|
1
|
Lutz F, Hornburg SM, Möller K, Viehweger F, Schlichter R, Menz A, Luebke AM, Kluth M, Hube-Magg C, Hinsch A, Lennartz M, Bernreuther C, Weidemann S, Lebok P, Fraune C, Sauter G, Dum D, Marx AH, Simon R, Gorbokon N, Burandt E, Minner S, Steurer S, Krech T, Jacobsen F, Clauditz TS. PAX6 is a useful marker for pancreatic origin of neuroendocrine neoplasms: A tissue microarray study evaluating more than 19,000 tumors from 150 different tumor types. Hum Pathol 2024; 154:105695. [PMID: 39571690 DOI: 10.1016/j.humpath.2024.105695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 11/11/2024] [Accepted: 11/18/2024] [Indexed: 12/01/2024]
Abstract
PAX6 immunohistochemistry (IHC) was proposed as a tool to identify a pancreatic origin of neuroendocrine neoplasms (NENs). To evaluate the diagnostic utility of PAX6 IHC, a tissue microarray containing 19,214 samples from 150 tumor types was analyzed. Data on progesterone receptor (PR) and glutamate decarboxylase 2 (GAD2) expression were available from previous studies. PAX6 staining occurred in 2.6% of 17,224 analyzable tumors and 60 tumor categories showed PAX6 positivity in at least one case. The highest rates of PAX6 positivity occurred in pancreatic (42.9-70.8%) and other NENs (up to 50.0%), testicular tumors (up to 58.3%), basal cell carcinomas of the skin (51.9%), squamous cell carcinomas of different organs (1.5-11.8%), and in gynecological tumors (up to 30%). For detection of pancreatic origin of NENs, sensitivity was highest for PAX6 (68.7%) followed by GAD2 (62.6%) and PR (52.5%) while specificity was highest for GAD2 (95.2%), followed by PR (91.3%), and PAX6 (91.1%). Of the analyzed combinations, the highest sensitivity (53.8%) and specificity (100%) was found for PAX6/GAD2, although combinations of PAX6/PR (49.5%/99.3%), PR/GAD2 (40.7%/98.9%), and PAX6/PR/GAD2 (40.6%/100%) did also result in high specificity. Only 14% of the 118 NENs with negativity for all three antibodies were of pancreatic origin. It is concluded that PAX6 IHC is useful to identify a pancreatic origin in case of NEN metastases of unknown origin. The combination with GAD2 and PR further increase the diagnostic performance of PAX6 and results in a >98% specificity in case of positivity for at least 2 of these markers.
Collapse
Affiliation(s)
- Florian Lutz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sophie-Marie Hornburg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Katharina Möller
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Florian Viehweger
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ria Schlichter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anne Menz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas M Luebke
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andrea Hinsch
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Bernreuther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David Dum
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas H Marx
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Natalia Gorbokon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| |
Collapse
|
|
2
|
Tao F, Zhu H, Xu J, Guo Y, Wang X, Shao L, Pan D, Li G, Fang R. Prognostic value of PAX8 in small cell lung cancer. Heliyon 2024; 10:e28251. [PMID: 38596099 PMCID: PMC11002052 DOI: 10.1016/j.heliyon.2024.e28251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 03/13/2024] [Accepted: 03/14/2024] [Indexed: 04/11/2024] Open
Abstract
Objectives Small cell lung cancer (SCLC) shows poor prognosis since it metastasizes widely at early stage. Paired box gene (PAX) 8 is a transcriptional factor of PAX family, of which the expression in lung cancer is a controversial issue, and its prognostic value of PAX8 in SCLC is still unclear. Materials and methods Overall, 184 subjects who were pathologically diagnosed with SCLC were enrolled in the study. Immunohistochemical analysis of PAX8 and Ki-67 were performed. The correlations between PAX8 expression and clinical features or Ki-67 index were further analyzed. Subsequently, an analysis of the association between PAX8, stage, Ki-67 status, and overall survival (OS) were performed in 169 subjects with follow-up information. Results PAX8 was positive in 53.8% (99/184) SCLC specimens. The positive rate is significantly higher in extensive-stage specimens (61.0%) than in limited-stage specimens (45.24%). PAX8 expression is positively correlated with Ki-67 index (P = 0.001) while negatively correlated with OS (HR = 3.725, 95% CI 1.943-7.139, P＜0.001). In combination groups, the PAX8 negative and limited stage group had the most promising OS. Conclusion PAX8 expression rate in SCLC specimens is not low. It has prognostic value in small cell lung cancer.
Collapse
Affiliation(s)
| | | | - Jiayun Xu
- Ningbo Clinical Pathology Diagnosis Center, Ningbo, Zhejiang 315211, PR China
| | - Yanan Guo
- Ningbo Clinical Pathology Diagnosis Center, Ningbo, Zhejiang 315211, PR China
| | - Xin Wang
- Ningbo Clinical Pathology Diagnosis Center, Ningbo, Zhejiang 315211, PR China
| | - Lei Shao
- Ningbo Clinical Pathology Diagnosis Center, Ningbo, Zhejiang 315211, PR China
| | - Deng Pan
- Ningbo Clinical Pathology Diagnosis Center, Ningbo, Zhejiang 315211, PR China
| | - Guosheng Li
- Ningbo Clinical Pathology Diagnosis Center, Ningbo, Zhejiang 315211, PR China
| | - Rong Fang
- Ningbo Clinical Pathology Diagnosis Center, Ningbo, Zhejiang 315211, PR China
| |
Collapse
|
|
3
|
Lennartz M, Benjamin Dünnebier N, Höflmayer D, Dwertmann Rico S, Kind S, Reiswich V, Viehweger F, Lutz F, Fraune C, Gorbokon N, Luebke AM, Hube-Magg C, Büscheck F, Menz A, Uhlig R, Krech T, Hinsch A, Burandt E, Sauter G, Simon R, Kluth M, Steurer S, Marx AH, Lebok P, Dum D, Minner S, Jacobsen F, Clauditz TS, Bernreuther C. GAD2 Is a Highly Specific Marker for Neuroendocrine Neoplasms of the Pancreas. Am J Surg Pathol 2024; 48:377-386. [PMID: 38271200 PMCID: PMC10930383 DOI: 10.1097/pas.0000000000002186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2024]
Abstract
Glutamate decarboxylase 2 (GAD2) is the most important inhibitory neurotransmitter and plays a role in insulin-producing β cells of pancreatic islets. The limitation of GAD2 expression to a few normal cell types makes GAD2 a potential immunohistochemical diagnostic marker. To evaluate the diagnostic utility of GAD2 immunohistochemistry, a tissue microarray containing 19,202 samples from 152 different tumor entities and 608 samples of 76 different normal tissue types was analyzed. In normal tissues, GAD2 staining was restricted to brain and pancreatic islet cells. GAD2 staining was seen in 20 (13.2%) of 152 tumor categories, including 5 (3.3%) tumor categories containing at least 1 strongly positive case. GAD2 immunostaining was most commonly seen in neuroendocrine carcinomas (58.3%) and neuroendocrine tumors (63.2%) of the pancreas, followed by granular cell tumors (37.0%) and neuroendocrine tumors of the lung (11.1%). GAD2 was only occasionally (<10% of cases) seen in 16 other tumor entities including paraganglioma, medullary thyroid carcinoma, and small cell neuroendocrine carcinoma of the urinary bladder. Data on GAD2 and progesterone receptor (PR) expression (from a previous study) were available for 95 pancreatic and 380 extrapancreatic neuroendocrine neoplasms. For determining a pancreatic origin of a neuroendocrine neoplasm, the sensitivity of GAD2 was 64.2% and specificity 96.3%, while the sensitivity of PR was 56.8% and specificity 92.6%. The combination of PR and GAD2 increased both sensitivity and specificity. GAD2 immunohistochemistry is a highly useful diagnostic tool for the identification of pancreatic origin in case of neuroendocrine neoplasms with unknown site of origin.
