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1
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Youssef MA, Gosnell J, Stevenson HL. Biliary Adenofibroma and the Threat of Malignant Transformation. Int J Surg Pathol 2025:10668969251331176. [PMID: 40221980 DOI: 10.1177/10668969251331176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/15/2025]
Abstract
Biliary adenofibroma (BAF) is a rare hepatic tumor with a high risk for malignant transformation. Since BAF shares many characteristics with other hepatic lesions, diagnosis usually requires meticulous evaluation. The literature review revealed 29 reported patients of BAF, with malignant transformation occurring in 45% of patients. High Ki-67 (>40%) and mutated/overexpressed p53 staining were associated with malignancy, but some patients also had malignant features with low Ki-67 (≤10%) and wild-type p53. We report an elderly female patient who was initially diagnosed with benign liver hemangioma based on an abdominal ultrasound. The mass enlarged by 4 cm raising concerns about potential complications, including hemorrhage, which led to hepatic segmental resection. Histopathological examination revealed predominantly BAF features with focal areas that showed malignant cholangiocarcinoma characteristics.
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Affiliation(s)
- Mohamed A Youssef
- Division of Nephrology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Joseph Gosnell
- Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA
| | - Heather L Stevenson
- John Sealy School of Medicine, Department of Pathology, The University of Texas Medical Branch, Galveston, TX, USA
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2
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Hashemi M, Nazdari N, Gholamiyan G, Paskeh MDA, Jafari AM, Nemati F, Khodaei E, Abyari G, Behdadfar N, Raei B, Raesi R, Nabavi N, Hu P, Rashidi M, Taheriazam A, Entezari M. EZH2 as a potential therapeutic target for gastrointestinal cancers. Pathol Res Pract 2024; 253:154988. [PMID: 38118215 DOI: 10.1016/j.prp.2023.154988] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 11/18/2023] [Accepted: 11/27/2023] [Indexed: 12/22/2023]
Abstract
Gastrointestinal (GI) cancers continue to be a major cause of mortality and morbidity globally. Understanding the molecular pathways associated with cancer progression and severity is essential for creating effective cancer treatments. In cancer research, there is a notable emphasis on Enhancer of zeste homolog 2 (EZH2), a key player in gene expression influenced by its irregular expression and capacity to attach to promoters and alter methylation status. This review explores the impact of EZH2 signaling on various GI cancers, such as colorectal, gastric, pancreatic, hepatocellular, esophageal, and cholangiocarcinoma. The primary function of EZH2 signaling is to facilitate the accelerated progression of cancer cells. Additionally, EZH2 has the capacity to modulate the reaction of GI cancers to chemotherapy and radiotherapy. Numerous pathways, including long non-coding RNAs and microRNAs, serve as upstream regulators of EZH2 in these types of cancer. EZH2's enzymatic activity enables it to attach to target gene promoters, resulting in methylation that modifies their expression. EZH2 could be considered as an independent prognostic factor, with increased expression correlating with a worse disease prognosis. Additionally, a range of gene therapies including small interfering RNA, and anti-tumor agents are being explored to target EZH2 for cancer treatment. This comprehensive review underscores the current insights into EZH2 signaling in gastrointestinal cancers and examines the prospect of therapies targeting EZH2 to enhance patient outcomes.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Naghmeh Nazdari
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ghazaleh Gholamiyan
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mahshid Deldar Abad Paskeh
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Ali Moghadas Jafari
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fateme Nemati
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Elaheh Khodaei
- Department of Dermatology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ghazal Abyari
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nazanin Behdadfar
- Young Researchers and Elite Club, Buinzahra Branch, Islamic Azad University, Buinzahra, Iran
| | - Behnaz Raei
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Rasoul Raesi
- Department of Health Services Management, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical-Surgical Nursing, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Noushin Nabavi
- Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, V6H3Z6 Vancouver, BC, Canada
| | - Peng Hu
- Department of Emergency, Shanghai Tenth People's Hospital, Tongji University, Shanghai 200072, China
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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3
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Caligiuri A, Becatti M, Porro N, Borghi S, Marra F, Pastore M, Taddei N, Fiorillo C, Gentilini A. Oxidative Stress and Redox-Dependent Pathways in Cholangiocarcinoma. Antioxidants (Basel) 2023; 13:28. [PMID: 38247453 PMCID: PMC10812651 DOI: 10.3390/antiox13010028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/23/2024] Open
Abstract
Cholangiocarcinoma (CCA) is a primary liver tumor that accounts for 2% of all cancer-related deaths worldwide yearly. It can arise from cholangiocytes of biliary tracts, peribiliary glands, and possibly from progenitor cells or even hepatocytes. CCA is characterized by high chemoresistance, aggressiveness, and poor prognosis. Potentially curative surgical therapy is restricted to a small number of patients with early-stage disease (up to 35%). Accumulating evidence indicates that CCA is an oxidative stress-driven carcinoma resulting from chronic inflammation. Oxidative stress, due to enhanced reactive oxygen species (ROS) production and/or decreased antioxidants, has been recently suggested as a key factor in cholangiocyte oncogenesis through gene expression alterations and molecular damage. However, due to different experimental models and conditions, contradictory results regarding oxidative stress in cholangiocarcinoma have been reported. The role of ROS and antioxidants in cancer is controversial due to their context-dependent ability to stimulate tumorigenesis and support cancer cell proliferation or promote cell death. On these bases, the present narrative review is focused on illustrating the role of oxidative stress in cholangiocarcinoma and the main ROS-driven intracellular pathways. Heterogeneous data about antioxidant effects on cancer development are also discussed.
