females. Its clinical manifestations are nonspecific and the diagnosis mostly depends on pathological examination. Surgical resection is the first choice of treatment for SPN with a good prognosis.
Collapse
Affiliation(s)
- Gen Sun
- From the Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Kang Fang
- From the Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiaowei Fu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Long Peng
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jiaming Shu
- Department of Oncology, Jiangxi Provincial People's Hospital, Nanchang, China
| | - Yi Tu
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yong Li
- From the Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Weidong Xiao
- From the Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| |
Collapse
|
|
6
|
Meng L, Zhan Y, Wei M, Yang R, Wang J, Weng S, Chen L, Zheng S, Dong K, Dong R. Single-cell RNA sequencing of solid pseudopapillary neoplasms of the pancreas in children. Cancer Sci 2023; 114:1986-2000. [PMID: 36721980 PMCID: PMC10154873 DOI: 10.1111/cas.15744] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 01/05/2023] [Accepted: 01/23/2023] [Indexed: 02/02/2023] Open
Abstract
Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare pancreatic tumor in children. Its origin remains elusive, along with its pathogenesis. Heterogeneity within SPN has not been previously described. In addition, low malignant but recurrent cases have occasionally been reported. To comprehensively unravel these profiles, single-cell RNA sequencing was performed using surgical specimens. We identified the cell types and suggested the origin of pancreatic endocrine progenitors. The Wnt/β-catenin pathway may be involved in tumorigenesis, while the epithelial-to-mesenchymal transition may be responsible for SPN recurrence. Furthermore, NOV, DCN were nominated as primary and S100A10, MGP as recurrent SPN marker genes, respectively. Our results provide insight into the pathogenesis of SPN.
Collapse
Affiliation(s)
- Lingdu Meng
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Yong Zhan
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Meng Wei
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China.,Department of Hematology, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ran Yang
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Junfeng Wang
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Shuting Weng
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Lian Chen
- Department of Pathology, Children's Hospital of Fudan University, Shanghai, China
| | - Shan Zheng
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Kuiran Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| | - Rui Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defect, Shanghai, China
| |
Collapse
|
|
7
|
Shang Y, Zhang Y, Pan E, Yang P, Xu L, Sun J. A refractory liver metastatic solid pseudopapillary neoplasm pancreas harbored CTNNB1 mutation showed good response to celecoxib: A case report. Front Oncol 2022; 12:1022290. [PMID: 36387184 PMCID: PMC9650638 DOI: 10.3389/fonc.2022.1022290] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 10/11/2022] [Indexed: 01/11/2025] Open
Abstract
Solid pseudopapillary neoplasm (SPN) of the pancreas is rare relatively low-grade malignant neoplasm and metastasis rarely. Surgical resection is the primary treatment option for primary and metastatic lesions of SPN, and chemotherapy is often ineffective in non-operable SPNs. SPNs are characterized by the presence of somatic CTNNB1 exon 3 mutations, leading to the activation of Wnt/β-catenin/Cox-2 signal pathway. Here, we firstly report that a refractory liver metastatic pancreatic SPN patient after the failure of multi-line chemotherapies benefited from the Cox-2 selective inhibitor (Celecoxib) based on CTNNB1 D32V mutation detected by next-generation sequencing (NGS), achieving a more than 22-month progression-free survival without any adverse events. Our case provides a potential treatment option for liver metastatic SPN patients with CTNNB1 mutations and highlights the application of NGS for the better treatment decision making.
Collapse
Affiliation(s)
- Yu Shang
- Department of Medical Oncology, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Yunkun Zhang
- Department of Medical Oncology, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Evenki Pan
- Department of Medical, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China
| | - Peng Yang
- Department of Medical, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China
| | - Lingling Xu
- Department of Medical Oncology, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Jinghua Sun
- Department of Medical Oncology, The Second Hospital of Dalian Medical University, Dalian, Liaoning, China
| |
Collapse
|
|
8
|
Ni L, Sun P, Ai M, Kong L, Xu R, Li J. Berberine inhibited the formation of metastasis by intervening the secondary homing of colorectal cancer cells in the blood circulation to the lung and liver through HEY2. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 104:154303. [PMID: 35802997 DOI: 10.1016/j.phymed.2022.154303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/17/2022] [Accepted: 06/26/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Metastasis is the leading cause of death in patients with colorectal cancer (CRC). The 5-year survival rate of CRC patients in whom the cancer has spread to distant sites is 13.5%. The most common sites of CRC metastasis are liver and lung. The principal therapies for CRC metastatic disease are surgery, but its benefits are limited. PURPOSE This study aimed to reveal the regulatory mechanism of berberine on secondary homing of CRC cells to form metastatic focus. This was more valuable than the previous direct study of the migration and metastasis characteristics of CRC cells. METHODS In this study, we used the functional enrichment analysis of differentially expressed genes after berberine treatment and investigated co-expression modules related with CRC metastasis by WGCNA. PPI and survival analyses of significant modules were also conducted. The biological functions of berberine in CRC lung and liver metastasis were investigated by a series of in vitro and in vivo experiments: MTT, colony formation and mouse tail vein injection. And we scanned through the entire extracellular domain of HEY2 protein for autodocking analysis with berberine. RESULTS We found the differentially expressed genes (DEGs) after berberine treatment were related with cancer progression and metastasis related pathways. Through WGCNA analysis, four cancer progression and metastasis related modules were detected. After PPI and survival analysis, we identified and validated HEY2 as a hub gene, high expression and poor survival at the metastatic stage. Functionally, berberine inhibited the survival, invasion and migration of CRC cells in vitro and in vivo. Mechanistically, berberine treatment down-regulated the expression of HEY2, metastasis related protein E-cadherin, β-catenin and Cyclin D1 during Mesenchymal epithelial transformation (MET). Berberine and HEY2 showed a significant interaction, and berberine binded to HEY2 protein at the residue HIS-99 interface with a hydrogen-bond distance of 1.9A. CONCLUSIONS We revealed that berberine could significantly inhibit the expression of hub gene HEY2 and metastasis related proteins E-cadherin and β-catenin and Cyclin D1 during MET in CRC lung and liver metastases. In total, HEY2 was a promising candidate biomarker for prognosis and molecular characteristics in CRC metastasis.
Collapse
Affiliation(s)
- Lulu Ni
- Department of Basic Medicine, Jiangnan University, Wuxi 214122, PR China
| | - Ping Sun
- Department of Pathology, The Affiliated Wuxi NO. 2 People's Hospital of Nanjing Medical University, Wuxi 214000,PR China
| | - Min Ai
- Laboratory Animal Center of Shanghai Jiao Tong University, Shanghai 200240, PR China
| | - Lingzhong Kong
- Department of Rehabilitation Acupuncture Medicine, Bozhou People's Hospital, Bozhou, Anhui 236800, PR China
| | - Rongrong Xu
- Department of Pathology, The Affiliated Wuxi NO. 2 People's Hospital of Nanjing Medical University, Wuxi 214000,PR China
| | - Jiangan Li
- Department of Emergency, The Affiliated Wuxi NO. 2 People's Hospital of Nanjing Medical University, No. 68 Zhongshan Road, Wuxi 214000, PR China.
| |
Collapse
|
|
9
|
Molecular Alterations in Solid Pseudopapillary Neoplasm of the Pancreas: The Achilles Heel in Conquering Pancreatic Tumorigenesis. Pancreas 2021; 50:1343-1347. [PMID: 35041331 DOI: 10.1097/mpa.0000000000001928] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Solid pseudopapillary neoplasms of the pancreas are overwhelmingly benign tumors predominately observed in women in the third decade of life. However, their malignant potential, based on local recurrences and metastases, has brought into question the available evidence on their biological behavior. Solid pseudopapillary neoplasms have distanced themselves from other pancreatic tumors with varying morphological appearance, immune profile, and histogenesis. In review of the literature, PubMed was queried using search strings, including "solid pseudopapillary neoplasm" and "molecular," and "immunohistochemistry." Alternative searches were also conducted given the variability in tumor name, including "solid pseudopapillary tumor" and "Frantz tumor." This article provides an in-depth review into the molecular pathways that contribute to the pathogenesis of solid pseudopapillary neoplasms. It also discusses the implications of existing molecular pathways toward tumor aggressiveness and recurrence potential.
Collapse
|
|
10
|
Paradis V. Hepatocellular Carcinomas: Towards a pathomolecular approach. Liver Int 2021; 41 Suppl 1:83-88. [PMID: 34155797 DOI: 10.1111/liv.14867] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 02/28/2021] [Indexed: 12/24/2022]
Abstract
Molecular analysis of primary liver malignancies has provided a refinement of the pathological diagnosis of this entity and the identification of an increasing number of tumor subtypes of hepatocellular proliferation, either malignant (hepatocellular carcinomas) or benign (hepatocellular adenomas). Besides the diagnosis, a combined pathomolecular approach can also provide further insights into patient prognosis, and help select patients who can benefit from targeted therapies. Hepatocellular carcinomas define a heterogeneous group of malignant hepatocellular proliferation at various levels: macroscopic, histological and molecular. While most carcinomas occur in patients with chronic liver diseases and advanced fibrosis in the background liver, some arise from the malignant transformation of a pre-existing hepatocellular adenoma. TERT promoter mutations are the most frequent genomic alterations observed in the process of malignancy, and they occur early in the process of liver carcinogenesis. Overall, a more active biopsy strategy should be considered a key step in the management of patients with HCC.