Collapse
Affiliation(s)
- Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | | | - Doris Höflmayer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | | | - Simon Kind
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Viktor Reiswich
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Florian Viehweger
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Florian Lutz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Natalia Gorbokon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Andreas M. Luebke
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Anne Menz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Ria Uhlig
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck
| | - Andrea Hinsch
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Andreas H. Marx
- Department of Pathology, Academic Hospital Fuerth, Fuerth Germany
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck
| | - David Dum
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | - Till S. Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg
| | | |
Collapse
|
|
4
|
Abstract
Most pancreatic neuroendocrine neoplasms are slow-growing, and the patients may survive for many years, even after distant metastasis. The tumors usually display characteristic organoid growth patterns with typical neuroendocrine morphology. A smaller portion of the tumors follows a more precipitous clinical course. The classification has evolved from morphologic patterns to the current World Health Organization classification, with better-defined grading and prognostic criteria. Recent advances in molecular pathology have further improved our understanding of the pathogenesis of these tumors. Various issues and challenges remain, including the correct recognition of a neuroendocrine neoplasm, accurate classification and grading of the tumor, and differentiation from mimickers. This review focuses on the practical aspects during the workup of pancreatic neuroendocrine neoplasms and attempts to provide a general framework to help achieve an accurate diagnosis, classification, and grading.
Collapse
|
|
5
|
Smolkova B, Kataki A, Earl J, Ruz-Caracuel I, Cihova M, Urbanova M, Buocikova V, Tamargo S, Rovite V, Niedra H, Schrader J, Kohl Y. Liquid biopsy and preclinical tools for advancing diagnosis and treatment of patients with pancreatic neuroendocrine neoplasms. Crit Rev Oncol Hematol 2022; 180:103865. [PMID: 36334880 DOI: 10.1016/j.critrevonc.2022.103865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
|
|
6
|
Yin F, Wu ZH, Lai JP. New insights in diagnosis and treatment of gastroenteropancreatic neuroendocrine neoplasms. World J Gastroenterol 2022; 28:1751-1767. [PMID: 35633912 PMCID: PMC9099195 DOI: 10.3748/wjg.v28.i17.1751] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 01/06/2022] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare epithelial neoplasms derived from pluripotent endocrine cells along the gastrointestinal tract and pancreas. GEP-NENs are classified into well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Despite overlapping morphological features, GEP-NENs vary in molecular biology, epigenetic, clinical behavior, treatment response, and prognosis features and remain an unmet clinical challenge. In this review, we introduce recent updates on the histopathologic classification, including the tumor grading and staging system, molecular genetics, and systemic evaluation of the diagnosis and treatment of GEP-NENs at different anatomic sites, together with some insights into the diagnosis of challenging and unusual cases. We also discuss the application of novel therapeutic approaches for GEP-NENs, including peptide receptor radionuclide therapy, targeted therapy, and immunotherapy with immune checkpoint inhibitors. These findings will help improve patient care with precise diagnosis and individualized treatment of patients with GEP-NENs.
Collapse
Affiliation(s)
- Feng Yin
- Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, MO 65212, United States
| | - Zi-Hao Wu
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
| | - Jin-Ping Lai
- Department of Pathology, Kaiser Permanente Sacramento Medical Center, Sacramento, CA 95825, United States
| |
Collapse
|
|
7
|
Lymphoid Enhancer Binding Factor 1 (LEF1) and Paired Box Gene 8 (PAX8): A Limited Immunohistochemistry Panel to Distinguish Solid Pseudopapillary Neoplasms and Pancreatic Neuroendocrine Tumors. Appl Immunohistochem Mol Morphol 2021; 28:776-780. [PMID: 32723981 DOI: 10.1097/pai.0000000000000830] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Solid pseudopapillary neoplasms (SPNs) and pancreatic neuroendocrine tumors (PanNETs) are distinctive entities. However, due to overlapping morphologies, distinguishing them remains a diagnostic challenge. Our study investigates the utility of immunohistochemistry for nuclear lymphoid enhancer binding factor 1 (LEF1) and paired box gene 8 (PAX8) in differentiating these 2 entities. LEF1 and PAX8 immunohistochemistry were performed on fine-needle aspiration cell blocks and surgical resection specimens diagnosed as SPN or PanNET at our institution from January 2007 to August 2016. Eight SPN and 25 PanNET cell blocks and 17 SPN and 34 PanNET surgical resection specimens were examined. On cell blocks, positive staining for LEF1 had high frequency, sensitivity, and specificity for SPN (88%, 88%, and 88%) as did positive staining for PAX8 for PanNET (76%, 76%, and 75%). The findings on surgical resection specimens were consistent with those from cell blocks (LEF1+ in SPN: 100%, 100%, and 97%; PAX8+ in PanNET: 59%, 59%, and 100%). A combined LEF1+/PAX8- phenotype showed high sensitivity and specificity for SPN (cell block: 63% and 100%; surgical specimen: 100% and 98%) as did a LEF1-/PAX8+ phenotype for PanNET (cell block: 64% and 100%; surgical specimen: 59% and 100%). SPN and PanNET exhibit opposite immunophenotypic profiles with LEF1+/PAX8- in SPN and LEF1-/PAX8+ in PanNET. The combination of these 2 stains provides an effective means of distinguishing these 2 entities.
Collapse
|
|
8
|
Tabasaran J, Schuhmann M, Ebinger M, Honegger J, Renovanz M, Schittenhelm J. PAX6 is frequently expressed in ependymal tumours and associated with prognostic relevant subgroups. J Clin Pathol 2021; 75:759-765. [PMID: 34183436 DOI: 10.1136/jclinpath-2021-207526] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 05/20/2021] [Indexed: 01/20/2023]
Abstract
AIMS An ependymoma shows divergent morphological and molecular features depending on their location. The paired box 6 (PAX6) transcription factor is a putative tumour suppressor and drives cancer cells towards a stem cell-like state. A transcriptome study reported high PAX6 expression in ependymal tumours, but data on protein expression are lacking. METHODS We, therefore, analysed PAX6 expression by immunohistochemistry in 172 ependymoma samples and correlated its expression to histology, WHO grade, anatomical location and molecular subgroups. RESULTS Mean PAX6 nuclear expression in ependymoma was 27.5% (95% CI 23.3 to 31.7). PAX6 expression in subependymoma (mean: 5%) was significantly lower compared with myxopapillary (30%), WHO grade II (26%) and anaplastic ependymoma (35%). Supratentorial ependymomas also displayed significant lower PAX6 levels (15%) compared with spinal cord tumours (30%). Expression levels in YAP1-fused ependymoma (41%) were higher compared with REL-associated protein (RELA)-fusion positive tumours (17%), while PAX6 expression was similar in posterior fossa group A (33%) and B (29%) ependymomas. Kaplan-Meier analysis in RELA-fusion positive ependymomas and posterior fossa group B showed a significant better outcome for PAX6 at or above the cut-off of 19.45% compared with tumours with PAX6 below the cut-off. CONCLUSIONS We demonstrate that PAX6 is frequently expressed in human ependymal tumours and immunohistochemistry may be helpful in determining prognostic relevant subgroups.
Collapse
Affiliation(s)
- Julian Tabasaran
- Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - Martin Schuhmann
- Department of Neurosurgery, Eberhard Karls University of Tuebingen, Baden-Württemberg, Germany.,Center for Neuro-Oncology, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Division of Pediatric Neurosurgery, Department of Neurosurgery, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - Martin Ebinger
- Department Pediatric Hematology/Oncology, Children's University Hospital, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - Jürgen Honegger
- Department of Neurosurgery, Eberhard Karls University of Tuebingen, Baden-Württemberg, Germany.,Center for Neuro-Oncology, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - Mirjam Renovanz
- Department of Neurosurgery, Eberhard Karls University of Tuebingen, Baden-Württemberg, Germany.,Center for Neuro-Oncology, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany.,Interdisciplinary Division of Neuro-Oncology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| | - Jens Schittenhelm
- Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany .,Center for Neuro-Oncology, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of Tuebingen, Eberhard Karls University of Tuebingen, Tuebingen, Germany
| |
Collapse
|
|
9
|
Kimura K, Tsuchiya J, Kitazume Y, Kishino M, Akahoshi K, Kudo A, Tanaka S, Tanabe M, Tateishi U. Dynamic Enhancement Pattern on CT for Predicting Pancreatic Neuroendocrine Neoplasms with Low PAX6 Expression: A Retrospective Observational Study. Diagnostics (Basel) 2020; 10:919. [PMID: 33182335 PMCID: PMC7695321 DOI: 10.3390/diagnostics10110919] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/05/2020] [Accepted: 11/06/2020] [Indexed: 12/20/2022] Open
Abstract
Paired box 6 (PAX6) is a transcription factor that plays a critical role in tumor suppression, implying that the downregulation of PAX6 promotes tumor growth and invasiveness. This study aimed to examine dynamic computed tomography (CT) features for predicting pancreatic neuroendocrine neoplasms (Pan-NENs) with low PAX6 expression. We retrospectively evaluated 51 patients with Pan-NENs without synchronous liver metastasis to assess the pathological expression of PAX6. Two radiologists analyzed preoperative dynamic CT images to determine morphological features and enhancement patterns. We compared the CT findings between low and high PAX6 expression groups. Pathological analysis identified 11 and 40 patients with low and high PAX6 expression, respectively. Iso- or hypoenhancement types in the arterial and portal phases were significantly associated with low PAX6 expression (p = 0.009; p = 0.001, respectively). Low PAX6 Pan-NENs showed a lower portal enhancement ratio than high PAX6 Pan-NENs (p = 0.044). The combination based on enhancement types (iso- or hypoenhancement during arterial and portal phases) and portal enhancement ratio (≤1.22) had 54.5% sensitivity, 92.5% specificity, and 84.3% accuracy in identifying low PAX6 Pan-NENs. Dynamic CT features, including iso- or hypoenhancement types in the arterial and portal phases and lower portal enhancement ratio may help predict Pan-NENs with low PAX6 expression.