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Affiliation(s)
- Alessandra Caligiuri
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
| | - Matteo Becatti
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Nunzia Porro
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Serena Borghi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
| | - Mirella Pastore
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
| | - Niccolò Taddei
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Claudia Fiorillo
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (M.B.); (N.P.); (S.B.); (N.T.)
| | - Alessandra Gentilini
- Department of Experimental and Clinical Medicine, University of Florence, 50139 Florence, Italy; (A.C.); (F.M.); (M.P.)
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Makk E, Bohonyi N, Oszter A, Éles K, Tornóczky T, Tóth A, Kálmán E, Kovács K. Comparative analysis of EZH2, p16 and p53 expression in uterine carcinosarcomas. Pathol Oncol Res 2023; 29:1611547. [PMID: 38146588 PMCID: PMC10749357 DOI: 10.3389/pore.2023.1611547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 11/28/2023] [Indexed: 12/27/2023]
Abstract
Introduction: The role of p16 and p53 immunohistochemistry in the diagnosis of rare and aggressive uterine carcinosarcoma (UCS) has been well established. However, enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and a member of the polycomb group family is a relatively new biomarker, with limited published data on its significance in this tumor type. The goal of this study was to examine EZH2 expression in UCS and its components, in correlation with morphological features, and p16 and p53 staining patterns. Methods: Twenty-eight UCSs were included in the study. EZH2, p16 and p53 immunoreactivity were assessed independently by two pathologists in both tumor components (epithelial and mesenchymal). EZH2 and p16 immunostains were scored semiquantitatively: based on the percentage and intensity of tumor cell staining a binary staining index ("high- or low-expressing") was calculated. The p53 staining pattern was evaluated as wild-type or aberrant (diffuse nuclear, null, or cytoplasmic expression). Statistical tests were used to evaluate the correlation between staining patterns for all three markers and the different tumor components and histotypes. Results: High EZH2 and p16 expression and aberrant p53 patterns were present in 89.3% 78.6% and 85.7% of the epithelial component and in 78.6%, 62.5% and 82.1% of the mesenchymal component, respectively. Differences among these expression rates were not found to be significant (p > 0.05). Regarding the epithelial component, aberrant p53 pattern was found to be significantly (p = 0.0474) more frequent in the serous (100%) than in endometrioid (66.6%) histotypes. Within the mesenchymal component, p53 null expression pattern occurred significantly (p = 0.0257) more frequently in heterologous sarcoma components (71.4%) compared to the homologous histotype (18.8%). Conclusion: In conclusion, EZH2, p16 and p53 seem to play a universal role in the pathogenesis of UCS; however, a distinctive pattern of p53 expression appears to exist between the serous and endometrioid carcinoma components and also between the homologous and heterologous sarcoma components.
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Affiliation(s)
- Evelin Makk
- Department of Pathology, University of Pécs Medical School, Pécs, Hungary
| | - Noémi Bohonyi
- Department of Obstretrics and Gynaecology, University of Pécs Medical School, Pécs, Hungary
| | - Angéla Oszter
- Department of Pathology, University of Pécs Medical School, Pécs, Hungary
| | - Klára Éles
- Department of Pathology, University of Pécs Medical School, Pécs, Hungary
| | - Tamás Tornóczky
- Department of Pathology, University of Pécs Medical School, Pécs, Hungary
| | - Arnold Tóth
- Department of Medical Imaging, University of Pécs Medical School, Pécs, Hungary
| | - Endre Kálmán
- Department of Pathology, University of Pécs Medical School, Pécs, Hungary
| | - Krisztina Kovács
- Department of Pathology, University of Pécs Medical School, Pécs, Hungary
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Zhang SL, Wang HL. Ancillary tests for hepatobiliary neoplasms: what we know and what we need to know. Hum Pathol 2023; 141:183-200. [PMID: 36775105 DOI: 10.1016/j.humpath.2023.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/29/2023] [Accepted: 02/04/2023] [Indexed: 02/12/2023]
Abstract
Ancillary tests are commonly used in the surgical pathology setting for diagnosing challenging neoplastic diseases of the liver and biliary tract, while histology and clinical correlation remain to be critically important. With continuous discoveries, more and more useful ancillary tests have become available, which can help distinguish between malignant and benign hepatocellular neoplasms, malignant and benign biliary tract entities, and intrahepatic and metastatic carcinomas. This review will focus on existing and emerging biomarkers (such as glutamine synthetase, organic anion transporting polypeptide 1B3, insulin-like growth factor-II mRNA binding protein-3, S100P, SMAD4, enhancer of zeste homolog 2, albumin, hepatocyte nuclear factor-1β, etc.) that can be used for the diagnosis, classification and prognostication of hepatobiliary neoplasms.