Collapse
Affiliation(s)
- Valérie Paradis
- Department of Pathology, Université de Paris, Hôpital Beaujon, Paris, France
| |
Collapse
|
|
11
|
La Rosa S, Bongiovanni M. Pancreatic Solid Pseudopapillary Neoplasm: Key Pathologic and Genetic Features. Arch Pathol Lab Med 2021; 144:829-837. [PMID: 31958381 DOI: 10.5858/arpa.2019-0473-ra] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/05/2019] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Solid pseudopapillary neoplasm of the pancreas is a low-grade malignant tumor generally associated with a good prognosis. Solid pseudopapillary neoplasms show peculiar morphologic features, but sometimes the differential diagnosis with other pancreatic neoplasms (ie, pancreatic neuroendocrine tumors) can be a challenging task, especially in cytologic or biopsy specimens. In these cases immunohistochemistry is a useful tool, but the diagnostic utility of several proposed immunohistochemical markers is questionable. In recent years, despite several attempts to characterize the pathogenetic, molecular, and prognostic features of solid pseudopapillary neoplasms, they still remain unclear. OBJECTIVE.— To give the reader a comprehensive update on this entity. DATA SOURCES.— The PubMed database (US National Library of Medicine) was searched using the following string: pseudopapillary tumor [AND/OR] neoplasm [AND/OR] pancreas. All articles written in English were included. In addition, because a heterogeneous terminology has been used in the past to define solid pseudopapillary neoplasms, the reference lists of each paper selected in the PubMed database were also reviewed. CONCLUSIONS.— This review gives a comprehensive update on the pathologic, clinical, and molecular features of solid pseudopapillary neoplasms, particularly addressing issues and challenges related to diagnosis. In addition, we have tried to correlate the molecular alterations with the morphologic and clinical features.
Collapse
Affiliation(s)
- Stefano La Rosa
- From the Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland (Dr La Rosa); Synlab Swiss SA, Pathology, Lausanne, Switzerland (Dr Bongiovanni)
| | - Massimo Bongiovanni
- From the Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland (Dr La Rosa); Synlab Swiss SA, Pathology, Lausanne, Switzerland (Dr Bongiovanni)
| |
Collapse
|
|
12
|
Abudalou M, Vega EA, Dhingra R, Holzwanger E, Krishnan S, Kondratiev S, Niakosari A, Conrad C, Stallwood CG. Solid pseudopapillary neoplasm-diagnostic approach and post-surgical follow up: Three case reports and review of literature. World J Clin Cases 2021; 9:1682-1695. [PMID: 33728313 PMCID: PMC7942041 DOI: 10.12998/wjcc.v9.i7.1682] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/23/2020] [Accepted: 01/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Solid pseudopapillary neoplasm (SPN) is a rare tumor that was first described by Frantz in 1959. Although this tumor is benign, some may have malignant potential that can be predicted based on demographics, imaging characteristics, and pathologic evaluation. This case series presents 3 SPN cases with discussion on gender differences, preoperative predictors of malignancy, and a suggested algorithm for diagnostic approach as well as post-surgical follow up.
CASE SUMMARY Three adult patients in a tertiary hospital found to have SPN, one elderly male and two young females. Each of the cases presented with abdominal pain and were discovered incidentally. Two cases underwent endoscopic ultrasound with fine needle aspiration and biopsy to assess tumor markers and immuno-histochemical staining (which were consistent with SPN before undergoing surgery), and one case underwent surgery directly after imaging. The average tumor size was 5 cm. Diagnosis was confirmed by histology. Two patients had post-surgical complications requiring intervention.
CONCLUSION Demographic and imaging characteristics can be sufficient to establish diagnosis for SPN, while malignant cases require pre-operative evaluation with endoscopic ultrasound fine needle aspiration/fine needle biopsy.
Collapse
Affiliation(s)
- Mohammad Abudalou
- Department of Internal Medicine, St. Elizabeth Medical Center, Brighton, MA 02135, United States
| | - Eduardo A Vega
- Department of General Surgery, St. Elizabeth Medical Center, Brighton, MA 02135, United States
| | - Rohit Dhingra
- Department of Gastroenterology, Tufts Medical Center, Boston, MA 02111, United States
| | - Erik Holzwanger
- Department of Gastroenterology, Tufts Medical Center, Boston, MA 02111, United States
| | - Sandeep Krishnan
- Department of Gastroenterology, St. Elizabeth Medical Center, Brighton, MA 02135, United States
| | - Svetlana Kondratiev
- Department of Pathology, St. Elizabeth Medical Center, Brighton, MA 02135, United States
| | - Ali Niakosari
- Department of Radiology, St. Elizabeth Medical Center, Brighton, MA 02135, United States
| | - Claudius Conrad
- Department of General Surgery, St. Elizabeth Medical Center, Brighton, MA 02135, United States
| | - Christopher G Stallwood
- Department of Gastroenterology, St. Elizabeth Medical Center, Brighton, MA 02135, United States
| |
Collapse
|
|
13
|
Jin Y, Ran C, Li F, Cheng N. Melanoma of unknown primary in the pancreas: should it be considered primary? BMC Surg 2020; 20:76. [PMID: 32299408 PMCID: PMC7164174 DOI: 10.1186/s12893-020-00731-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 03/27/2020] [Indexed: 12/22/2022] Open
Abstract
Abstract
Background
Malignant melanoma is characterized as highly malignant due to its rapid growth and early metastasis. Metastatic melanoma from occult primary is rare. Melanoma of unknown primary in pancreas are even rear. But it is a biologically ill-defined and clinically understudied concept.
Case presentation
In this report, a 43-year-old man was diagnosed with pancreatic carcinoma. Extended total pancreatectomy together with portal vein reconstruction and extensive lymphadenectomy were performed in our hospital. The patient was diagnosed with pancreatic malignant melanoma after pathological examination. He was still alive 20 months after the operation without any evidence of recurrence.
Conclusion
The described case highlights the possibility of primary pancreatic malignant melanoma and the treatment strategies of this rare carcinoma.
Collapse
|
|
14
|
Isoform-specific promotion of breast cancer tumorigenicity by TBX3 involves induction of angiogenesis. J Transl Med 2020; 100:400-413. [PMID: 31570773 PMCID: PMC7044113 DOI: 10.1038/s41374-019-0326-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 08/13/2019] [Accepted: 09/03/2019] [Indexed: 12/15/2022] Open
Abstract
TBX3 is a member of the highly conserved family of T-box transcription factors involved in embryogenesis, organogenesis and tumor progression. While the functional role of TBX3 in tumorigenesis has been widely studied, less is known about the specific functions of the different isoforms (TBX3iso1 and TBX3iso2) which differ in their DNA-binding domain. We therefore sought to investigate the functional consequence of this highly conserved splice event as it relates to TBX3-induced tumorigenesis. By utilizing a nude mouse xenograft model, we have identified differential tumorigenic potential between TBX3 isoforms, with TBX3iso1 overexpression more commonly associated with invasive carcinoma and high tumor vascularity. Transcriptional analysis of signaling pathways altered by TBX3iso1 and TBX3iso2 overexpression revealed significant differences in angiogenesis-related genes. Importantly, osteopontin (OPN), a cancer-associated secreted phosphoprotein, was significantly up-regulated with TBX3iso1 (but not TBX3iso2) overexpression. This pattern was observed across three non/weakly-tumorigenic breast cancer cell lines (21PT, 21NT, and MCF7). Up-regulation of OPN in TBX3iso1 overexpressing cells was associated with induction of hyaluronan synthase 2 (HAS2) expression and increased retention of hyaluronan in pericellular matrices. These transcriptional changes were accompanied by the ability to induce endothelial cell vascular channel formation by conditioned media in vitro, which could be inhibited through addition of an OPN neutralizing antibody. Within the TCGA breast cancer cohort, we identified an 8.1-fold higher TBX3iso1 to TBX3iso2 transcript ratio in tumors relative to control, and this ratio was positively associated with high-tumor grade and an aggressive molecular subtype. Collectively, the described changes involving TBX3iso1-dependent promotion of angiogenesis may thus serve as an adaptive mechanism within breast cancer cells, potentially explaining differences in tumor formation rates between TBX3 isoforms in vivo. This study is the first of its kind to report significant functional differences between the two TBX3 isoforms, both in vitro and in vivo.
Collapse
|
|
15
|
Jorgensen MS, Velez-Velez LM, Asbun H, Colon-Otero G. Everolimus Is Effective Against Metastatic Solid Pseudopapillary Neoplasm of the Pancreas: A Case Report and Literature Review. JCO Precis Oncol 2019; 3:1-6. [DOI: 10.1200/po.18.00304] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
|
|
16
|
Wang J, Gerrard G, Poskitt B, Dawson K, Trivedi P, Foroni L, El-Bahrawy M. Targeted next generation sequencing of pancreatic solid pseudopapillary neoplasms show mutations in Wnt signaling pathway genes. Pathol Int 2019; 69:193-201. [PMID: 30811747 DOI: 10.1111/pin.12778] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 01/10/2019] [Indexed: 12/11/2022]
Abstract
Solid pseudopapillary neoplasms of the pancreas are rare neoplasms that have been shown to harbor recurrent somatic pathogenic variants in the beta-catenin gene, CTNNB1. Here, we used targeted next generation sequencing to analyze these tumors for other associated mutations. Six cases of solid pseudopapillary neoplasms were studied. DNA extracted from formalin-fixed paraffin embedded tissue blocks was analyzed using the Ion Torrent platform, with the 50-gene Ampliseq Cancer Hotspot Panel v2 (CHPv2), with further variant validation performed by Sanger sequencing. Four tumors (67%) were confirmed to harbor mutations within CTNNB1, two with c.109T > G p.(Ser37Ala) and two with c.94G > A p.(Asp32Asn). One case showed a frameshift deletion in the Adenomatous Polyposis Coli gene, APC c.3964delG p.(Glu1322Lysfs*93) with a variant allele frequency of 42.6%. Sanger sequencing on non-tumoral tissue confirmed the variant was somatic. The patient with the APC mutation developed metastasis and died. In addition to the four cases harboring CTNNB1 variants, we found a case characterized by poor outcome, showing a rare frameshift deletion in the APC gene. Since the APC product interacts with beta-catenin, APC variants may, in addition to CTNNB1, contribute to the pathogenesis of solid pseudopapillary neoplasms via the Wnt signaling pathway.