Collapse
Affiliation(s)
- Koichiro Kimura
- Department of Diagnostic Radiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 1138510, Japan; (J.T.); (Y.K.); (M.K.); (U.T.)
| | - Junichi Tsuchiya
- Department of Diagnostic Radiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 1138510, Japan; (J.T.); (Y.K.); (M.K.); (U.T.)
| | - Yoshio Kitazume
- Department of Diagnostic Radiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 1138510, Japan; (J.T.); (Y.K.); (M.K.); (U.T.)
| | - Mitsuhiro Kishino
- Department of Diagnostic Radiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 1138510, Japan; (J.T.); (Y.K.); (M.K.); (U.T.)
| | - Keiichi Akahoshi
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 1138510, Japan; (K.A.); (A.K.); (M.T.)
| | - Atsushi Kudo
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 1138510, Japan; (K.A.); (A.K.); (M.T.)
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 1138510, Japan;
| | - Minoru Tanabe
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 1138510, Japan; (K.A.); (A.K.); (M.T.)
| | - Ukihide Tateishi
- Department of Diagnostic Radiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 1138510, Japan; (J.T.); (Y.K.); (M.K.); (U.T.)
| |
Collapse
|
|
10
|
Mohanty SK, Tiwari A, Bhardwaj N, Chuang F, Kim E, Lugo H, Yuan X, Diffalha SA, Peralta-Venturina M, Balzer B, Dhall D. Positivity for SATB2 distinguishes Islet1 positive rectal neuroendocrine tumours from pancreaticoduodenal neuroendocrine tumours. J Clin Pathol 2020; 74:582-588. [PMID: 32934105 DOI: 10.1136/jclinpath-2020-206645] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 07/14/2020] [Accepted: 08/02/2020] [Indexed: 12/19/2022]
Abstract
AIMS Determining the site of origin of a metastatic neuroendocrine tumour (NET) can be challenging and has important prognostic and therapeutic implications. An immunohistochemical (IHC) panel consisting of TTF1, CDX2, PAX8/PAX6 and Islet1 is often employed. However, there can be a significant IHC overlap among different primary sites. Herein, we sought to determine the utility of including Special AT-rich sequence binding protein-2 (SATB2) in the IHC panel that is used for determining the site of origin of a metastatic NET. METHODS Paraffin tissue microarrays consisting of 137 primary NETs (26 lung, 22 jejunoileal, 8 appendix, 5 stomach, 4 duodenum, 17 rectum and 55 pancreas) were stained for SATB2, in addition to the well-described lineage-associated markers, such as TTF1, CDX2, PAX6 and Islet1. Additionally, a tissue microarray consisting of 21 metastatic NETs (1 lung, 1 stomach, 8 jejunoileal and 11 pancreas) was stained for TTF1, CDX2, SATB2 and Islet1. The results were recorded as no staining, weak staining and moderate to strong staining. RESULTS All appendiceal NETs and majority (88%) of the rectal NETs were positive for SATB2. All primary foregut NETs (stomach, pancreas, duodenum and lung) were negative for SATB2, except for one pulmonary NET with weak staining. However, among the metastatic tumours, 5 of 11 pancreatic NETs, 1 stomach NET, 1 lung NET and 2 of 8 jejunoileal NETs showed weak staining. Receiver operating characteristic analysis incorporating sensitivity and specificity data of IHC panel, considering moderate to strong staining as truly positive cases, showed that inclusion of SATB2 to the previously described NET IHC panel outperformed the panel without SATB2, raising the specificity for pancreaticoduodenal NETs from 81.2% to 100%, with a positive predictive value (PPV) of 100% and negative predictive value (NPV) of 82.22% (p<0.0001); for appendiceal NETs the specificity changed from 99.1% to 98.5% and sensitivity increased from 11.8% to 80%, with a PPV and NPV of 66.67% and 99.26%, respectively (p<0.0001); and for rectal NETs the specificity increased from 97.6% to 99.3% and sensitivity raised from 7.1% to 66.7%, with a PPV and NPV of 80% and 98.53%, respectively (p<0.0001). CONCLUSIONS SATB2 stain is useful in differentiatingIslet1/PAX6 positive pancreatic and rectal NETs, as rectal NETs are typically moderately to strongly positive for SATB2 and pancreatic NETs are usually negative or weakly positive for SATB2. Moderate to strong staining for SATB2 is suggestive of an appendiceal or a rectal primary. SATB2 may complement the panel of CDX2, TTF1 and Islet1 in determining the site of origin of an NET in a metastatic setting.
Collapse
Affiliation(s)
- Sambit Kumar Mohanty
- Pathology and Laboratory Medicine, Advanced Medical Research Institute, Bhubaneswar, Odisha, India.,Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Ankit Tiwari
- Pathology and Laboratory Medicine, Advanced Medical Research Institute, Bhubaneswar, Odisha, India
| | - Nitin Bhardwaj
- Pathology and Laboratory Medicine, Advanced Medical Research Institute, Bhubaneswar, Odisha, India
| | - Fai Chuang
- Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Evelyn Kim
- Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Hector Lugo
- Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Xiaopu Yuan
- Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Sameer Al Diffalha
- Pathology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
| | | | - Bonnie Balzer
- Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Deepti Dhall
- Pathology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA
| |
Collapse
|
|
11
|
Jin M, Gao D, Wang R, Sik A, Liu K. Possible involvement of TGF‑β‑SMAD‑mediated epithelial‑mesenchymal transition in pro‑metastatic property of PAX6. Oncol Rep 2020; 44:555-564. [PMID: 32627030 PMCID: PMC7336511 DOI: 10.3892/or.2020.7644] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 05/12/2020] [Indexed: 01/15/2023] Open
Abstract
Paired box 6 (PAX6) is a transcription factor that has oncogenic features. In breast cancer, PAX6 facilitates tumor progression; however, the underlying mechanism is largely unknown. The majority of breast cancer-related mortalities are associated with metastasis of cancer cells. Therefore, the present study aimed to investigate the role of PAX6 in breast tumor metastasis. PAX6 was stably overexpressed in breast cancer cells to perform tumor migration and metastasis assays in vitro and in vivo. In addition, the expression of PAX6 and transforming growth factor β (TGF-β)-SMAD signaling associated proteins on human breast cancer tissue array, as well as key factors involved in epithelial-mesenchymal transition (EMT) were assayed to explore the mechanism underlying metastasis of breast cancer cells. The expression levels of PAX6 were demonstrated to be increased in human breast cancer tissues and associated with poor clinical outcomes. Overexpression of PAX6 markedly promoted metastasis. Further investigation revealed that PAX6 overexpression increased TGF-β-SMAD signaling pathway and induced EMT. These results suggested that highly expressed PAX6 led to EMT through TGF-β-SMAD signaling pathway, thereby promoting cell metastasis and ultimately affecting survival in patients with breast cancer. Taken together, findings indicated that PAX6 may serve as a therapeutic target for the clinical treatment of breast cancer and the underlying mechanism could be used to overcome metastasis of cancer cells.