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Affiliation(s)
- Sarah L Zhang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine and Ronald Reagan Medical Center, University of California at Los Angeles, Los Angeles, CA, 90095, USA
| | - Hanlin L Wang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine and Ronald Reagan Medical Center, University of California at Los Angeles, Los Angeles, CA, 90095, USA.
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6
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El Jabbour T, Molnar A, Lagana SM. Challenges in Diagnosing and Reporting Cholangiocarcinoma. Surg Pathol Clin 2023; 16:599-608. [PMID: 37536891 DOI: 10.1016/j.path.2023.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/05/2023]
Abstract
Intrahepatic cholangiocarcinoma is a challenge to the practicing surgical pathologist for several reasons. It is rare in many parts of the world, and thus practical exposure may be limited. Related to the fact of its rarity is the fact that more common tumors which frequently metastasize to the liver can be morphologically indistinguishable (eg, pancreatic ductal adenocarcinoma). Immunohistochemical testing is generally non-contributory in this context. Other difficulties arise from the protean morphologic manifestations of cholangiocarcinoma (ie, small duct vs. large duct) and the existence of combined cholangiocarcinoma and hepatocellular carcinoma. These, and other issues of concern to the practicing diagnostic pathologist are discussed herein.
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Affiliation(s)
| | - Attila Molnar
- Mount Sinai Morningside and Mount Sinai West, Department of Pathology, 1000 Tenth Avenue, First floor, Room G183, New York, NY 10019, USA
| | - Stephen M Lagana
- New York-Presbyterian /Columbia University, Irving Medical Center, 622 W168th St, Vc14-209, New York, NY 10032, USA.
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Hirayama AB, Mello ESD, Alves VAF. INTRAHEPATIC BILIARY PROLIFERATIONS: HISTOPATHOLOGY AND POTENTIAL IMMUNOHISTOCHEMICAL MARKERS. ARQUIVOS DE GASTROENTEROLOGIA 2023; 60:393-403. [PMID: 37792770 DOI: 10.1590/s0004-2803.23032023-107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 07/27/2023] [Indexed: 10/06/2023]
Abstract
•Intrahepatic biliary proliferations represent a spectrum varying from reactive to malignant entities. •Clinical and imaging patterns may be similar, requiring histopathological and immunohistochemistry for precise diagnosis. Intrahepatic biliary proliferations represent a spectrum from reactive (ductular reaction, some with atypical architecture), hamartomatous (von Meyenburg complex), benign (bile duct adenoma) and precursor/borderline entities (biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct) to fully malignant (cholangiocarcinoma) neoplasms. Clinical pictures and even imaging patterns may be similar, requiring refined studies aiming at histopathological and immunohistochemistry for more precise diagnosis, essential for correct patient management. This article discusses updated concepts and definitions of most relevant entities aiming more specifically at the differential diagnosis in practice, focusing on morphology and immunohistochemistry, with a discussion of potential markers to help distinguishing between benign and malignant lesions.
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Affiliation(s)
- André Bubna Hirayama
- Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
- CICAP - Anatomia Patológica, Hospital Alemão Oswaldo Cruz, São Paulo, SP, Brasil
| | - Evandro Sobroza de Mello
- Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
- CICAP - Anatomia Patológica, Hospital Alemão Oswaldo Cruz, São Paulo, SP, Brasil
| | - Venâncio Avancini Ferreira Alves
- Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
- CICAP - Anatomia Patológica, Hospital Alemão Oswaldo Cruz, São Paulo, SP, Brasil
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8
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Simoncini G, Orsatti A, Malvi D, Tardio ML, Maloberti T, de Biase D, D'Errico A, Vasuri F. NRAS-mutated oncocytic benign liver lesion in an organ donor: Pitfalls and troubles in frozen section diagnosis and risk assessment. Pathol Res Pract 2023; 246:154531. [PMID: 37182314 DOI: 10.1016/j.prp.2023.154531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/08/2023] [Accepted: 05/09/2023] [Indexed: 05/16/2023]
Abstract
BACKGROUND In the transplant setting, the definition of the risk of neoplastic transmission from donor to recipient often requires intraoperative pathological evaluation on frozen sections. Although most lesions can be easily classified into acceptable or unacceptable risk according to the Italian National Guidelines, there are cases in which unusual histologic features cannot be further investigated because of the lack of ancillary techniques on frozen sections. CASE PRESENTATION Here we present a case of a liver lesion in a 51-year-old male donor, subjected to histopathological on-call examination. The frozen sections showed a well-demarcated lesion consisting of epithelioid cells disposed in laminar structures and intermingled with a dense lymphocytic population: this led to organ discard with interruption of the donation process. The definitive histological analysis required an extensive immunohistochemical (IHC) investigation: the final diagnosis was "bile duct adenoma with oncocytic features", eventually confirmed by a strongly positive anti-mitochondrial IHC. Finally, an NGS panel analysis was performed, which revealed NRAS mutation. DISCUSSION To the best of our knowledge, this is the first case of oncocytic bile duct adenoma confirmed by anti-mitochondrial IHC and with NRAS mutation. The most challenging aspect of this case was represented by the transplant setting. In fact, the oncocytic features and the dense lymphocytic infiltrate represented concomitant unusual histological features that led to the halt of the organ donation procedures.