Collapse
Affiliation(s)
- Jayson Wang
- Department of Cellular Pathology, St George's Hospital, London, UK
| | - Gareth Gerrard
- Department of Medicine, Centre for Haematology, Imperial College London, London, UK
- Sarah Cannon Molecular Diagnostics, HCA Healthcare UK, London, UK
| | - Ben Poskitt
- Sarah Cannon Molecular Diagnostics, HCA Healthcare UK, London, UK
| | - Kay Dawson
- Department of Histopathology, Imperial College London, Hammersmith Hospital, London, UK
| | - Pritesh Trivedi
- Department of Histopathology, Imperial College London, Hammersmith Hospital, London, UK
| | - Letizia Foroni
- Department of Medicine, Centre for Haematology, Imperial College London, London, UK
| | - Mona El-Bahrawy
- Department of Histopathology, Imperial College London, Hammersmith Hospital, London, UK
- Faculty of Medicine, Department of Pathology, University of Alexandria, Alexandria, Egypt
| |
Collapse
|
|
17
|
Netrin Family: Role for Protein Isoforms in Cancer. J Nucleic Acids 2019; 2019:3947123. [PMID: 30923634 PMCID: PMC6408995 DOI: 10.1155/2019/3947123] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 02/06/2019] [Indexed: 12/27/2022] Open
Abstract
Netrins form a family of secreted and membrane-associated proteins. Netrins are involved in processes for axonal guidance, morphogenesis, and angiogenesis by regulating cell migration and survival. These processes are of special interest in tumor biology. From the netrin genes various isoforms are translated and regulated by alternative splicing. We review here the diversity of isoforms of the netrin family members and their known and potential roles in cancer.
Collapse
|
|
18
|
Calvani J, Lopez P, Sarnacki S, Molina TJ, Gibault L, Fabre M, Scharfmann R, Capito C, Galmiche L. Solid pseudopapillary neoplasms of the pancreas do not express major pancreatic markers in pediatric patients. Hum Pathol 2019; 83:29-35. [DOI: 10.1016/j.humpath.2018.08.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 08/02/2018] [Accepted: 08/03/2018] [Indexed: 12/26/2022]
|
|
19
|
Neill KG, Saller J, Al Diffalha S, Centeno BA, Malafa MP, Coppola D. EGFR L861Q Mutation in a Metastatic Solid-pseudopapillary Neoplasm of the Pancreas. Cancer Genomics Proteomics 2018; 15:201-205. [PMID: 29695402 DOI: 10.21873/cgp.20078] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 02/20/2018] [Accepted: 03/09/2018] [Indexed: 02/07/2023] Open
Abstract
Solid-pseudopapillary neoplasm of the pancreas (SPN) is a rare neoplasm that is typically indolent in nature. Surgical resection is the preferred method of treatment and often associated with a good prognosis. Local invasion and metastasis have been reported in a small subset of patients. Currently, there are limited data on the molecular mutation profile of invasive and metastatic SPN. In this report, we present the case of a 38-year-old female with a locally-invasive and unresectable SPN that, despite exhaustive chemoradiotherapy, progressed to liver metastasis. Pyrosequencing of the primary pancreatic tumor antecedent to metastasis showed an uncommon EGFR mutation at L861Q in the kinase domain of exon 21. This finding, if confirmed in additional cases of metastatic SPN, would support preoperative testing for EGFR mutation analysis to detect aggressive SPNs.
Collapse
Affiliation(s)
- Kevin G Neill
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - James Saller
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Sameer Al Diffalha
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Barbara A Centeno
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A.,Department of Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Mokenge P Malafa
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A
| | - Domenico Coppola
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A. .,Department of Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A.,Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, U.S.A.,Department of Oncological Sciences, University of South Florida, Tampa, FL, U.S.A
| |
Collapse
|
|
20
|
Primary Ovarian Solid Pseudopapillary Neoplasm With CTNNB1 c.98C>G (p.S33C) Point Mutation. Int J Gynecol Pathol 2018; 37:110-116. [DOI: 10.1097/pgp.0000000000000396] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
|
|
21
|
Wu DC, Zhang MF, Su SG, Fang HY, Wang XH, He D, Xie YY, Liu XH. HEY2, a target of miR-137, indicates poor outcomes and promotes cell proliferation and migration in hepatocellular carcinoma. Oncotarget 2018; 7:38052-38063. [PMID: 27191260 PMCID: PMC5122371 DOI: 10.18632/oncotarget.9343] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 04/26/2016] [Indexed: 01/26/2023] Open
Abstract
HEY2, a bHLH transcription factor, has been implicated in the progression of human cancers. Here, we showed that HEY2 expression was markedly increased in HCC, compared with the adjacent nontumorous tissues. High HEY2 expression was closely correlated with tumor multiplicity, tumor differentiation and TNM stage. Kaplan-Meier analyses revealed that HEY2 expression was significantly associated with poor overall and disease-free survival in a training cohort of 361 patients with HCC. The prognostic implication of HEY2 was validated in another cohort of 169 HCC patients. Multivariate Cox regression model indicated HEY2 as an independent factor for overall survival in HCC (Hazard ratio = 1.645, 95% confident interval: 1.309-2.067, P<0.001). We also demonstrated that HEY2 expression was inhibited by miR-137. In clinical samples, HEY2 expression was reversely associated to miR-137 expression. Furthermore, overexpression of HEY2 increased cell viabilities, colony formation and cell migration, whereas knockdown of HEY2 resulted in the opposite phenotypes. Collectively, our data suggest HEY2 as a promising biomarker for unfavorable outcomes and a novel therapeutic target for the clinical management of HCC.
Collapse
Affiliation(s)
- Dan-Chun Wu
- Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Mei-Fang Zhang
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shu-Guang Su
- Department of Pathology, The Affiliated Hexian Memorial Hospital of Southern Medical University, Guangzhou, China
| | - Heng-Ying Fang
- Department of Nursing, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xue-Hua Wang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Dan He
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yuan-Yuan Xie
- Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xu-Hui Liu
- Department of Emergency, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
22
|
Naar L, Spanomichou DA, Mastoraki A, Smyrniotis V, Arkadopoulos N. Solid Pseudopapillary Neoplasms of the Pancreas: A Surgical and Genetic Enigma. World J Surg 2018; 41:1871-1881. [PMID: 28251269 DOI: 10.1007/s00268-017-3921-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Solid pseudopapillary neoplasms of the pancreas are rare tumors accounting for 1-2% of pancreatic exocrine neoplasms. This entity was first described by Dr. Frantz in 1959 and was defined by the World Health Organization in 1996 as "solid pseudopapillary tumor." It is most often a benign neoplasm, but 10-15% of the cases are malignant. Over the past decades, the incidence of this tumor is increasing. However, many surgeons are still unfamiliar with this neoplasm and its unique characteristics, which can lead to pitfalls in the diagnosis and treatment. The correct diagnosis of SPNP is of utmost importance since it has a low malignant potential and with the appropriate treatment, patients have a long life expectancy. There are many genetic alterations, involving various signaling pathways that have been associated with SPNP and are very important in diagnosing the tumor. The cornerstone of SPNP treatment includes surgical excision of the tumor, preserving as much pancreatic tissue as possible. We review the information in the literature regarding more organ-preserving techniques and possible clinical features that might indicate a malignant potential, thus demanding a more radical intraoperative excision.
Collapse
Affiliation(s)
- Leon Naar
- 4th Department of Surgery, Athens University Medical School, ATTIKON University Hospital, 1 Rimini Street, Chaidari, 12462, Athens, Greece
| | - Despoina-Amalia Spanomichou
- 4th Department of Surgery, Athens University Medical School, ATTIKON University Hospital, 1 Rimini Street, Chaidari, 12462, Athens, Greece
| | - Aikaterini Mastoraki
- 4th Department of Surgery, Athens University Medical School, ATTIKON University Hospital, 1 Rimini Street, Chaidari, 12462, Athens, Greece.
| | - Vassilios Smyrniotis
- 4th Department of Surgery, Athens University Medical School, ATTIKON University Hospital, 1 Rimini Street, Chaidari, 12462, Athens, Greece
| | - Nikolaos Arkadopoulos
- 4th Department of Surgery, Athens University Medical School, ATTIKON University Hospital, 1 Rimini Street, Chaidari, 12462, Athens, Greece
| |
Collapse
|
|
23
|
Kim EK, Jang M, Park M, Kim H. LEF1, TFE3, and AR are putative diagnostic markers of solid pseudopapillary neoplasms. Oncotarget 2017; 8:93404-93413. [PMID: 29212159 PMCID: PMC5706805 DOI: 10.18632/oncotarget.21854] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 09/23/2017] [Indexed: 12/11/2022] Open
Abstract
The diagnosis of solid pseudopapillary neoplasms (SPNs) is challenging because some SPNs share many similar morphological and immunohistochemical features with other pancreatic neoplasms. In this study, we investigated potential diagnostic markers of SPN. Based on the SPN-specific upregulated genes from a previous DNA microarray and proteome study, we selected six immunohistochemical markers [beta-catenin, androgen receptor (AR), lymphoid enhancer-binding factor 1 (LEF1), transcription factor for immunoglobulin heavy-chain enhancer 3 (TFE3), fused in sarcoma (FUS), and WNT inhibitory factor 1 (WIF-1)]. We also evaluated the Ki-67 proliferative index to investigate its associations with prognosis. To validate these markers, we studied 91 SPNs as well as 51 pancreatic ductal carcinomas (PDC) and 48 neuroendocrine tumors (NET) as controls. We found frequent and diffuse nuclear expressions of β-catenin (98.9%), AR (81.3%), LEF1 (93.4%), TFE3 (74.7%), FUS (84.6%), and cytoplasmic expression of WIF-1 (96.7%) in SPNs. In contrast, PDCs and NETs showed no expression. (P < 0.001). When beta-catenin, LEF1, and TFE3 staining were combined, the sensitivity and specificity were 100% and 91.9%, respectively. Four (4.4%) SPNs showed distant metastasis and these tumors were associated with a relatively high Ki-67 proliferative index (≥ 5%; P = 0.013). We identified LEF1, TFE3, and AR as putative diagnostic markers of SPN, auxiliary to β-catenin. Incorporated into an immunohistochemical panel, these markers could be beneficial to distinguish SPN from PDC and NET. In addition, we suggest that the Ki-67 proliferative index can be a predictive marker of metastasis in SPNs.