Collapse
Affiliation(s)
- Meng Jin
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250103, P.R. China
| | - Daili Gao
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250103, P.R. China
| | - Rongchun Wang
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250103, P.R. China
| | - Attila Sik
- Institute of Physiology, Medical School, University of Pécs, H‑7624 Pécs, Hungary
| | - Kechun Liu
- Biology Institute, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong 250103, P.R. China
| |
Collapse
|
|
12
|
Kudo A, Akahoshi K, Ito S, Akashi T, Shimada S, Ogura T, Ogawa K, Ono H, Mitsunori Y, Ban D, Tateishi U, Tanaka S, Tanabe M. Downregulated Pancreatic Beta Cell Genes Indicate Poor Prognosis in Patients With Pancreatic Neuroendocrine Neoplasms. Ann Surg 2020; 271:732-739. [PMID: 29979246 DOI: 10.1097/sla.0000000000002911] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
OBJECTIVE To predict metachronous liver metastasis after pancreatectomy for pancreatic neuroendocrine neoplasms (Pan-NENs). SUMMARY OF BACKGROUND DATA Liver metastasis determines the prognosis of patients with Pan-NENs, but no index exists in the WHO 2017 classification for this prediction. METHODS Between April 2014 and March 2018, resected primary tumors from 20 patients with or without simultaneous liver metastasis were examined using genome-wide gene expression analysis. For validation analysis, resected primary tumors from 62 patients without simultaneous liver metastasis were examined for PAX6 expression. RESULTS Gene expression profiling revealed pancreatic beta cell genes (NES, -2.0; P < 0.001) as the most downregulated set in patients with simultaneous liver metastasis. In the test study, PAX6 was the most valuable index for liver metastasis (log FC, -3.683; P = 0.0096). Multivariate analysis identified PAX6 expression (hazard ratio, 0.2; P = 0.03) as an independent risk factor for metachronous liver metastasis-free survival (mLM-FS). The 5-year mLM-FS of patients with high versus low PAX6 expression was significantly better (95% vs 66%, respectively; P < 0.0001). The 5-year overall survival rate of was also better than in those with high versus low PAX6 expression (100% vs 87%, respectively). Patients with low PAX 6 expression were significantly younger and leaner, had a higher Ki-67 index (P = 0.01, 0.007, 0.008, respectively), and showed a higher mitotic rate than patients with high PAX6 expression. CONCLUSIONS Downregulated pancreatic beta cell genes involving PAX6 in primary tumors may predict mLM and poor overall survival after primary tumor resection in Pan-NEN patients.
Collapse
Affiliation(s)
- Atsushi Kudo
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Keiichi Akahoshi
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sakiko Ito
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takumi Akashi
- Department of Human Pathology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shu Shimada
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshiro Ogura
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kosuke Ogawa
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroaki Ono
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yusuke Mitsunori
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Daisuke Ban
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ukihide Tateishi
- Department of Diagnostic Radiology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Minoru Tanabe
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| |
Collapse
|
|
13
|
Expression of PAX3 Distinguishes Biphenotypic Sinonasal Sarcoma From Histologic Mimics. Am J Surg Pathol 2019; 42:1275-1285. [PMID: 29863547 DOI: 10.1097/pas.0000000000001092] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Biphenotypic sinonasal sarcoma (BSNS) is a distinctive, anatomically restricted, low-grade spindle cell sarcoma that shows considerable histologic overlap with other cellular spindle cell neoplasms. This tumor type shows both myogenic and neural differentiation, which can be demonstrated by immunohistochemistry; however, the available diagnostic markers are relatively nonspecific. BSNS is characterized by PAX3 rearrangements, with MAML3 as the most common fusion partner. Our aim was to determine whether immunohistochemistry using a monoclonal PAX3 antibody could distinguish BSNS from potential histologic mimics, as well as to evaluate a widely available polyclonal PAX8 antibody, which is known to cross-react with other paired box transcription factor family members. Immunohistochemistry for PAX3 and PAX8 was performed on whole sections of 15 BSNS (10 with confirmed PAX3 rearrangement) and 10 cases each of the following histologic mimics: malignant peripheral nerve sheath tumor, monophasic synovial sarcoma, spindle cell rhabdomyosarcoma (RMS), solitary fibrous tumor, sinonasal hemangiopericytoma, and cellular schwannoma, as well as alveolar RMS (which harbors PAX3 or PAX7 gene rearrangements). BSNS showed consistent expression of PAX3 (15/15), all multifocal-to-diffuse and most with moderate-to-strong intensity of staining. One single case of spindle cell RMS showed PAX3 expression (1/10), and all other histologic mimics were completely PAX3-negative. In contrast, nuclear staining for PAX8 was present in all 15 BSNS, 7/10 malignant peripheral nerve sheath tumor, 3/10 cellular schwannomas, 2/10 sinonasal hemangiopericytomas, 1/10 synovial sarcoma, 1 spindle cell RMS, and 1 solitary fibrous tumor. All cases of alveolar RMS were positive for PAX8, and most were also positive for PAX3 (8/10). Immunohistochemical expression of PAX3 is highly sensitive (100%) and specific (98%) for BSNS. A polyclonal PAX8 antibody also stains BSNS (likely due to cross-reactivity with PAX3) but has much lower specificity (75%), with frequent expression in numerous mimics.
Collapse
|
|
14
|
Kei S, Adeyi OA. Practical Application of Lineage-Specific Immunohistochemistry Markers: Transcription Factors (Sometimes) Behaving Badly. Arch Pathol Lab Med 2019; 144:626-643. [PMID: 31385722 DOI: 10.5858/arpa.2019-0226-ra] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Transcription factors (TFs) are proteins that regulate gene expression and control RNA transcription from DNA. Lineage-specific TFs have increasingly been used by pathologists to determine tumor lineage, especially in the setting of metastatic tumors of unknown primary, among other uses. With experience gathered from its daily application and increasing pitfalls reported from immunohistochemical studies, these often-touted highly specific TFs are not as reliable as once thought. OBJECTIVES.— To summarize the established roles of many of the commonly used TFs in clinical practice and to discuss known and potential sources for error (eg, false-positivity from cross-reactivity, aberrant, and overlap "lineage-specific" expression) in their application and interpretation. DATA SOURCES.— Literature review and the authors' personal practice experience were used. Several examples selected from the University Health Network (Toronto, Ontario, Canada) are illustrated. CONCLUSIONS.— The application of TF diagnostic immunohistochemistry has enabled pathologists to better assess the lineage/origin of primary and metastatic tumors. However, the awareness of potential pitfalls is essential to avoid misdiagnosis.
Collapse
Affiliation(s)
- Si Kei
- From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (Dr Lou); and the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis (Dr Adeyi)
| | - Oyedele A Adeyi
- From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (Dr Lou); and the Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis (Dr Adeyi)
| |
Collapse
|
|
15
|
Alexandraki KI, Tsoli M, Kyriakopoulos G, Angelousi A, Nikolopoulos G, Kolomodi D, Kaltsas GA. Current concepts in the diagnosis and management of neuroendocrine neoplasms of unknown primary origin. MINERVA ENDOCRINOL 2019; 44:378-386. [PMID: 30991795 DOI: 10.23736/s0391-1977.19.03012-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Neuroendocrine neoplasms (NENs) of unknown primary origin (UPO-NENs) are advanced neoplasms constituting 11-22% of all NENs that by definition their primary tissue of origin has not been identified with standard diagnostic work-up. Delineating the primary site of origin of UPO-NENs has important implications for selecting the appropriate treatment and overall prognosis. The small bowel, followed by the lung and pancreas are the most prevalent primary sites of origin of UPO-NENs that are uncovered during an extensive and prolonged diagnostic work-up; however, a number of UPO-NENs may still remain occult even after prolonged follow-up. A number of diagnostic algorithms that incorporate histopathological, molecular, imaging (either morphological or functional imaging), and serum biomarkers can help to identify the primary tumor origin. It is expected that advances in these fields will help reduce significantly the number of UPO-NENs.