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Affiliation(s)
- Giulia Simoncini
- Pathology Unit, IRCCS Azienda-Ospedaliero Universitaria di Bologna, Italy
| | - Agnese Orsatti
- Pathology Unit, IRCCS Azienda-Ospedaliero Universitaria di Bologna, Italy
| | - Deborah Malvi
- Pathology Unit, IRCCS Azienda-Ospedaliero Universitaria di Bologna, Italy.
| | - Maria L Tardio
- Pathology Unit, IRCCS Azienda-Ospedaliero Universitaria di Bologna, Italy
| | - Thais Maloberti
- Department of Medicine, University of Bologna, Bologna, Italy
| | - Dario de Biase
- Department of Pharmacy and biotechnology (FaBiT), University of Bologna, Bologna, Italy
| | | | - Francesco Vasuri
- Pathology Unit, IRCCS Azienda-Ospedaliero Universitaria di Bologna, Italy
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Motoko S, Yasunori S, Yasuni N. Bile duct adenoma and small-sized small duct type intrahepatic cholangiocarcinoma show distinct differences in genetic alterations, expression of IMP3 and EZH2 and stromal and inflammatory components. Histopathology 2023. [PMID: 37140546 DOI: 10.1111/his.14932] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/11/2023] [Accepted: 04/13/2023] [Indexed: 05/05/2023]
Abstract
AIMS Given that bile duct adenoma was significantly more prevalent in the liver with small duct type intrahepatic cholangiocarcinoma (small duct iCCA), compared to other primary liver carcinomas, we examined the possibility of bile duct adenoma as a precursor of small duct iCCA by analysing genetic alterations and other features in bile duct adenomas. METHODS AND RESULTS Subjects included 33 bile duct adenomas and 17 small-sized (up to 2 cm in diameter) small duct iCCAs. Genetic alterations were examined by direct sequencing for hot-spot regions and immunohistochemical staining. The expression of p16INK4a , EZH2 and IMP3 and stromal and inflammatory components were also examined. Genetic alterations examined including BRAF were not detected in bile duct adenomas, whereas genetic alterations of p53 (47%), ARID1A (41%), PBRM1 (12%), MTAP (12%), IDH1 (6%), KRAS (6%) and TERT promoter (6%) were detected in 16 small-sized small duct iCCA (94%) (P < 0.01). The expression of IMP3 and EZH2 was not detected in bile duct adenomas, whereas it was detected in most small duct iCCA (94%) (P < 0.01). Immature stroma and neutrophilic infiltration were significantly more prevalent in small duct iCCA, compared to bile duct adenoma (P < 0.01). CONCLUSION Bile duct adenomas and small-sized small duct iCCAs show distinct differences in genetic alterations, expression of IMP3 and EZH2 and stromal and inflammatory components. There was no evidence suggesting that bile duct adenoma is a precursor of small duct iCCA. Immunohistochemical staining for IMP3, EZH2, p53, ARID1A and MTAP may be useful for differential diagnosis between bile duct adenomas and small duct iCCAs.