Collapse
Affiliation(s)
- Eun Kyung Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Mi Jang
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Minhee Park
- Departments of Pathology and Brain, Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hoguen Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.,Departments of Pathology and Brain, Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea.,Healthcare Review and Assessment Committee, Health Insurance Review & Assessment Service, Seoul, Republic of Korea
| |
Collapse
|
|
24
|
Solid pseudopapillary tumor of the pancreas: Experience at a tertiary care centre of Northern India. Int J Surg Case Rep 2017; 39:225-230. [PMID: 28858740 PMCID: PMC5581377 DOI: 10.1016/j.ijscr.2017.07.064] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 07/25/2017] [Indexed: 12/31/2022] Open
Abstract
SPT is rare, but treatable pancreatic tumor. While clinical signs and symptoms are relatively nonspecific, characteristic findings on imaging and histology separate these tumors from the more malignant pancreatic tumors. The identification of a large bulky pancreatic tumour in a child or woman should raise suspicions of solid pseudopapillary tumour of the pancreas. Surgical excision offers the best chance for cure and should always be attempted irrespective of the magnitude of resection involved. Patients with SPT have an excellent prognosis after surgical excision. The prognosis is favorable even in the presence of distant metastasis. Introduction Solid pseudopapillary tumor (SPT) of the pancreas is rare, accounting for 0.13–2.7% of all pancreatic tumors. It is unique, has low malignant potential and predominantly affects young women. Radiological and pathological studies have revealed that the tumor is quite different from other pancreatic tumors. But the cell origin of SPT and tumorigenesis are still enigmatic. Abdominal mass is the most common presenting symptom. Due to the paucity of the number of cases, the natural history of the disease is not fully understood. This study was undertaken to examine the clinico-pathological characteristics of the disease and to evaluate the outcome of surgical intervention in a tertiary referral care centre. Materials and methods A retrospective analysis of all patients diagnosed and treated for SPN in our hospital over a period of 10 years (2005–2015) was carried out. A database of the characteristics of these patients was developed. In all, 11 patients were identified. A CT scan of the abdomen was performed in all the patients and the findings revealed a mass in the pancreas. The investigations performed included routine blood investigations, chest X-ray, CA-19-9 level and either an ultrasound or a CT Scan of the abdomen. Results During the time period of 10 years, of 349 patients with pancreatic malignancy admitted to our department, only 11 were diagnosed as having SPN (3.15%). Ten patients were women (90%) and one patient was a man (10%). The patients had a median age of 27.6 years (range 17–41). The most common symptoms were abdominal pain and dullness. Eight patients (72.7%) presented with abdominal pain or abdominal dullness and three patient (27%) were asymptomatic. All the 11 patients were taken up for surgery. Three patients underwent distal pancreatectomy with splenectomy, three patients underwent the total mass excision and one patient underwent total pancreatic resection. Three required extended distal pancreatectomy with splenectomy. One underwent spleen-preserving distal pancreatectomy. Conclusion SPT is rare, but treatable pancreatic tumor. While clinical signs and symptoms are relatively nonspecific, characteristic findings on imaging and histology separate these tumors from the more malignant pancreatic tumors. The prognosis is favorable even in the presence of distant metastasis. Although surgical resection is generally curative, a close follow-up is advised in order to diagnose a local recurrence or distant metastasis.
Collapse
|
|
25
|
Zhang Y, Han X, Wu H, Zhou Y. Bioinformatics analysis of transcription profiling of solid pseudopapillary neoplasm of the pancreas. Mol Med Rep 2017. [PMID: 28627654 PMCID: PMC5562055 DOI: 10.3892/mmr.2017.6800] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Solid pseudopapillary neoplasm (SPN) of the pancreas is a low-grade malignant neoplasm that accounts for ~5% of cystic pancreatic tumors and ~0.9–2.7% of exocrine pancreatic tumors. The transcription profiling data (GSE43795) of 14 SPN and 6 control samples were downloaded from the Gene Expression Omnibus (GEO) database. Using the Limma package, Student's t-tests were performed to identify differentially expressed genes (DEGs) between SPN and control samples [with the following criterion: False discovery rate (FDR)<0.01 and log2 fold-change (FC)≥3]. Pathway and functional enrichment analyses were performed to investigate the biological processes that the DEGs were involved in. Protein-protein interaction (PPI) network and sub-network analyses were conducted to comprehensively understand the interactions between DEGs. The screened DEGs were further annotated according to information relating to transcription factors and tumor associated genes (TAGs). A total of 710 upregulated and 710 downregulated DEGs were observed, including 74 transcriptional factors and 124 TAGs. Membrane metallo-endopeptidase (MME), matrix metalloproteinase (MMP)-2 and MMP-9 were also identified as key TAGs. Following PPI network analysis, hub nodes of epidermal growth factor receptor (EGFR), proto-oncogene tyrosine protein kinase Fyn (FYN), c-JUN (JUN), glucagon (GCG), c-Myc (MYC) and CD44 were identified, the majority of which participate in the epidermal growth factor receptor (ErbB) and gonadotropin-releasing hormone (GnRH) signaling pathways. A sub-network involving 70 gene nodes was also identified, with EGFR as the central gene. MME, MMP-2 and MMP-9 contribute to proliferative diabetic retinopathy and also involved in SPN. The genes EGFR, FYN, JUN, GCG, MYC and CD44 may therefore be key genes in SPN, and the ErbB and GnRH signaling pathways may be an important contributor to SPN progression.
Collapse
Affiliation(s)
- Yongping Zhang
- Department of Digestion, Xin Chang People's Hospital, Pancreatic Disease Research Center of Shanghai, Xinchang, Zhejiang 312500, P.R. China
| | - Xu Han
- Department of Gastroenterology, Shanghai Changhai Hospital, Second Military Medical University of China, Pancreatic Disease Research Center of Shanghai, Shanghai 214000, P.R. China
| | - Hao Wu
- Department of Gastroenterology, Shanghai Changhai Hospital, Second Military Medical University of China, Pancreatic Disease Research Center of Shanghai, Shanghai 214000, P.R. China
| | - Yifeng Zhou
- Digestive Department, Hangzhou First People's Hospital, Pancreatic Disease Research Center of Shanghai, Hangzhou, Zhejiang 310006, P.R. China
| |
Collapse
|
|
26
|
Guo M, Luo G, Jin K, Long J, Cheng H, Lu Y, Wang Z, Yang C, Xu J, Ni Q, Yu X, Liu C. Somatic Genetic Variation in Solid Pseudopapillary Tumor of the Pancreas by Whole Exome Sequencing. Int J Mol Sci 2017; 18:81. [PMID: 28054945 PMCID: PMC5297715 DOI: 10.3390/ijms18010081] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 12/21/2016] [Accepted: 12/28/2016] [Indexed: 12/31/2022] Open
Abstract
Solid pseudopapillary tumor of the pancreas (SPT) is a rare pancreatic disease with a unique clinical manifestation. Although CTNNB1 gene mutations had been universally reported, genetic variation profiles of SPT are largely unidentified. We conducted whole exome sequencing in nine SPT patients to probe the SPT-specific insertions and deletions (indels) and single nucleotide polymorphisms (SNPs). In total, 54 SNPs and 41 indels of prominent variations were demonstrated through parallel exome sequencing. We detected that CTNNB1 mutations presented throughout all patients studied (100%), and a higher count of SNPs was particularly detected in patients with older age, larger tumor, and metastatic disease. By aggregating 95 detected variation events and viewing the interconnections among each of the genes with variations, CTNNB1 was identified as the core portion in the network, which might collaborate with other events such as variations of USP9X, EP400, HTT, MED12, and PKD1 to regulate tumorigenesis. Pathway analysis showed that the events involved in other cancers had the potential to influence the progression of the SNPs count. Our study revealed an insight into the variation of the gene encoding region underlying solid-pseudopapillary neoplasm tumorigenesis. The detection of these variations might partly reflect the potential molecular mechanism.