Collapse
Affiliation(s)
- Krystallenia I Alexandraki
- Unit of Endocrinology, First Department of Internal Medicine, Laiko University Hospital, National and Kapodistrian University of Athens, Athens, Greece -
| | - Marina Tsoli
- Unit of Endocrinology, First Department of Internal Medicine, Laiko University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Anna Angelousi
- Unit of Endocrinology, First Department of Internal Medicine, Laiko University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Nikolopoulos
- Unit of Endocrinology, First Department of Internal Medicine, Laiko University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Denise Kolomodi
- Unit of Endocrinology, First Department of Internal Medicine, Laiko University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Gregory A Kaltsas
- Unit of Endocrinology, First Department of Internal Medicine, Laiko University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| |
Collapse
|
|
16
|
Qian Z, Zhang Q, Hu Y, Zhang T, Li J, Liu Z, Zheng H, Gao Y, Jia W, Hu A, Li B, Hao J. Investigating the mechanism by which SMAD3 induces PAX6 transcription to promote the development of non-small cell lung cancer. Respir Res 2018; 19:262. [PMID: 30594196 PMCID: PMC6311080 DOI: 10.1186/s12931-018-0948-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 11/22/2018] [Indexed: 01/08/2023] Open
Abstract
Background This study investigated the function of SMAD3 (SMAD family member 3) in regulating PAX6 (paired box 6) in non-small cell lung cancer. Methods First, qRT-PCR was employed to detect SMAD3 expression in cancer tissues along with normal tissues and four cell lines, including BEAS-2B, H125, HCC827 and A549 cells. SMAD3 was knocked down by small interference RNA (siRNA), and then its expression was determined via qRT-PCR and Western blot analysis. The correlation between SMAD3 and PAX6 was determined by double luciferase reporter experiments and chromatin immunoprecipitation (ChIP) assay. Cell viability was evaluated by CCK-8 and colony forming assays, while cell migration and invasion were detected by Transwell analysis. Results SMAD3 and PAX6 were upregulated in lung cancer tissues and cancer cells. Knocking down SMAD3 and PAX6 by transfection with siRNAs specifically suppressed the expression of SMAD3 and PAX6 mRNA and protein levels. SMAD3 could promote PAX6 transcriptional activity by binding to its promoter. Reduced expression of SMAD3 led to the downregulation of PAX6 mRNA and protein levels along with decreased cell migration, invasion, proliferation and viability in A549 and HCC827 cells. PAX6 overexpression altered the si-SMAD3-induced inhibition of cell migration, invasion, proliferation and viability in A549 and HCC827 cells. Additionally, PAX6 knockdown alone also repressed the cell migration, invasion, proliferation and viability of the cell lines. Conclusions SMAD3 promotes the progression of non-small cell lung cancer by upregulating PAX6 expression. Electronic supplementary material The online version of this article (10.1186/s12931-018-0948-z) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Zhe Qian
- Department of General Medicine, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, No.9 Yard, Beiguan Street, Tongzhou District, Beijing, 101149, China
| | - Qiankun Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Shushan District, Hefei, 230022, Anhui, China
| | - Ying Hu
- Department of General Medicine, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, No.9 Yard, Beiguan Street, Tongzhou District, Beijing, 101149, China
| | - Tongmei Zhang
- Department of General Medicine, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, No.9 Yard, Beiguan Street, Tongzhou District, Beijing, 101149, China
| | - Jie Li
- Department of General Medicine, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, No.9 Yard, Beiguan Street, Tongzhou District, Beijing, 101149, China
| | - Zan Liu
- Department of General Medicine, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, No.9 Yard, Beiguan Street, Tongzhou District, Beijing, 101149, China
| | - Hua Zheng
- Department of General Medicine, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, No.9 Yard, Beiguan Street, Tongzhou District, Beijing, 101149, China
| | - Yuan Gao
- Department of General Medicine, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, No.9 Yard, Beiguan Street, Tongzhou District, Beijing, 101149, China
| | - Wenyun Jia
- Department of General Medicine, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, No.9 Yard, Beiguan Street, Tongzhou District, Beijing, 101149, China
| | - Aimin Hu
- Department of General Medicine, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, No.9 Yard, Beiguan Street, Tongzhou District, Beijing, 101149, China
| | - Baolan Li
- Department of General Medicine, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, No.9 Yard, Beiguan Street, Tongzhou District, Beijing, 101149, China.
| | - Jiqing Hao
- Department of Medical Oncology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Shushan District, Hefei, 230022, Anhui, China.
| |
Collapse
|
|
17
|
Abstract
Carcinoma of unknown primary is defined as metastatic carcinoma without a clinically obvious primary tumor. Determining the tissue of origin in carcinoma of unknown primary is important for site-directed therapy. Immunohistochemistry is the most widely used tool for the work-up of metastases, but molecular profiling assays are also available. This review provides an overview of immunohistochemical stains in the work-up of metastatic carcinoma, with a focus on newer site-specific markers, and discusses the role of gene expression profiling assays for determining tissue of origin. The utility of cytopathology specimens in the evaluation of carcinoma of unknown primary also is highlighted.
Collapse
Affiliation(s)
- Erika E Doxtader
- Department of Pathology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
| | - Deborah J Chute
- Department of Pathology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
| |
Collapse
|
|
18
|
Kyriakopoulos G, Mavroeidi V, Chatzellis E, Kaltsas GA, Alexandraki KI. Histopathological, immunohistochemical, genetic and molecular markers of neuroendocrine neoplasms. ANNALS OF TRANSLATIONAL MEDICINE 2018; 6:252. [PMID: 30069454 DOI: 10.21037/atm.2018.06.27] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Neuroendocrine neoplasms (NENs) arise from cells of the neuroendocrine system located in many sites amongst which most common are the gastrointestinal (GI) system and the lung. The efforts to assess the specific site of origin or predict the biological behavior of NENs is based upon a detailed study of neoplasm's architectural pattern, immunohistochemical, genetic and molecular profile. Immunohistochemistry is used to characterize the aggressivity of NENs, by assessing the proliferation index Ki-67, as well as the neuroendocrine differentiation by assessing chromogranin A (CgA) and CD56. Basal panels of immunohistochemical markers such as CDX-2, Isl-1, TTF-1, PAX6/8 are currently being used to allocate the neoplasms, while in dubious cases new markers are investigating. Unraveling the genetic and molecular mechanisms of NENs pathogenesis along with shedding light on the molecular heterogeneity of neoplasms and the individual patterns of molecular lesions, underlining these neoplasms may provide new tools in terms of diagnostics and therapeutics. Molecular targeted therapies (MTTs) such as everolimus and sunitinib have been the first example of druggable molecular targets implicated in NENs that have been approved for NEN treatment. New investigational drugs are developing along with genetic tests that may allow the identification of the specific subset of patients that will respond to each individual MTT. Multiparametrical molecular and genetic analysis such as the NETest and the MASTER are already in trials shedding light in a step-by-step management of NENs that allow not only the selection of an appropriate therapeutic option but also the identification of response to treatment or early relapse allowing an early amendment of the strategy. Summarizing the combination of histopathological, immunohistochemical, genetic and molecular profile of a NEN opens new horizons in the efficient management of NENs.
Collapse
Affiliation(s)
| | - Vasiliki Mavroeidi
- Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Eleftherios Chatzellis
- Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Gregory A Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Krystallenia I Alexandraki
- Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| |
Collapse
|
|
19
|
Yang MX, Coates RF, Ambaye A, Cortright V, Mitchell JM, Buskey AM, Zubarik R, Liu JG, Ades S, Barry MM. NKX2.2, PDX-1 and CDX-2 as potential biomarkers to differentiate well-differentiated neuroendocrine tumors. Biomark Res 2018; 6:15. [PMID: 29713473 PMCID: PMC5907358 DOI: 10.1186/s40364-018-0129-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 04/02/2018] [Indexed: 12/24/2022] Open
Abstract
Background Well-differentiated neuroendocrine tumors (NET) most frequently arise from the gastrointestinal tract (GI), pancreas, and lung. Patients often present as metastasis with an unknown primary, and the clinical management and outcome depend on multiple factors, including the accurate diagnosis with the tumor primary site. Determining the site of the NET with unknown primary remains challenging. Many biomarkers have been investigated in primary NETs and metastatic NETs, with heterogeneous sensitivity and specificity observed. Methods We used high-throughput tissue microarray (TMA) and immunohistochemistry (IHC) with antibodies against a panel of transcriptional factors including NKX2.2, PDX-1, PTF1A, and CDX-2 on archived formalin-fixed paraffin-embedded NETs, and investigated the protein expression pattern of these transcription factors in 109 primary GI (N = 81), pancreatic (N = 17), and lung (N = 11) NETs. Results Differential expression pattern of these markers was observed. In the GI and pancreatic NETs (N = 98), NKX2.2, PDX-1, and CDX-2 were immunoreactive in 82 (84%), 14 (14%), and 52 (52%) cases, respectively. PDX-1 was expressed mainly in the small intestinal and appendiceal NETs, occasionally in the pancreatic NETs, and not in the colorectal NETs. All three biomarkers including NKX2.2, PDX-1, and CDX-2 were completely negative in lung NETs. PTF1A was expressed in all normal and neuroendocrine tumor cells. Conclusions Our findings suggest that NKX2.2 was a sensitive and specific biomarker for the GI and pancreatic neuroendocrine tumors. We proposed that a panel of immunostains including NKX2.2, PDX-1, and CDX-2 may show diagnostic utility for the most common NETs.