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Affiliation(s)
- Sasaki Motoko
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Sato Yasunori
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Nakanuma Yasuni
- Division of Pathology, Fukui Saiseikai Hospital, Fukui, Japan
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10
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Zhu Y, Zhang L, Song X, Zhang Q, Wang T, Xiao H, Yu L. Pharmacological inhibition of EZH2 by ZLD1039 suppresses tumor growth and pulmonary metastasis in melanoma cells in vitro and in vivo. Biochem Pharmacol 2023; 210:115493. [PMID: 36898415 DOI: 10.1016/j.bcp.2023.115493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/31/2023] [Accepted: 03/02/2023] [Indexed: 03/12/2023]
Abstract
The incidence and mortality rate of malignant melanoma are increasing worldwide. Metastasis reduces the efficacy of current melanoma therapies and leads to poor prognosis for patients. EZH2 is a methyltransferase that promotes the proliferation, metastasis, and drug resistance of tumor cells by regulating transcriptional activity. EZH2 inhibitors could be effective in melanoma therapies. Herein, we aimed to investigate whether the pharmacological inhibition of EZH2 by ZLD1039, a potent and selective S-adenosyl-l-methionine-EZH2 inhibitor, suppresses tumor growth and pulmonary metastasis in melanoma cells. Results showed that ZLD1039 selectively reduced H3K27 methylation in melanoma cells by inhibiting EZH2 methyltransferase activity. Additionally, ZLD1039 exerted excellent antiproliferative effects on melanoma cells in 2D and 3D culture systems. Administration of ZLD1039 (100 mg/kg) by oral gavage caused antitumor effects in the A375 subcutaneous xenograft mouse model. RNA sequencing and GSEA revealed that the ZLD1039-treated tumors exhibited changes in the gene sets enriched from the "Cell Cycle" and "Oxidative Phosphorylation", whereas the "ECM receptor interaction" gene set had a negative enrichment score. Mechanistically, ZLD1039 induced G0/G1 phase arrest by upregulating p16 and p27 and inhibiting the functions of the cyclin D1/CDK6 and cyclin E/CDK2 complexes. Moreover, ZLD1039 induced apoptosis in melanoma cells via the mitochondrial reactive oxygen species apoptotic pathway, consistent with the changes in transcriptional signatures. ZLD1039 also exhibited excellent antimetastatic effects on melanoma cells in vitro and in vivo. Our data highlight that ZLD1039 may be effective against melanoma growth and pulmonary metastasis and thus could serve as a therapeutic agent for melanoma.
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Affiliation(s)
- Yongxia Zhu
- Department of Clinical Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu 610041, China
| | - Lidan Zhang
- Laboratory of Anesthesia & Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuejiao Song
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu 610041, China
| | - Qiangsheng Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu 610041, China
| | - Ting Wang
- Department of Clinical Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Hongtao Xiao
- Department of Clinical Pharmacy, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu 610041, China
| | - Luoting Yu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu 610041, China.
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11
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Kim SR, Kim SK, Fujii T, Kobayashi H, Okuda T, Hayakumo T, Nakai A, Fujii Y, Suzuki R, Sasase N, Otani A, Koma YI, Sasaki M, Kumabe T, Nakashima O. Drug-induced sarcoidosis-like reaction three months after BNT162b2 mRNA COVID-19 vaccination: A case report and review of literature. World J Clin Cases 2023; 11:177-186. [PMID: 36687201 PMCID: PMC9846985 DOI: 10.12998/wjcc.v11.i1.177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/21/2022] [Accepted: 12/19/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND A 70-year-old man with hepatitis C virus-related recurrent hepatocellular carcinoma was admitted for further diagnosis of a 1 cm iso-hyperechoic nodule in segment (S) 5. CASE SUMMARY Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) revealed the nodule in S5 with a defect at the hepatobiliary phase, hyperintensity on diffusion weighted imaging (DWI) and hypointensity on apparent diffusion coefficient (ADC) map. Contrast-enhanced computed tomography revealed hypervascularity at the early phase, and delayed contrast-enhancement was observed at the late phase. Contrast-enhanced ultrasound (US) revealed incomplete defect at the late vascular phase. Inflammatory liver tumor, lymphoproliferative disease, intrahepatic cholangiocarcinoma (small duct type) and bile duct adenoma were suspected through the imaging studies. US guided biopsy, however, showed a noncaseating hepatic sarcoid-like epithelioid granuloma (HSEG), and histopathological analysis disclosed spindle shaped epithelioid cells harboring Langhans-type multinucleated giant cells. One month after admission, EOB-MRI signaled the disappearance of the defect at the hepatobiliary phase, of hyperintensity on DWI, of hypointensity on ADC map, and no stain at the early phase. CONCLUSION That the patient had received BNT162b2 messenger RNA (mRNA) coronavirus disease 2019 vaccination 3 mo before the occurrence of HSEG, and that its disappearance was confirmed 4 mo after mRNA vaccination suggested that the drug-induced sarcoidosis-like reaction (DISR) might be induced by the mRNA vaccination. Fortunately, rechallenge of drug-induced DISR with the third mRNA vaccination was not confirmed.