Collapse
Affiliation(s)
- Meng Guo
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Guopei Luo
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Kaizhou Jin
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Jiang Long
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - He Cheng
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Yu Lu
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Zhengshi Wang
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Chao Yang
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Jin Xu
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Quanxing Ni
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Xianjun Yu
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Chen Liu
- Department of Pancreas Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| |
Collapse
|
|
27
|
Willmer T, Cooper A, Peres J, Omar R, Prince S. The T-Box transcription factor 3 in development and cancer. Biosci Trends 2017; 11:254-266. [DOI: 10.5582/bst.2017.01043] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Tarryn Willmer
- Department of Human Biology, Faculty of Health Sciences, Anzio Road, University of Cape Town
| | - Aretha Cooper
- Department of Human Biology, Faculty of Health Sciences, Anzio Road, University of Cape Town
| | - Jade Peres
- Department of Human Biology, Faculty of Health Sciences, Anzio Road, University of Cape Town
| | - Rehana Omar
- Department of Human Biology, Faculty of Health Sciences, Anzio Road, University of Cape Town
| | - Sharon Prince
- Department of Human Biology, Faculty of Health Sciences, Anzio Road, University of Cape Town
| |
Collapse
|
|
28
|
Nabavi S. Identifying candidate drivers of drug response in heterogeneous cancer by mining high throughput genomics data. BMC Genomics 2016; 17:638. [PMID: 27526849 PMCID: PMC4986197 DOI: 10.1186/s12864-016-2942-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 07/15/2016] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND With advances in technologies, huge amounts of multiple types of high-throughput genomics data are available. These data have tremendous potential to identify new and clinically valuable biomarkers to guide the diagnosis, assessment of prognosis, and treatment of complex diseases, such as cancer. Integrating, analyzing, and interpreting big and noisy genomics data to obtain biologically meaningful results, however, remains highly challenging. Mining genomics datasets by utilizing advanced computational methods can help to address these issues. RESULTS To facilitate the identification of a short list of biologically meaningful genes as candidate drivers of anti-cancer drug resistance from an enormous amount of heterogeneous data, we employed statistical machine-learning techniques and integrated genomics datasets. We developed a computational method that integrates gene expression, somatic mutation, and copy number aberration data of sensitive and resistant tumors. In this method, an integrative method based on module network analysis is applied to identify potential driver genes. This is followed by cross-validation and a comparison of the results of sensitive and resistance groups to obtain the final list of candidate biomarkers. We applied this method to the ovarian cancer data from the cancer genome atlas. The final result contains biologically relevant genes, such as COL11A1, which has been reported as a cis-platinum resistant biomarker for epithelial ovarian carcinoma in several recent studies. CONCLUSIONS The described method yields a short list of aberrant genes that also control the expression of their co-regulated genes. The results suggest that the unbiased data driven computational method can identify biologically relevant candidate biomarkers. It can be utilized in a wide range of applications that compare two conditions with highly heterogeneous datasets.
Collapse
Affiliation(s)
- Sheida Nabavi
- Computer Science and Engineering Department, Institute for Systems Genomics, University of Connecticut, 371 Fairfield Way, Unit 4155, Storrs, CT, 06268, USA.
| |
Collapse
|
|
29
|
Hackeng WM, Hruban RH, Offerhaus GJA, Brosens LAA. Surgical and molecular pathology of pancreatic neoplasms. Diagn Pathol 2016; 11:47. [PMID: 27267993 PMCID: PMC4897815 DOI: 10.1186/s13000-016-0497-z] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 05/28/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Histologic characteristics have proven to be very useful for classifying different types of tumors of the pancreas. As a result, the major tumor types in the pancreas have long been classified based on their microscopic appearance. MAIN BODY Recent advances in whole exome sequencing, gene expression profiling, and knowledge of tumorigenic pathways have deepened our understanding of the underlying biology of pancreatic neoplasia. These advances have not only confirmed the traditional histologic classification system, but also opened new doors to early diagnosis and targeted treatment. CONCLUSION This review discusses the histopathology, genetic and epigenetic alterations and potential treatment targets of the five major malignant pancreatic tumors - pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumor, solid-pseudopapillary neoplasm, acinar cell carcinoma and pancreatoblastoma.
Collapse
MESH Headings
- Biomarkers, Tumor/genetics
- Carcinoma, Acinar Cell/diagnosis
- Carcinoma, Acinar Cell/genetics
- Carcinoma, Acinar Cell/surgery
- Carcinoma, Pancreatic Ductal/diagnosis
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/surgery
- Eye Diseases, Hereditary/diagnosis
- Eye Diseases, Hereditary/genetics
- Eye Diseases, Hereditary/surgery
- Humans
- Neuroendocrine Tumors/diagnosis
- Neuroendocrine Tumors/genetics
- Neuroendocrine Tumors/surgery
- Optic Nerve Diseases/diagnosis
- Optic Nerve Diseases/genetics
- Optic Nerve Diseases/surgery
- Pancreas/pathology
- Pancreatic Neoplasms/diagnosis
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/surgery
Collapse
Affiliation(s)
- Wenzel M Hackeng
- Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Ralph H Hruban
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - G Johan A Offerhaus
- Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
| | - Lodewijk A A Brosens
- Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
| |
Collapse
|
|
30
|
Wang HC, Meng QC, Shan ZZ, Yuan Z, Huang XY. Overexpression of Tbx3 predicts poor prognosis of patients with resectable pancreatic carcinoma. Asian Pac J Cancer Prev 2015; 16:1397-401. [PMID: 25743805 DOI: 10.7314/apjcp.2015.16.4.1397] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND To determine the expressions of Tbx3, a member of subgroup belonging to T-box family, and its prognostic value in pancreatic carcinoma. MATERIALS AND METHODS We determined the expression levels of Tbx3 on both mRNA and protein levels in 30 pairs of fresh tumor tissues and paratumor tissues by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting, respectively. In addition, protein level of Tbx3 were identified using immunochemistry in 80 pairs of paraffin-embedded specimen. The correlations between Tbx3 expression and various clinicopathological parameters as well as overall survival were evaluated. RESULTS Tbx3 mRNA and protein levels in tumor tissues were significantly higher than in the paratumor tissues by qRT-PCR (0.05 ±0.007 vs. 0.087±0.001, p<0.001) and western blotting (1.134±0.043 vs. 0.287±0.017, p<0.001). The statistical analysis based on immunohistochemical evaluation suggested that Tbx3 aberrant expression was significantly associated with several conventional clinicopathological variables, such as gender, age, tumor position, preoperative CA19-9 level, pathological T staging and N staging. Univariate and multivariate analyses revealed that Tbx3 expression was an independent prognostic factor for overall survival (<0.001). CONCLUSIONS Our results suggest that overexpression of Tbx3 is associated with poor prognosis of pancreatic cancer patients. However, additional clinical trials are needed to accurately validate this observation.
Collapse
Affiliation(s)
- Hong-Cheng Wang
- Department of General Surgery, Sixth People's Hospital Affiliated Shanghai Jiao Tong University, Yi-shan Road, Shanghai, China E-mail :
| | | | | | | | | |
Collapse
|
|
31
|
Fischer K, Pflugfelder GO. Putative Breast Cancer Driver Mutations in TBX3 Cause Impaired Transcriptional Repression. Front Oncol 2015; 5:244. [PMID: 26579496 PMCID: PMC4625211 DOI: 10.3389/fonc.2015.00244] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 10/14/2015] [Indexed: 12/17/2022] Open
Abstract
The closely related T-box transcription factors TBX2 and TBX3 are frequently overexpressed in melanoma and various types of human cancers, in particular, breast cancer. The overexpression of TBX2 and TBX3 can have several cellular effects, among them suppression of senescence, promotion of epithelial-mesenchymal transition, and invasive cell motility. In contrast, loss of function of TBX3 and most other human T-box genes causes developmental haploinsufficiency syndromes. Stephens and colleagues (1), by exome sequencing of breast tumor samples, identified five different mutations in TBX3, all affecting the DNA-binding T-domain. One in-frame deletion of a single amino acid, p.N212delN, was observed twice. Due to the clustering of these mutations to the T-domain and for statistical reasons, TBX3 was inferred to be a driver gene in breast cancer. Since mutations in the T-domain generally cause loss of function and because the tumorigenic action of TBX3 has generally been attributed to overexpression, we determined whether the putative driver mutations had loss- or gain-of-function properties. We tested two in-frame deletions, one missense, and one frameshift mutant protein for DNA-binding in vitro, and for target gene repression in cell culture. In addition, we performed an in silico analysis of somatic TBX mutations in breast cancer, collected in The Cancer Genome Atlas (TCGA). Both the experimental and the in silico analysis indicate that the observed mutations predominantly cause loss of TBX3 function.
Collapse
|
|
32
|
Park M, Lim JS, Lee HJ, Na K, Lee MJ, Kang CM, Paik YK, Kim H. Distinct Protein Expression Profiles of Solid-Pseudopapillary Neoplasms of the Pancreas. J Proteome Res 2015; 14:3007-14. [PMID: 26148796 DOI: 10.1021/acs.jproteome.5b00423] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Solid-pseudopapillary neoplasm (SPN) is an uncommon pancreatic tumor with mutation in CTNNB1 and distinct clinical and pathological features. We compared the proteomic profiles of SPN to mRNA expression. Pooled SPNs and pooled non-neoplastic pancreatic tissues were examined with high-resolution mass spectrometry. We identified 329 (150 up-regulated and 179 down-regulated) differentially expressed proteins in SPN. We identified 191 proteins (58.1% of the 329 dysregulated proteins) with the same expression tendencies in SPN based on mRNA data. Many overexpressed proteins were related to signaling pathways known to be activated in SPNs. We found that several proteins involved in Wnt signaling, including DKK4 and β-catenin, and proteins that bind β-catenin, such as FUS and NONO, were up-regulated in SPNs. Molecules involved in glycolysis, including PKM2, ENO2, and HK1, were overexpressed in accordance to their mRNA levels. In summary, SPN showed (1) distinct protein expression changes that correlated with mRNA expression, (2) overexpression of Wnt signaling proteins and proteins that bind directly to β-catenin, and (3) overexpression of proteins involved in metabolism. These findings may help develop early diagnostic biomarkers and molecular targets.