Collapse
Affiliation(s)
- Michelle X Yang
- 1Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, 111 Colchester Avenue, Burlington, VT 05401 USA
| | - Ryan F Coates
- 1Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, 111 Colchester Avenue, Burlington, VT 05401 USA
| | - Abiy Ambaye
- 1Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, 111 Colchester Avenue, Burlington, VT 05401 USA
| | - Valerie Cortright
- 1Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, 111 Colchester Avenue, Burlington, VT 05401 USA
| | - Jeannette M Mitchell
- 1Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, 111 Colchester Avenue, Burlington, VT 05401 USA
| | - Alexa M Buskey
- 1Department of Pathology and Laboratory Medicine, University of Vermont Medical Center, 111 Colchester Avenue, Burlington, VT 05401 USA
| | - Richard Zubarik
- 2Gastroenterology, University of Vermont Medical Center, Burlington, VT USA
| | - James G Liu
- Applied Pathology Systems, Worcester, MA USA
| | - Steven Ades
- 4Medical Oncology, University of Vermont Medical Center, Burlington, VT USA
| | - Maura M Barry
- 4Medical Oncology, University of Vermont Medical Center, Burlington, VT USA
| |
Collapse
|
|
20
|
Primary breast carcinomas with neuroendocrine features: Clinicopathological features and analysis of tumor growth patterns in 36 cases. Ann Diagn Pathol 2018; 34:122-130. [PMID: 29661717 DOI: 10.1016/j.anndiagpath.2018.03.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 03/30/2018] [Indexed: 12/17/2022]
Abstract
Primary breast carcinoma with neuroendocrine features (NEBC) is an uncommon tumor. In the classification of WHO 2012, these tumors were categorized as: 1- neuroendocrine tumor, well-differentiated; 2- neuroendocrine carcinoma, poorly differentiated/small cell carcinoma; and 3- invasive breast carcinoma with neuroendocrine differentiation. In this study, we reviewed NEBC except poorly differentiated/small cell carcinoma variant in order to define the morphological growth patterns and cytonuclear details of these tumors. All breast surgical excision materials between 2007 and 2016 were re-evaluated in terms of neuroendocrine differentiation. Thirty-six cases showing positive staining for synaptophysin and/or chromogranin A in ≥50% of tumor cells were included in the study. All cases were female with a mean age of 67.4. Mean tumor diameter was 26 mm. Multifocality was noted in 5 cases. Grossly, they were mostly infiltrative mass lesions. T stages, identified in 34 cases, were as follows: 13 cases with pT1; 19 pT2 and 2 pT3. We described schematically 4 types of patterns depending on predominant growth pattern, except one case: 1) Large-sized solid cohesive groups (6 cases), 2) Small- to medium-sized solid cohesive groups with trabeculae/ribbons and glandular structures (6 cases), 3) Mixed growth patterns (20 cases), 4) Invasive tumor with prominent extracellular and/or intracellular mucin (3 cases). The tumor cells were mostly polygonal-oval with eosinophilic/eosinophilic-granular cytoplasm. The nuclei of tumor cells were mostly round to oval with evenly distributed chromatin. Only 5 cases showed high grade nuclear and histological features. Molecular subtypes of the cases were as follows: 33 luminal A, 2 luminal B, and 1 triple negative. NEBC should come to mind when a tumor display one of the morphological patterns described above, composed of monotonous cells with mild to moderate nuclear pleomorphism and abundant eosinophilic/eosinophilic granular or clear cytoplasm, especially in elderly patients.
Collapse
|
|
21
|
Xiang X, Wang Y, Zhang H, Piao J, Muthusamy S, Wang L, Deng Y, Zhang W, Kuang R, Billadeau DD, Huang S, Lai J, Urrutia R, Kang N. Vasodilator-stimulated phosphoprotein promotes liver metastasis of gastrointestinal cancer by activating a β1-integrin-FAK-YAP1/TAZ signaling pathway. NPJ Precis Oncol 2018; 2:2. [PMID: 29872721 PMCID: PMC5871906 DOI: 10.1038/s41698-017-0045-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 12/06/2017] [Accepted: 12/28/2017] [Indexed: 12/26/2022] Open
Abstract
Extracellular matrix (ECM)-induced β1-integrin-FAK signaling promotes cell attachment, survival, and migration of cancer cells in a distant organ so as to enable cancer metastasis. However, mechanisms governing activation of the β1-integrin-FAK signaling remain incompletely understood. Here, we report that vasodilator-stimulated phosphoprotein (VASP), an actin binding protein, is required for ECM-mediated β1-integrin-FAK-YAP1/TAZ signaling in gastrointestinal (GI) cancer cells and their liver metastasis. In patient-derived samples, VASP is upregulated in 53 of 63 colorectal cancers and 43 of 53 pancreatic ductal adenocarcinomas and high VASP levels correlate with liver metastasis and reduced patient survival. In a Matrigel-based 3-dimensional (3D) culture model, short hairpin RNA (shRNA)-mediated VASP knockdown in colorectal cancer cells (KM12L4, HCT116, and HT29) and pancreatic cancer cells (L3.6 and MIA PaCa-1) suppresses the growth of 3D cancer spheroids. Mechanistic studies reveal that VASP knockdown suppresses FAK phosphorylation and YAP1/TAZ protein levels, but not Akt or Erk-related pathways and that YAP1/TAZ proteins are enhanced by the β1-integrin-FAK signaling. Additionally, VASP regulates the β1-integrin-FAK-YAP1/TAZ signaling by at least two mechanisms: (1) promoting ECM-mediated β1-integrin activation and (2) regulating YAP1/TAZ dephosphorylation at downstream of RhoA to enhance the stability of YAP1/TAZ proteins. In agreement with these, preclinical studies with two experimental liver metastasis mouse models demonstrate that VASP knockdown suppresses GI cancer liver metastasis, β1-integrin activation, and YAP1/TAZ levels of metastatic cancer cells. Together, our data support VASP as a treatment target for liver metastasis of colorectal and pancreatic cancers.
Collapse
Affiliation(s)
- Xiaoyu Xiang
- Tumor Microenvironment and Metastasis, The Hormel Institute, University of Minnesota, Austin, MN 55912 USA
| | - Yuanguo Wang
- Tumor Microenvironment and Metastasis, The Hormel Institute, University of Minnesota, Austin, MN 55912 USA
| | - Hongbin Zhang
- Tumor Microenvironment and Metastasis, The Hormel Institute, University of Minnesota, Austin, MN 55912 USA
| | - Jinhua Piao
- Department of Pathology, St. Louis University, School of Medicine, St. Louis, MO 63104 USA
| | - Selvaraj Muthusamy
- Department of Pathology, St. Louis University, School of Medicine, St. Louis, MO 63104 USA
| | - Lei Wang
- Cell Death and Cancer Genetics, The Hormel Institute, University of Minnesota, Austin, MN 55912 USA
| | - Yibin Deng
- Cell Death and Cancer Genetics, The Hormel Institute, University of Minnesota, Austin, MN 55912 USA
| | - Wei Zhang
- Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455 USA
| | - Rui Kuang
- Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN 55455 USA
| | | | | | - Jinping Lai
- Department of Pathology, St. Louis University, School of Medicine, St. Louis, MO 63104 USA
| | - Raul Urrutia
- GI Research Unit, Mayo Clinic, Rochester, MN 55905 USA
| | - Ningling Kang
- Tumor Microenvironment and Metastasis, The Hormel Institute, University of Minnesota, Austin, MN 55912 USA
| |
Collapse
|
|
22
|
Pathological Analysis of Abdominal Neuroendocrine Tumors. Updates Surg 2018. [DOI: 10.1007/978-88-470-3955-1_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
|
|
23
|
廖 晓, 尹 蔚, 王 芳, 邬 力, 黄 柏. [Construction of a lentiviral vector carrying short?hairpin RNA targeting PAX6 and its effect on proliferation of glioma U251 cells in vitro]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2017; 37:1603-1608. [PMID: 29292252 PMCID: PMC6744028 DOI: 10.3969/j.issn.1673-4254.2017.12.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Indexed: 06/07/2023]
Abstract
OBJECTIVE To construct a lentiviral vector for delivering short hairpin RNA (shRNA) targeting PAX6 and investigate its effect on the proliferation of glioma U251 cells in vitro. METHODS Two small interfering RNA sequences targeting PAX6 gene were designed based on the reported sequence of PAX6 and annealed to form a double?stranded chain, which was inserted into a lentiviral vector to construct the recombinant lentiviral vector shRNA?PAX6. The recombinant vector was infected into U251 cells, and the expression of PAX6 mRNA and protein in the cells was detected by real?time PCR and Western blotting, respectively. The changes in the proliferation of U251 cells after the infection was assessed using MTT assay. RESULTS Double enzyme digestion of the lentiviral vector pLKD?CMV?G&NR?U6?shRNA yielded an 8208?bp fragment, and colony PCR and sequencing analysis confirmed successful construction of the lentiviral vector shRNA?PAX6. Infection of the cells with shRNA?PAX6 caused a significant reduction of the expressions of PAX6 mRNA and protein (P<0.05) and resulted in obviously increased proliferation of U251 cells (P<0.05). CONCLUSION We successfully constructed the recombinant vector shRNA?PAX6 for silencing PAX6 gene. PAX6 gene silencing results in increased proliferation of U251 cells in vitro.