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Affiliation(s)
- Soo Ryang Kim
- Department of Gastroenterology, Kobe Asahi Hospital, Kobe 6530801, Hyogo, Japan
| | - Soo Ki Kim
- Department of Gastroenterology, Kobe Asahi Hospital, Kobe 6530801, Hyogo, Japan
| | - Takako Fujii
- Department of Gastroenterology, Kobe Asahi Hospital, Kobe 6530801, Hyogo, Japan
| | - Hisato Kobayashi
- Department of Radiology, Kobe Asahi Hospital, Kobe 6530801, Hyogo, Japan
| | - Toyokazu Okuda
- Department of Gastroenterology, Kobe Asahi Hospital, Kobe 6530801, Hyogo, Japan
| | - Takanobu Hayakumo
- Department of Gastroenterology, Kobe Asahi Hospital, Kobe 6530801, Hyogo, Japan
| | - Atsushi Nakai
- Department of Gastroenterology, Kobe Asahi Hospital, Kobe 6530801, Hyogo, Japan
| | - Yumi Fujii
- Department of Gastroenterology, Kobe Asahi Hospital, Kobe 6530801, Hyogo, Japan
| | - Ryuji Suzuki
- Department of Clinical Laboratory, Kobe Asahi Hospital, Kobe 6530801, Hyogo, Japan
| | - Noriko Sasase
- Department of Pharmacy, Kobe Asahi Hospital, Kobe 6530801, Hyogo, Japan
| | - Aya Otani
- Department of Pharmacy, Kobe Asahi Hospital, Kobe 6530801, Hyogo, Japan
| | - Yu-ichiro Koma
- Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 6530801, Hyogo, Japan
| | - Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa 9208640, Ishikawa, Japan
| | - Tsutomu Kumabe
- Department of Gastroenterology, Kumabe Clinic, Kumamoto 8611331, Kumamoto, Japan
| | - Osamu Nakashima
- Laboratory Services Center, St. Mary's Hospital, Kurume 830-8543, Fukuoka, Japan
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12
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Sarcognato S, Sacchi D, Fassan M, Fabris L, Cadamuro M, Zanus G, Cataldo I, Covelli C, Capelli P, Furlanetto A, Guido M. Benign biliary neoplasms and biliary tumor precursors. Pathologica 2021; 113:147-157. [PMID: 34294933 PMCID: PMC8299320 DOI: 10.32074/1591-951x-251] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 01/04/2021] [Indexed: 12/21/2022] Open
Abstract
Benign biliary tumor are common lesions that are often an incidental finding in subjects who undergo medical imaging tests for other conditions. Most are true neoplasms while few result from reactive or malformative proliferation. Benign tumors have no clinical consequences, although the premalignant nature or potential for malignant transformation is of concern in some cases. The main practical problem for pathologists is the need to differentiate them from malignant biliary tumours, which is not always straightforward. Premalignant lesions of the bile duct have been described, although their incidence has been poorly characterized. These lesions include biliary mucinous cystic neoplasms, intraductal papillary neoplasms of the bile duct, and biliary intraepithelial neoplasia. In this article, histopathology of benign biliary tumors and biliary tumor precursors is discussed, with a focus on the main diagnostic criteria.
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Affiliation(s)
| | - Diana Sacchi
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Matteo Fassan
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Luca Fabris
- Department of Molecular Medicine - DMM, University of Padova, Padova, Italy
| | | | - Giacomo Zanus
- 4 Surgery Unit, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
- Department of Surgery, Oncology and Gastroenterology - DISCOG, University of Padova, Padova, Italy
| | - Ivana Cataldo
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Claudia Covelli
- Pathology Unit, Fondazione IRCCS “Casa Sollievo della Sofferenza”, San GiovanniRotondo, Italy
| | - Paola Capelli
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | | | - Maria Guido
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
- Department of Medicine - DIMED, University of Padova, Padova, Italy
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13
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Sarcognato S, Sacchi D, Fassan M, Fabris L, Cadamuro M, Zanus G, Cataldo I, Capelli P, Baciorri F, Cacciatore M, Guido M. Cholangiocarcinoma. Pathologica 2021; 113:158-169. [PMID: 34294934 PMCID: PMC8299326 DOI: 10.32074/1591-951x-252] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 01/04/2021] [Indexed: 12/27/2022] Open
Abstract
Liver cancer represents the third leading cause of cancer-related death worldwide. Cholangiocarcinoma (CCA) is the second most common type of liver cancer after hepatocellular carcinoma, accounting for 10-15% of all primary liver malignancies. Both the incidence and mortality of CCA have been steadily increasing during the last decade. Moreover, most CCAs are diagnosed at an advanced stage, when therapeutic options are very limited. CCA may arise from any tract of the biliary system and it is classified into intrahepatic, perihilar, and distal CCA, according to the anatomical site of origin. This topographical classification also reflects distinct genetic and histological features, risk factors, and clinical outcomes. This review focuses on histopathology of CCA, its differential diagnoses, and its diagnostic pitfalls.