Collapse
Affiliation(s)
| | - Jong-Sun Lim
- §Yonsei Proteome Research Center and Department of Integrated Omics for Biomedical Science, World Class University Program, Yonsei University, Seoul 120-749, Korea
| | - Hyoung-Joo Lee
- §Yonsei Proteome Research Center and Department of Integrated Omics for Biomedical Science, World Class University Program, Yonsei University, Seoul 120-749, Korea
| | - Keun Na
- §Yonsei Proteome Research Center and Department of Integrated Omics for Biomedical Science, World Class University Program, Yonsei University, Seoul 120-749, Korea
| | - Min Jung Lee
- §Yonsei Proteome Research Center and Department of Integrated Omics for Biomedical Science, World Class University Program, Yonsei University, Seoul 120-749, Korea
| | | | - Young-Ki Paik
- §Yonsei Proteome Research Center and Department of Integrated Omics for Biomedical Science, World Class University Program, Yonsei University, Seoul 120-749, Korea
| | | |
Collapse
|
|
33
|
Alpha-methylacyl-CoA racemase is expressed in a majority of pancreatic neoplasms of neuroendocrine, acinar, and solid pseudopapillary differentiation. Pathology 2015; 47:466-8. [PMID: 26126032 DOI: 10.1097/pat.0000000000000278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
34
|
Duconseil P, Gilabert M, Gayet O, Loncle C, Moutardier V, Turrini O, Calvo E, Ewald J, Giovannini M, Gasmi M, Bories E, Barthet M, Ouaissi M, Goncalves A, Poizat F, Raoul JL, Secq V, Garcia S, Viens P, Iovanna J, Dusetti N. Transcriptomic analysis predicts survival and sensitivity to anticancer drugs of patients with a pancreatic adenocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:1022-32. [PMID: 25765988 DOI: 10.1016/j.ajpath.2014.11.029] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 11/03/2014] [Accepted: 11/25/2014] [Indexed: 12/15/2022]
Abstract
A major impediment to the effective treatment of patients with pancreatic ductal adenocarcinoma (PDAC) is the molecular heterogeneity of this disease, which is reflected in an equally diverse pattern of clinical outcome and in responses to therapies. We developed an efficient strategy in which PDAC samples from 17 consecutive patients were collected by endoscopic ultrasound-guided fine-needle aspiration or surgery and were preserved as breathing tumors by xenografting and as a primary culture of epithelial cells. Transcriptomic analysis was performed from breathing tumors by an Affymetrix approach. We observed significant heterogeneity in the RNA expression profile of tumors. However, the bioinformatic analysis of these data was able to discriminate between patients with long- and short-term survival corresponding to patients with moderately or poorly differentiated PDAC tumors, respectively. Primary culture of cells allowed us to analyze their relative sensitivity to anticancer drugs in vitro using a chemogram, similar to the antibiogram for microorganisms, establishing an individual profile of drug sensitivity. As expected, the response was patient dependent. We also found that transcriptomic analysis predicts the sensitivity of cells to the five anticancer drugs most frequently used to treat patients with PDAC. In conclusion, using this approach, we found that transcriptomic analysis could predict the sensitivity to anticancer drugs and the clinical outcome of patients with PDAC.
Collapse
Affiliation(s)
- Pauline Duconseil
- Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France
| | - Marine Gilabert
- Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France
| | - Odile Gayet
- Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France
| | - Celine Loncle
- Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France
| | - Vincent Moutardier
- Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France; Department of Surgery, Hôpital Nord, Marseille, France
| | - Olivier Turrini
- Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France; Paoli-Calmettes Institute, Marseille, France
| | - Ezequiel Calvo
- Genomic Center, CHUL Research Centre, Quebec City, Quebec, Canada
| | | | | | - Mohamed Gasmi
- Department of Gastroenterology, Hôpital Nord, Marseille, France
| | | | - Marc Barthet
- Department of Gastroenterology, Hôpital Nord, Marseille, France
| | - Mehdi Ouaissi
- Department of Surgery, La Timone Hospital, Marseille, France
| | | | | | | | - Veronique Secq
- Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France; Department of Surgery, Hôpital Nord, Marseille, France
| | - Stephane Garcia
- Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France; Department of Surgery, Hôpital Nord, Marseille, France
| | | | - Juan Iovanna
- Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France.
| | - Nelson Dusetti
- Cancer Research Center of Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille University and Paoli-Calmettes Institute, Scientific and Technological Park of Luminy, Marseille, France.
| |
Collapse
|
|
35
|
Overexpression of lymphoid enhancer-binding factor 1 (LEF1) in solid-pseudopapillary neoplasms of the pancreas. Mod Pathol 2014; 27:1355-63. [PMID: 24658583 PMCID: PMC4318228 DOI: 10.1038/modpathol.2014.40] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Revised: 01/13/2014] [Accepted: 01/15/2014] [Indexed: 12/13/2022]
Abstract
Solid-pseudopapillary neoplasms are rare, but are distinctive pancreatic tumors of low-malignant potential. While the histogenesis of these tumors is unclear, they are often associated with gain-of-function mutations in the catenin (cadherin-associated protein), beta 1 (88 kDa), or CTNNB1 gene, resulting in nuclear accumulation of CTNNB1. CTNNB1 is a central component of the Wnt signaling pathway and mediates gene expression through the lymphoid enhancer-binding factor 1 (LEF1) /T-cell factor transcription complex. Although LEF1 has a pivotal role in the transactivation of Wnt/CTNNB1 responsive genes, the status of LEF1 in solid-pseudopapillary neoplasms and other pancreatic tumors has not been examined. We analyzed both LEF1 and CTNNB1 in a large cohort of pancreatic tumors (n=155). In all cases of solid-pseudopapillary neoplasms including surgical resections (n=27) and cytologic samples (n=8) had strong and diffuse nuclear labeling for both LEF1 and CTNNB1. The surrounding uninvolved pancreatic parenchyma was devoid of any LEF1 staining. All resection and cytologic specimens from well-differentiated pancreatic neuroendocrine tumors (n=44; n=29, respectively), high-grade pancreatic neuroendocrine carcinomas (n=2; n=1), pancreatic ductal adenocarcinomas (n=25; n=12), and acinar cell carcinomas (n=9; n=2) studied were negative for both nuclear LEF1 and CTNNB1. However, nuclear LEF1 and CTNNB1 were detected in all four resected pancreatoblastomas (no cytologic specimens were available for immunolabeling), but primarily centered around and within squamoid corpuscles. In summary, abnormal CTNNB1 accumulation was accompanied by nuclear LEF1 overexpression in both solid-pseudopapillary neoplasms and pancreatoblastomas. But, in contrast to pancreatoblastomas, a diffuse, nuclear labeling was observed in solid-pseudopapillary neoplasms and further implicates the CTNNB1/LEF1 transcriptional complex in the development of solid-pseudopapillary neoplasms. In addition, as part of an immunohistochemical panel, LEF1 can be a useful ancillary stain in the diagnosis of solid-pseudopapillary neoplasms.
Collapse
|
|
36
|
Shen W, Clemente MJ, Hosono N, Yoshida K, Przychodzen B, Yoshizato T, Shiraishi Y, Miyano S, Ogawa S, Maciejewski JP, Makishima H. Deep sequencing reveals stepwise mutation acquisition in paroxysmal nocturnal hemoglobinuria. J Clin Invest 2014; 124:4529-38. [PMID: 25244093 DOI: 10.1172/jci74747] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 07/10/2014] [Indexed: 12/13/2022] Open
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disease of hematopoietic stem cells that is associated with hemolysis, marrow failure, and thrombophilia. PNH has been considered a monogenic disease that results from somatic mutations in the gene encoding PIGA, which is required for biosynthesis of glycosylphosphatidylinisotol-anchored (GPI-anchored) proteins. The loss of certain GPI-anchored proteins is hypothesized to provide the mutant clone with an extrinsic growth advantage, but some features of PNH argue that there are intrinsic drivers of clonal expansion. Here, we performed whole-exome sequencing of paired PNH+ and PNH- fractions on samples taken from 12 patients as well as targeted deep sequencing of an additional 36 PNH patients. We identified additional somatic mutations that resulted in a complex hierarchical clonal architecture, similar to that observed in myeloid neoplasms. In addition to mutations in PIGA, mutations were found in genes known to be involved in myeloid neoplasm pathogenesis, including TET2, SUZ12, U2AF1, and JAK2. Clonal analysis indicated that these additional mutations arose either as a subclone within the PIGA-mutant population, or prior to PIGA mutation. Together, our data indicate that in addition to PIGA mutations, accessory genetic events are frequent in PNH, suggesting a stepwise clonal evolution derived from a singular stem cell clone.
Collapse
|
|
37
|
Abstract
Solid-pseudopapillary neoplasm of the pancreas (SPN) is an uncommon low-grade malignant neoplasm occurring mostly in young women. In addition to its distinctive pathological appearance of pseudopapillae with poorly cohesive neoplastic cells, rare variants exist raising the differential diagnosis especially with neuroendocrine neoplasms. The overall prognosis for patients with SPNs is excellent after surgical resection. Nevertheless, 10% of cases may have malignant behavior characterized by tumor recurrence and/or metastasis. Despite numerous studies, the histogenesis of this neoplasm remains unclear. Distinctive molecular alterations such as the presence of CTNNB1 mutations are observed in nearly all cases, while mutations classically observed in ductal adenocarcinoma, such as KRAS, TP53, and SMAD4, are not observed in SPNs, reinforcing its distinct nature compared to all other pancreatic neoplasms. Recent transcriptional studies have shown that activation of the Wnt/beta-catenin pathway in these tumors is associated with the upregulation of genes belonging to Notch, Hedgehog, and androgen receptor signaling pathways.