Collapse
Affiliation(s)
- 晓红 廖
- />中南大学湘雅医学院生理学系，湖南 长沙 410078Department of Physiology, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - 蔚兰 尹
- />中南大学湘雅医学院生理学系，湖南 长沙 410078Department of Physiology, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - 芳 王
- />中南大学湘雅医学院生理学系，湖南 长沙 410078Department of Physiology, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - 力祥 邬
- />中南大学湘雅医学院生理学系，湖南 长沙 410078Department of Physiology, Xiangya School of Medicine, Central South University, Changsha 410078, China
| | - 柏胜 黄
- />中南大学湘雅医学院生理学系，湖南 长沙 410078Department of Physiology, Xiangya School of Medicine, Central South University, Changsha 410078, China
| |
Collapse
|
|
24
|
Alexandraki K, Angelousi A, Boutzios G, Kyriakopoulos G, Rontogianni D, Kaltsas G. Management of neuroendocrine tumors of unknown primary. Rev Endocr Metab Disord 2017; 18:423-431. [PMID: 29199361 DOI: 10.1007/s11154-017-9437-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Neuroendocrine neoplams (NENs) are mostly relatively indolent malignancies but a significant number have metastatic disease at diagnosis mainly to the liver. Although in the majority of such cases the primary origin of the tumor can be identified, in approximately 11-22% no primary tumor is found and such cases are designated as NENs of unknown primary origin (UPO). This has significant therapeutic implications with respect to potentially resectable hepatic disease and/or application of appropriate medical therapy, either chemotherapeutic agents or targeted treatment, as the response to various treatments varies according to the origin of the primary tumor. This lack of tumor specific orientated treatment may also account for the relatively poorer prognosis of NENs of UPO compared to metastatic NENs with a known primary site. In the majority of cases the primary tumors are located in the small bowel and the lung, but a number may still elude detection. Occasionally the presence of a functional syndrome may direct to the specific tissue of origin but in the majority of cases a number of biochemical, imaging, histopathological and molecular modalities are utilized to help identify the primary origin of the tumor and direct treatment accordingly. Several diagnostic algorithms have recently been developed to help localize an occult primary tumor; however, in a number of cases no lesion is identified even after prolonged follow-up. It is expected that the delineation of the molecular signature of the different NENs may help identify such cases and provide appropriate treatment.
Collapse
Affiliation(s)
- Krystallenia Alexandraki
- Division of Endocrinology, Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna Angelousi
- Division of Endocrinology, Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Georgios Boutzios
- Division of Endocrinology, Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | - Gregory Kaltsas
- Division of Endocrinology, Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
| |
Collapse
|
|
25
|
Abstract
Pathologists use immunohistochemistry is their day-to-day practices to assist in distinguishing site of origin of metastatic carcinomas. Here, the work-up is discussed neuroendocrine carcinomas, squamous cell carcinomas and adenocarcinomas with particular attention to tumor incident rates and predictive values of the best-performing immunohistochemical markers.
Collapse
Affiliation(s)
- Edward B Stelow
- Department of Pathology, University of Virginia, Charlottesville, VA, United States.
| | - Hadi Yaziji
- Vitro Molecular Laboratories, Miami, FL, United States
| |
Collapse
|
|
26
|
Wang HL, Kim CJ, Koo J, Zhou W, Choi EK, Arcega R, Chen ZE, Wang H, Zhang L, Lin F. Practical Immunohistochemistry in Neoplastic Pathology of the Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas. Arch Pathol Lab Med 2017; 141:1155-1180. [PMID: 28854347 DOI: 10.5858/arpa.2016-0489-ra] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
CONTEXT - Immunomarkers with diagnostic, therapeutic, or prognostic values have been increasingly used to maximize the benefits of clinical management of patients with neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. OBJECTIVES - To review the characteristics of immunomarkers that are commonly used in surgical pathology practice for neoplasms of the gastrointestinal tract, liver, biliary tract, and pancreas, and to summarize the clinical usefulness of immunomarkers that have been discovered in recent years in these fields. DATA SOURCES - Data sources include literature review, authors' research data, and personal practice experience. CONCLUSIONS - Immunohistochemistry is an indispensable tool for the accurate diagnosis of neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. Useful immunomarkers are available to help distinguish malignant neoplasms from benign conditions, determine organ origins, and subclassify neoplasms that are morphologically and biologically heterogeneous. Specific immunomarkers are also available to help guide patient treatment and assess disease aggressiveness, which are keys to the success of personalized medicine. Pathologists will continue to play a critical role in the discovery, validation, and application of new biomarkers, which will ultimately improve patient care.
Collapse
|
|
27
|
Immunohistochemical Characterization of the Origins of Metastatic Well-differentiated Neuroendocrine Tumors to the Liver. Am J Surg Pathol 2017; 41:915-922. [PMID: 28498280 DOI: 10.1097/pas.0000000000000876] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Metastatic neoplasms of unknown primary site pose a major challenge to patient management. As targeted therapies are now being tailored to neuroendocrine tumors (NETs) of different primary sites, identifying the origin of metastatic NETs has become increasingly important. Compared with more extensive efforts on metastatic adenocarcinomas of unknown primary, the literature on metastatic NETs (often to the liver) is relatively sparse and most studies are based on primary tumors. We sought to study metastatic well-differentiated NETs to the liver to identify markers that predict the site of origin. Eighty-five metastatic NETs to the liver were retrieved from the pathology archive. The primary sites were determined based on either pathologic review of the primary tumors (in most cases) or radiologic/clinical findings. Immunohistochemical labeling for TTF1, CDX2, ISL1, NKX2.2, and PDX1 was performed on either tissue microarrays or whole sections. The primary sites of the NETs in the study cohort included: pancreas (35%), small intestine (32%), rectum (8%), stomach (2%), bile duct (1%), lung (9%), and unknown primary (12%). We found predominant expression of TTF1 in lung carcinoid (63%), CDX2 in small intestinal (89%) and ISL1 in pancreatic NETs (77%), respectively. NKX2.2 was mainly expressed in NETs of the digestive organs. PDX1 was detected in a small percentage of pancreatic, small intestinal and the single bile duct NET. There was no statistically significant association between tumor grade (World Health Organization G1 vs. G2) and the expression of any of the above markers. The 3-marker panel (TTF1, CDX2, and ISL1) had sensitivities of 81%, 89%, and 63%, specificities of 100%, 94%, and 100%, positive predictive values of 100%, 89%, and 100%, and negative predictive values of 84%, 94%, and 96% in separating metastatic NETs into 3 major primary sites: pancreas/rectum, small intestine, and lung, respectively, with an overall accuracy of 82%. Furthermore, this panel predicted a primary site for 6 of the 10 NETs of unknown primary, which reduced the NETs of unknown primary from 12% to 5%. Thus, through immunohistochemical study of a large series of metastatic NETs to the liver, we have demonstrated the utility of a 3-marker panel for the identification of one or more potential primary sites of most metastatic NETs, which could provide practical guidance in patient management.