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Affiliation(s)
| | - Diana Sacchi
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Matteo Fassan
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Luca Fabris
- Department of Molecular Medicine - DMM, University of Padova, Padova, Italy
| | | | - Giacomo Zanus
- 4Surgery Unit, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
- Department of Surgery, Oncology and Gastroenterology - DISCOG, University of Padova, Padova, Italy
| | - Ivana Cataldo
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Paola Capelli
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | | | | | - Maria Guido
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
- Department of Medicine - DIMED, University of Padova, Padova, Italy
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14
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Gonzalez RS, Raza A, Propst R, Adeyi O, Bateman J, Sopha SC, Shaw J, Auerbach A. Recent Advances in Digestive Tract Tumors: Updates From the 5th Edition of the World Health Organization "Blue Book". Arch Pathol Lab Med 2021; 145:607-626. [PMID: 32886739 DOI: 10.5858/arpa.2020-0047-ra] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2020] [Indexed: 11/06/2022]
Abstract
CONTEXT.— The World Health Organization Classification of Tumours: Digestive System Tumors, 5th edition, was published in 2019 and shows several impactful changes as compared with the 4th edition published in 2010. Changes include a revised nomenclature of serrated lesions and revamping the classification of neuroendocrine neoplasms. Appendiceal goblet cell adenocarcinoma is heavily revised, and intrahepatic cholangiocarcinoma is split into 2 subtypes. New subtypes of colorectal carcinoma and hepatocellular carcinoma are described. Precursor lesions are emphasized with their own entries, and both dysplastic and invasive lesions are generally recommended to be graded using a 2-tier system. Hematolymphoid tumors, mesenchymal tumors, and genetic tumor syndromes each have their own sections in the 5th edition. New hematolymphoid lesions include monomorphic epitheliotropic intestinal T-cell lymphoma; duodenal-type follicular lymphoma; intestinal T-cell lymphoma, not otherwise specified; and indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. This paper will provide an in-depth look at the changes in the 5th edition as compared with the 4th edition. OBJECTIVE.— To provide a comprehensive, in-depth update on the World Health Organization classification of digestive tumors, including changes to nomenclature, updated diagnostic criteria, and newly described entities. DATA SOURCES.— The 5th edition of the World Health Organization Classification of Tumours: Digestive System Tumours, as well as the 4th edition. CONCLUSIONS.— The World Health Organization has made many key changes in its newest update on tumors of the digestive system. Pathologists should be aware of these changes and incorporate them into their practice as able or necessary.
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Affiliation(s)
- Raul S Gonzalez
- The Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (Gonzalez)
| | - Anwar Raza
- The Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, California (Raza, Propst)
| | - Robert Propst
- The Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, California (Raza, Propst)
| | - Oyedele Adeyi
- The Department of Pathology, University of Minnesota, Minneapolis (Adeyi, Bateman)
| | - Justin Bateman
- The Department of Pathology, University of Minnesota, Minneapolis (Adeyi, Bateman)
| | - Sabrina C Sopha
- The Department of Pathology, University of Maryland Baltimore Washington Medical Center, Glen Burnie (Sopha)
| | - Janet Shaw
- The Joint Pathology Center, Silver Spring, Maryland (Shaw, Auerbach)
| | - Aaron Auerbach
- The Joint Pathology Center, Silver Spring, Maryland (Shaw, Auerbach)
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15
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Thongchot S, Vidoni C, Ferraresi A, Loilome W, Khuntikeo N, Sangkhamanon S, Titapun A, Isidoro C, Namwat N. Cancer-Associated Fibroblast-Derived IL-6 Determines Unfavorable Prognosis in Cholangiocarcinoma by Affecting Autophagy-Associated Chemoresponse. Cancers (Basel) 2021; 13:cancers13092134. [PMID: 33925189 PMCID: PMC8124468 DOI: 10.3390/cancers13092134] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/22/2021] [Accepted: 04/26/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary We aimed to validate with clinical and molecular data the hypothesis that CAF infiltration and release of IL-6 predict poor prognosis in CCA patients following dysregulation of autophagy in cancer cells. Stromal IL-6 and cancer-cell-associated autophagy proteins were assayed by Tissue MicroArray immunohistochemistry and their expression correlated with overall survival (OS) in a cohort of 70 CCA patients. We found that patients bearing a CCA with low stromal IL-6 and active autophagy flux in the cancer cells have the best prognosis and this correlates with a more effective response to post-operative chemotherapy. A similar trend was observed in CCA patients from the TCGA database. In vitro experiments with primary CAFs isolated from human CCA showed that IL-6 impairs the autophagy-associated apoptotic response to 5-FU in human CCA cells. Stromal IL-6 inhibition of autophagy in cancer cells was confirmed in an animal model of CCA. Our data support a therapeutic strategy that includes drugs limiting the stromal inflammation and enhancing autophagy to improve the survival of CCA patients. Abstract Background: Interleukin-6 (IL-6) released by cancer-associated fibroblasts (CAFs) has been shown to associate with the malignant behavior of cholangiocarcinoma (CCA). Here, we aimed to validate with clinical and molecular data the hypothesis that CAF infiltration and release of IL-6 predict poor prognosis in CCA patients following dysregulation of autophagy in cancer cells. Methods: Stromal IL-6 and cancer-cell-associated autophagy proteins LC3 and p62 were assayed by Tissue MicroArray immunohistochemistry and their expression correlated with overall survival (OS) in a cohort of 70 CCA patients. The 5-FU cytotoxicity and autophagy were determined in CCA cells cultured with CAF-conditioned medium. Results: We show that patients bearing a CCA with low production of stromal IL-6 and active autophagy flux in the cancer cells have the best prognosis and this correlates with a more effective response to post-operative chemotherapy. A similar trend was observed in CCA patients from the TCGA database. In vitro genetic manipulation of IL-6 production by primary CAFs isolated from human CCA showed that IL-6 impairs the autophagy-associated apoptotic response to 5-FU in human CCA cells. Stromal IL-6 inhibition of autophagy in cancer cells was confirmed in an animal model of CCA. Conclusion: Our data support a therapeutic strategy that includes autophagy-enhancing drugs along with adjuvants limiting the stromal inflammation (i.e., the secretion of IL-6) to improve the survival of CCA patients.