Collapse
Affiliation(s)
- Benoît Terris
- Service de Pathologie, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Hôpitaux universitaires Paris-Centre, Site Cochin, Paris, France.
| | | |
Collapse
|
|
38
|
Park M, Kim M, Hwang D, Park M, Kim WK, Kim SK, Shin J, Park ES, Kang CM, Paik YK, Kim H. Characterization of gene expression and activated signaling pathways in solid-pseudopapillary neoplasm of pancreas. Mod Pathol 2014; 27:580-93. [PMID: 24072181 DOI: 10.1038/modpathol.2013.154] [Citation(s) in RCA: 81] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Revised: 06/28/2013] [Accepted: 07/01/2013] [Indexed: 12/11/2022]
Abstract
Solid-pseudopapillary neoplasm is an uncommon pancreatic tumor with distinct clinicopathologic features. Solid-pseudopapillary neoplasms are characterized by mutations in exon 3 of CTNNB1. However, little is known about the gene and microRNA expression profiles of solid-pseudopapillary neoplasms. Thus, we sought to characterize solid-pseudopapillary neoplasm-specific gene expression and identify the signaling pathways activated in these tumors. Comparisons of gene expression in solid-pseudopapillary neoplasm to pancreatic ductal carcinomas, neuroendocrine tumors, and non-neoplastic pancreatic tissues identified solid-pseudopapillary neoplasm-specific mRNA and microRNA profiles. By analyzing 1686 (1119 upregulated and 567 downregulated) genes differentially expressed in solid-pseudopapillary neoplasm, we found that the Wnt/β-catenin, Hedgehog, and androgen receptor signaling pathways, as well as genes involved in epithelial mesenchymal transition, are activated in solid-pseudopapillary neoplasms. We validated these results experimentally by assessing the expression of β-catenin, WIF-1, GLI2, androgen receptor, and epithelial-mesenchymal transition-related markers with western blotting and immunohistochemistry. Our analysis also revealed 17 microRNAs, especially the miR-200 family and miR-192/215, closely associated with the upregulated genes associated with the three pathways activated in solid-pseudopapillary neoplasm and epithelial mesenchymal transition. Our results provide insight into the molecular mechanisms underlying solid-pseudopapillary neoplasm tumorigenesis and its characteristic less epithelial cell differentiation than the other common pancreatic tumors.
Collapse
Affiliation(s)
- Minhee Park
- Departments of Pathology and BK21 for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Minhyung Kim
- School of Interdisciplinary Bioscience and Bio engineering, Pohang University, Pohang, Korea
| | - Daehee Hwang
- School of Interdisciplinary Bioscience and Bio engineering, Pohang University, Pohang, Korea
| | - Misun Park
- Departments of Pathology and BK21 for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Won Kyu Kim
- Departments of Pathology and BK21 for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Kyum Kim
- Departments of Pathology and BK21 for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jihye Shin
- BRI, Korea Institute of Science and Technology, Seoul, Korea
| | - Eun Sung Park
- Medical Convergence Research Institute, Yonsei University College of Medicine, Seoul, Korea
| | - Chang Moo Kang
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Young-Ki Paik
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea
| | - Hoguen Kim
- Departments of Pathology and BK21 for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| |
Collapse
|
|
39
|
Ganeshan DM, Paulson E, Tamm EP, Taggart MW, Balachandran A, Bhosale P. Solid pseudo-papillary tumors of the pancreas: current update. ABDOMINAL IMAGING 2013; 38:1373-1382. [PMID: 23775388 DOI: 10.1007/s00261-013-0015-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Solid pseudo-papillary tumors are rare pancreatic tumors, which occur in females and are typically indolent neoplasms. However, atypical, aggressive variants can occur with locally advanced disease or metastases. They have characteristic imaging features, which vary according to size. This article provides a current update on the molecular biology, histopathology, clinico-radiological features, and management of these tumors.
Collapse
Affiliation(s)
- Dhakshina Moorthy Ganeshan
- Department of Diagnostic Imaging, Body Imaging section, Unit 1473, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030-4009, USA,
| | | | | | | | | | | |
Collapse
|
|
40
|
Guan ZW, Sun L, Wang YQ, Xu BX. Solid pseudopapillary tumor of the pancreas and concomitant urogenital malformations in a young woman. Diagn Pathol 2013; 8:35. [PMID: 23445554 PMCID: PMC3606420 DOI: 10.1186/1746-1596-8-35] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Accepted: 02/20/2013] [Indexed: 02/06/2023] Open
Abstract
Abstract Solid pseudopapillary tumor (SPT) of the pancreas is a rare pancreatic tumor with low malignant potential. It occurs characteristically more often in young women. SPT associated with extra- and pancreatic anomalies are occasionally reported. Here we report a case of pancreatic SPT with concomitant urogenital malformations including solitary kidney and uterus didelphys in a 25-year-old woman. The patient underwent central pancreatectomy, and SPT was confirmed with pathological results. Recurrence or metastasis was not found after 14 months of follow-up. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4264758678755142
Collapse
Affiliation(s)
- Zhi-Wei Guan
- Department of Nuclear Medicine, Chinese PLA General Hospital, Ruxing road 28, Beijing 100853, China
| | | | | | | |
Collapse
|
|
41
|
Kobayashi T, Ozasa M, Miyashita K, Saga A, Miwa K, Saito M, Morioka M, Takeuchi M, Takenouchi N, Yabiku T, Kanno H, Yuzawa S, Tanino M, Tanaka S, Kawakami H, Asaka M, Sakamoto N. Large solid-pseudopapillary neoplasm of the pancreas with aberrant protein expression and mutation of β-catenin: a case report and literature review of the distribution of β-catenin mutation. Intern Med 2013; 52:2051-6. [PMID: 24042511 DOI: 10.2169/internalmedicine.52.9512] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Solid-pseudopapillary neoplasms (SPN) are rare pancreatic tumors. The etiology of SPN involves mutations in the gene that encodes β-catenin (CTNNB1). We herein report the case of a 23-year-old woman with a large SPN with proliferating tumor cells that displayed both solid and pseudo-papillary patterns. The simultaneous nuclear accumulation and loss of membrane localization of β-catenin and E-cadherin was specifically observed in the tumor cells. Further, the tumor cells were shown to harbor a missense mutation in exon 3 of CTNNB1. We also present a review of the literature describing the clustering of CTNNB1 mutations in patients with SPN.
Collapse
Affiliation(s)
- Takahiko Kobayashi
- Department of Gastroenterology, Hokkaido University, Graduate School of Medicine, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Samad A, Shah AA, Stelow EB, Alsharif M, Cameron SEH, Pambuccian SE. Cercariform cells: another cytologic feature distinguishing solid pseudopapillary neoplasms from pancreatic endocrine neoplasms and acinar cell carcinomas in endoscopic ultrasound-guided fine-needle aspirates. Cancer Cytopathol 2012; 121:298-310. [PMID: 23765692 DOI: 10.1002/cncy.21259] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Revised: 09/27/2012] [Accepted: 10/08/2012] [Indexed: 01/17/2023]
Abstract
BACKGROUND Solid pseudopapillary neoplasm (SPPN) is a rare tumor of unknown origin that occurs predominantly in the body or tail of the pancreas in young women. The authors recently identified cercariform (Greek: tailed) cells, similar to those described in urothelial carcinomas, as a consistent cytologic feature in ultrasound-guided fine-needle aspiration (EUS-FNA) samples from SPPNs. The objective of the current multi-institutional study was to define the value of these cells in the differential diagnosis of SPPN with other neoplasms characterized cytologically by the presence of monotonous, uniform cells in pancreatic aspirates: pancreatic neuroendocrine tumors (Pan-NETs) and acinar cell carcinomas (ACCs). METHODS The files of 4 academic hospitals were searched for SPPNs, Pan-NETs, and ACCs that were diagnosed by EUS-FNA. The slides were reviewed, and several cytologic features were recorded semiquantitatively to identify discriminating features between SPPNs, Pan-NETs, and ACCs. RESULTS From the analysis of 18 SPPNs, 4 ACCs, and 20 Pan-NETs, the following cytologic features were identified as common to all 3 neoplasms: single cells and rosettes/acinar cell groups, round-to-plasmacytoid cells, pale-to-granular cytoplasm, fine vacuoles, and binucleated cells. Papillary structures, cercariform cells, large cytoplasmic vacuoles, reniform nuclei, hyaline globules/magenta-colored material, and degenerative features (cholesterol crystals, calcifications, foam cells, or giant cells) were significantly more common in SPPNs. Prominent nuclear grooves were encountered in only 4 of 18 SPPNs. CONCLUSIONS The current results indicated that the presence of cercariform cells is another useful clue for the cytologic diagnosis of SPPN in challenging cases.