Collapse
|
|
28
|
Mohanty SK, Kim SA, DeLair DF, Bose S, Laury AR, Chopra S, Mertens RB, Dhall D. Comparison of metastatic neuroendocrine neoplasms to the breast and primary invasive mammary carcinomas with neuroendocrine differentiation. Mod Pathol 2016; 29:788-98. [PMID: 27125358 DOI: 10.1038/modpathol.2016.69] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 02/24/2016] [Accepted: 03/06/2016] [Indexed: 12/29/2022]
Abstract
Metastatic neuroendocrine neoplasms to the breast may show considerable morphologic overlap with primary mammary carcinomas, particularly those showing evidence of neuroendocrine differentiation, and may be misdiagnosed as such. Accurate distinction between these two entities is crucial for determination of appropriate clinical management. The histologic and immunohistochemical features of metastatic neuroendocrine neoplasms to the breast were studied and compared with the features of primary invasive mammary carcinomas with neuroendocrine differentiation, which served as controls. Of the metastatic neuroendocrine neoplasms, 15 were well-differentiated neuroendocrine tumors with carcinoid tumor-type morphology and 7 were poorly differentiated/high-grade neuroendocrine carcinomas with small-cell or large-cell neuroendocrine carcinoma morphology. The majority of the metastatic neoplasms originated in the lung and gastrointestinal tract. There were histologic similarities between metastatic neuroendocrine neoplasms and invasive mammary carcinomas with neuroendocrine differentiation, both of which exhibited neuroendocrine histologic features (nested and trabecular architecture, minimal tubular differentiation, and characteristic nuclear features). Only one case of the invasive mammary carcinomas with neuroendocrine differentiation was modified Bloom-Richardson grade 1 (largely due to minimal tubular differentiation on most such tumors), and the invasive mammary carcinomas with neuroendocrine differentiation were often associated with in situ carcinoma. Immunohistochemistry was helpful in distinguishing metastatic neuroendocrine neoplasms from invasive mammary carcinomas with neuroendocrine differentiation. Whereas the majority of invasive mammary carcinomas with neuroendocrine differentiation were positive for estrogen receptor and GATA3, metastatic neuroendocrine neoplasms were typically negative for estrogen receptor and GATA3, and metastatic well-differentiated neuroendocrine tumors often showed immunoreactivity for site-specific markers. Although the histologic and immunohistochemical features of a breast tumor may raise the suspicion of a metastatic neuroendocrine neoplasm, the pathologic findings should be interpreted in the context of the clinical history and imaging findings in order to establish an accurate diagnosis.
Collapse
Affiliation(s)
- Sambit K Mohanty
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Stacey A Kim
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Deborah F DeLair
- Department of Pathology and Laboratory Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Shikha Bose
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Anna R Laury
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Shefali Chopra
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Richard B Mertens
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Deepti Dhall
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| |
Collapse
|
|
29
|
Cykowski MD, Takei H, Baskin DS, Rivera AL, Powell SZ. Epithelial and organ-related marker expression in pituitary adenomas. Neuropathology 2016; 36:354-64. [PMID: 26991787 DOI: 10.1111/neup.12284] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Revised: 11/25/2015] [Accepted: 11/25/2015] [Indexed: 01/04/2023]
Abstract
The histologic expression of epithelial and organ-related immunohistochemical markers in primary sellar region tumors has received little attention to date. This lack of empirical data may lead to mistaken assumptions in the evaluation of sellar region neoplasms. To address this issue, the frequency and specificity of epithelial (cytokeratin 7(CK7), CK20) and organ-related differentiation markers (gross cystic disease fluid protein-15 (GCDFP-15), thyroid transcription factor-1 (TTF-1), Napsin A, paired box 8 (PAX-8), hepatocyte paraffin 1 (HepPar1) and estrogen receptor (ER)) were studied in 40 patients with adenomas comprising five hormonal sub-types. Non-parametric statistical procedures were used to examine associations between marker expression and tumor sub-type. CK7 and CK20 immunoreactivity were seen in 48% and 8% of tumors, respectively, although never in a diffuse pattern. CK20 expression was nearly exclusive to corticotrophs, whereas CK7 frequently highlighted cells with dendritic-type morphology. The specificity of organ-related differentiation markers was 100% (monoclonal Napsin A, GCDFP-15 and TTF-1), 97% (HepPar1 and PAX-8), 90% (polyclonal Napsin A) and 72% (ER); no tumors demonstrated significant co-expression of these organ-related markers with either CK7 or CK20. The first major conclusion of this study is that CK7 staining in adenoma is more frequent than has been previously than has been previously described. CK7 immunoreactive cells often displayed a dendritic-type morphology, including within large macroadenomas, which raises the question as to whether these represent tumor cells with folliculo-stellate cell-type differentiation, as these also have dendritic cell-type morphology and express CK7 in non-neoplastic glands. The second major conclusion, which confirms earlier findings, is that CK20 staining is a very infrequent immunohistochemical finding in adenomas that is virtually limited to corticotrophs and thus is helpful in diagnostic confirmation of that sub-type. The final conclusion is in regard to those features that separate adenomas from sellar region metastases: adenomas do not demonstrate significant expression of TTF-1, monoclonal Napsin A, PAX-8, HepPar1 or GCDFP-15, nor do they exhibit diffuse expression of CK7 and CK20.
Collapse
Affiliation(s)
- Matthew D Cykowski
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA
| | - Hidehiro Takei
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA.,Houston Methodist Neurologic Institute, Houston Methodist Hospital, Houston, Texas, USA
| | - David S Baskin
- Department of Neurosurgery and Kenneth R Peak Brain and Pituitary Tumor Center, Houston Methodist Hospital, Houston, Texas, USA.,Houston Methodist Neurologic Institute, Houston Methodist Hospital, Houston, Texas, USA
| | - Andreana L Rivera
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA.,Houston Methodist Neurologic Institute, Houston Methodist Hospital, Houston, Texas, USA
| | - Suzanne Z Powell
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas, USA.,Houston Methodist Neurologic Institute, Houston Methodist Hospital, Houston, Texas, USA
| |
Collapse
|
|
30
|
Zhao Y, Lu G, Ke X, Lu X, Wang X, Li H, Ren M, He S. miR-488 acts as a tumor suppressor gene in gastric cancer. Tumour Biol 2016. [PMID: 26738864 DOI: 10.1007/s13277-015-4645-y.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
MicroRNAs (miRNAs) are small, non-coding RNAs that modulate development, cell proliferation, and apoptosis. The deregulated expression of microRNAs is found in carcinogenesis including gastric cancer (GC). In this study, we showed that the expression levels of miR-488 were downregulated in GC tissues compared to in non-tumor tissues. In addition, the expression of miR-488 was also lower in GC cell lines in contrast with the gastric epithelial cell line (GES). In addition, the expression level of miR-488 was negatively correlated with the TNM stage in GC patients, and lower miR-488 expression was found in tumors with advanced TNM stage. The ectopic expression of miR-488 suppressed the GC cell proliferation, cell cycle, colony information, and migration. PAX6 was identified as a direct target gene of miR-488 in HGC-27. Moreover, we found that the expression level of PAX6 was upregulated in the GC tissues compared with the non-tumor tissues. The PAX6 expression level was correlated with the cancer TNM stage, and higher PAX6 expression was found in tumors with advanced TNM stage. Furthermore, there was an inverse correlation between PAX6 and miR-488 expression levels in GC tissues. Therefore, these studies demonstrated that miR-488 might act as a tumor suppressor miRNA in the development of GC.
Collapse
Affiliation(s)
- Yan Zhao
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Guifang Lu
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xiquan Ke
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xinlan Lu
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xin Wang
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Hongxia Li
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Mudan Ren
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Shuixiang He
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| |
Collapse
|
|
31
|
Zhao Y, Lu G, Ke X, Lu X, Wang X, Li H, Ren M, He S. miR-488 acts as a tumor suppressor gene in gastric cancer. Tumour Biol 2016; 37:8691-8. [PMID: 26738864 DOI: 10.1007/s13277-015-4645-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Accepted: 12/13/2015] [Indexed: 12/12/2022] Open
Affiliation(s)
- Yan Zhao
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Guifang Lu
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xiquan Ke
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xinlan Lu
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Xin Wang
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Hongxia Li
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Mudan Ren
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Shuixiang He
- Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| |
Collapse
|
|
32
|
Koo J, Dhall D. Problems with the diagnosis of metastatic neuroendocrine neoplasms. Which diagnostic criteria should we use to determine tumor origin and help guide therapy? Semin Diagn Pathol 2015; 32:456-68. [PMID: 26573790 DOI: 10.1053/j.semdp.2015.09.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Neuroendocrine neoplasms (NENs) can often present with metastatic disease before the primary tumor is discovered. Metastatic lesions are generally classified as well differentiated and poorly differentiated for prognostic and therapeutic purposes. In addition, for well-differentiated neuroendocrine tumors (WDNETs), pathologists are expected to determine the site of origin, if not already known, and grade the tumors. However, it is often difficult for pathologists to provide this information with certainty without knowing the site of tumor origin, as different criteria have been proposed by WHO for classification of gastrointestinal and pulmonary NENs. In this review, we will discuss the current classification and grading schema of NENs and their impact on clinical care, the differential diagnosis of NENs, the use of immunohistochemical stains that help identify tumor site of origin, and a proposed approach for the diagnosis and classification of metastatic NENs.
Collapse
Affiliation(s)
- Jamie Koo
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Deepti Dhall
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
| |
Collapse
|