Collapse
Affiliation(s)
- Arbaz Samad
- Department of Laboratory Medicine and Pathology, University of Minnesota, University of Minnesota Medical Center, Fairview, Minneapolis, Minnesota, USA
| | | | | | | | | | | |
Collapse
|
|
43
|
Ye J, Ma M, Cheng D, Yuan F, Deng X, Zhan Q, Shen B, Peng C. Solid-pseudopapillary tumor of the pancreas: clinical features, pathological characteristics, and origin. J Surg Oncol 2012; 106:728-735. [PMID: 22688864 DOI: 10.1002/jso.23195] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 05/21/2012] [Indexed: 01/17/2023]
Abstract
OBJECTIVE [corrected] To study clinically pathological features and origin of solid-pseudopapillary tumor of pancreas (SPT). PATIENTS AND METHODS Clinical and pathological data of 82 cases with SPT were retrospectively studied. SAS6.12 statistics package was used for analysis. P < 0.05 was regarded as statistically significant difference. RESULTS The SPT patients included 70 females and 12 males, with a median age of 31 years old. The mean tumor size was 6.71 ± 4.42 cm. Vascular or organs was invaded in nine cases. The clinical and pathological characteristics show no significant difference between male and female patients. In the non-encapsulate group (22 cases), the tumor was larger (P = 0.0015), exogenous growth pattern (P = 0.0194), and would probably involve major vascular or organs (P = 1.697E-06). The typical features of SPT include pseudopapillary pattern with fibro vascular stalks by uniform poorly cohesive polygonal cells. The tumor cell expresses a variety of immune markers in heterogeneity. Under electron microscope, there are some electron dense granules, about 8-1.2 µm in diameter, with membrane similar to the zymogen granules in SPT cell cytoplasm. CONCLUSIONS SPT with incomplete capsule often presents malignant behaviors. SPT shows multi-heterogeneity, which is caused by the disorder in the development of pancreatic stem cell.
Collapse
Affiliation(s)
- Jinhua Ye
- Department of General Surgery, Institute of Digestive Surgery, Ruijin Hospital, Shanghai JiaoTong University Medical college, Shanghai, China
| | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Krug S, Bartsch DK, Schober M, Librizzi D, Pfestroff A, Burbelko M, Moll R, Michl P, Gress TM. Successful selective internal radiotherapy (SIRT) in a patient with a malignant solid pseudopapillary pancreatic neoplasm (SPN). Pancreatology 2012; 12:423-7. [PMID: 23127531 DOI: 10.1016/j.pan.2012.07.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 07/14/2012] [Accepted: 07/16/2012] [Indexed: 12/11/2022]
Abstract
Solid pseudopapillary neoplasms of the pancreas (SPNs, Gruber-Frantz-Tumor) are a rare entity representing 1-5% of all exocrine pancreatic tumors. The pseudocystic lesions preferentially affect young females <30 years, are mostly benign (∼90%) and normally present with unspecific symptoms. We describe the case of a 16-years-old Asian woman that was initially diagnosed with an SPN in the pancreatic head with mesenterial and hepatic metastases. After diagnosis, an extensive tumor resection was performed including pyloric-preserving pancreatic head resection followed by sequential resection of all hepatic metastases. After the patient was diagnosed with a hepatic recurrence and high intrahepatic tumor load, we chose a multimodal procedure and performed a selective internal radiotherapy (SIRT). Four years after SIRT and 10 years after initial diagnosis of metastatic SPN, the patient is in a good condition without any evidence for hepatic recurrence. This case represents a rare clinical course of a malignant and invasive SPN with an exceptionally long survival despite of high initial tumor burden. The selective internal radiotherapy is a suitable approach for inducing long-term remissions of the strongly vascularized liver metastases.
Collapse
Affiliation(s)
- S Krug
- Department of Gastroenterology, Endocrinology and Metabolism, Philipps-University Marburg, Marburg, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Washkowitz AJ, Gavrilov S, Begum S, Papaioannou VE. Diverse functional networks of Tbx3 in development and disease. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE 2012; 4:273-83. [PMID: 22334480 DOI: 10.1002/wsbm.1162] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The T-box transcription factor Tbx3 plays multiple roles in normal development and disease. In order to function in different tissues and on different target genes, Tbx3 binds transcription factors or other cofactors specific to temporal or spatial locations. Examining the development of the mammary gland, limbs, and heart as well as the biology of stem cells and cancer provides insights into the diverse and common functions that Tbx3 can perform. By either repressing or activating transcription of target genes in a context-dependent manner, Tbx3 is able to modulate differentiation of immature progenitor cells, control the rate of cell proliferation, and mediate cellular signaling pathways. Because the direct regulators of these cellular processes are highly context-dependent, it is essential that Tbx3 has the flexibility to regulate transcription of a large group of targets, but only become a active on a small cohort of them at any given time or place. Moreover, Tbx3 must be responsive to the variety of different upstream factors that are present in different tissues. Only by understanding the network of genes, proteins, and molecules with which Tbx3 interacts can we hope to understand the role that Tbx3 plays in normal development and how its aberrant expression can lead to disease. Because of its myriad functions in disparate developmental and disease contexts, Tbx3 is an ideal candidate for a systems-based approach to genetic function and interaction.
Collapse
Affiliation(s)
- Andrew J Washkowitz
- Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA
| | | | | | | |
Collapse
|
|
46
|
Yin C, Kikuchi K, Poss KD, Stainier DYR. Hand2 regulates extracellular matrix remodeling essential for gut-looping morphogenesis in zebrafish. Dev Cell 2010; 18:973-84. [PMID: 20627079 PMCID: PMC2908152 DOI: 10.1016/j.devcel.2010.05.009] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2009] [Revised: 02/19/2010] [Accepted: 03/24/2010] [Indexed: 12/19/2022]
Abstract
Extracellular matrix (ECM) remodeling is critical for organogenesis, yet its molecular regulation is poorly understood. In zebrafish, asymmetric migration of the epithelial lateral plate mesoderm (LPM) displaces the gut leftward, allowing correct placement of the liver and pancreas. To observe LPM migration at cellular resolution, we transgenically expressed EGFP under the control of the regulatory sequences of the bHLH transcription factor gene hand2. We found that laminin is distributed along the LPM/gut boundary during gut looping, and that it appears to become diminished by the migrating hand2-expressing cells. Laminin diminishment is necessary for LPM migration and is dependent on matrix metalloproteinase (MMP) activity. Loss of Hand2 function causes reduced MMP activity and prolonged laminin deposition at the LPM/gut boundary, leading to failed asymmetric LPM migration and gut looping. Our study reveals an unexpected role for Hand2, a key regulator of cell specification and differentiation, in modulating ECM remodeling during organogenesis.
Collapse
Affiliation(s)
- Chunyue Yin
- Department of Biochemistry and Biophysics, Programs in Developmental Biology, Genetics and Human Genetics, Cardiovascular Research Institute, Liver Center and Diabetes Center, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Kazu Kikuchi
- Department of Cell Biology, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA
| | - Kenneth D. Poss
- Department of Cell Biology, Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA
| | - Didier Y. R. Stainier
- Department of Biochemistry and Biophysics, Programs in Developmental Biology, Genetics and Human Genetics, Cardiovascular Research Institute, Liver Center and Diabetes Center, University of California, San Francisco, San Francisco, CA 94158, USA
| |
Collapse
|
|
47
|
Hager T, Königsrainer A, Gassner I, Klein-Franke A, Sergi C, Hager J. Solid-pseudopapillary tumor of the pancreas in a 12-year-old girl – 7 years follow-up and histopathological reevaluation: Case report and subject review. Eur Surg 2010; 42:96-102. [DOI: 10.1007/s10353-010-0525-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
|
|
48
|
Yassin ER, Sarma NJ, Abdul-Nabi AM, Dombrowski J, Han Y, Takeda A, Yaseen NR. Dissection of the transformation of primary human hematopoietic cells by the oncogene NUP98-HOXA9. PLoS One 2009; 4:e6719. [PMID: 19696924 PMCID: PMC2725295 DOI: 10.1371/journal.pone.0006719] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2009] [Accepted: 07/28/2009] [Indexed: 11/18/2022] Open
Abstract
NUP98-HOXA9 is the prototype of a group of oncoproteins associated with acute myeloid leukemia. It consists of an N-terminal portion of NUP98 fused to the homeodomain of HOXA9 and is believed to act as an aberrant transcription factor that binds DNA through the homeodomain. Here we show that NUP98-HOXA9 can regulate transcription without binding to DNA. In order to determine the relative contributions of the NUP98 and HOXA9 portions to the transforming ability of NUP98-HOXA9, the effects of NUP98-HOXA9 on primary human CD34+ cells were dissected and compared to those of wild-type HOXA9. In contrast to previous findings in mouse cells, HOXA9 had only mild effects on the differentiation and proliferation of primary human hematopoietic cells. The ability of NUP98-HOXA9 to disrupt the differentiation of primary human CD34+ cells was found to depend primarily on the NUP98 portion, whereas induction of long-term proliferation required both the NUP98 moiety and an intact homeodomain. Using oligonucleotide microarrays in primary human CD34+ cells, a group of genes was identified whose dysregulation by NUP98-HOXA9 is attributable primarily to the NUP98 portion. These include RAP1A, HEY1, and PTGS2 (COX-2). Their functions may reflect the contribution of the NUP98 moiety of NUP98-HOXA9 to leukemic transformation. Taken together, these results suggest that the effects of NUP98-HOXA9 on gene transcription and cell transformation are mediated by at least two distinct mechanisms: one that involves promoter binding through the homeodomain with direct transcriptional activation, and another that depends predominantly on the NUP98 moiety and does not involve direct DNA binding.
Collapse
Affiliation(s)
- Enas R. Yassin
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Nayan J. Sarma
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Anmaar M. Abdul-Nabi
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - James Dombrowski
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Ye Han
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Akiko Takeda
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
| | - Nabeel R. Yaseen
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
- Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America
- * E-mail:
| |
Collapse
|