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Affiliation(s)
- Suyanee Thongchot
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (S.T.); (W.L.)
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, Italy; (C.V.); (A.F.)
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Chiara Vidoni
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, Italy; (C.V.); (A.F.)
| | - Alessandra Ferraresi
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, Italy; (C.V.); (A.F.)
| | - Watcharin Loilome
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (S.T.); (W.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (N.K.); (S.S.); (A.T.)
| | - Narong Khuntikeo
- Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (N.K.); (S.S.); (A.T.)
- Department of Surgery, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand
| | - Sakkarn Sangkhamanon
- Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (N.K.); (S.S.); (A.T.)
- Department of Pathology, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand
| | - Attapol Titapun
- Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (N.K.); (S.S.); (A.T.)
- Department of Surgery, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand
| | - Ciro Isidoro
- Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale “A. Avogadro”, Via Solaroli 17, 28100 Novara, Italy; (C.V.); (A.F.)
- Correspondence: (C.I.); (N.N.); Tel.: +39-(0321)-660507 (C.I.); +66-6-3635-2491 (N.N.)
| | - Nisana Namwat
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (S.T.); (W.L.)
- Cholangiocarcinoma Research Institute, Khon Kaen University, 123 Mitraparp Highway, Khon Kaen 40002, Thailand; (N.K.); (S.S.); (A.T.)
- Correspondence: (C.I.); (N.N.); Tel.: +39-(0321)-660507 (C.I.); +66-6-3635-2491 (N.N.)
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16
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Tone K, Ohno S, Honda M, Notsu A, Sasaki K, Sugino T. Application of enhancer of zeste homolog 2 immunocytochemistry to bile cytology. Cancer Cytopathol 2021; 129:612-621. [PMID: 33788988 DOI: 10.1002/cncy.22426] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 02/22/2021] [Accepted: 02/24/2021] [Indexed: 01/26/2023]
Abstract
BACKGROUND Bile cytology has low diagnostic sensitivity and requires ancillary techniques. This study assessed the utility of enhancer of zeste homolog 2 (EZH2) immunocytochemistry (ICC) in bile cytology. METHODS A total of 141 bile cytology specimens from 141 patients were evaluated retrospectively. Papanicolaou-stained slides were immunostained with an antibody to EZH2. After calculation of the EZH2 labeling index (LI), the cutoff value was determined via receiver operating characteristic curve analysis. Cytological performance with and without EZH2 ICC was evaluated with reference to the final diagnosis. RESULTS The area under the curve for the EZH2 LI was 0.955, and the cutoff value for identifying benign bile samples versus malignant ones was 24.0%. The sensitivity and specificity values for malignancy were 53.4% and 100% for routine cytology only, 89.0% and 95.7% for EZH2 ICC only, and 89.8% and 95.7% for a combination of routine cytology and EZH2 ICC. The sensitivities of EZH2 ICC only and a combination of routine cytology and EZH2 ICC were significantly improved in comparison with routine cytology only (P < .001). EZH2 ICC alone had a sensitivity of 68.0% and a specificity of 85.7% in bile samples with atypical cytology, a sensitivity of 87.0% in samples that were suspicious for malignancy, and a sensitivity of 85.7% and a specificity of 100% in samples that were negative for malignancy. CONCLUSIONS EZH2 ICC improved the diagnostic sensitivity for pancreatobiliary adenocarcinoma in bile cytology. This method is particularly meaningful in samples of indeterminate cytology and may be useful as an initial assessment to ensure that no cancer cells are missed.
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Affiliation(s)
- Kiyoshi Tone
- Division of Pathology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Sachiyo Ohno
- Division of Pathology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Masatake Honda
- Division of Pathology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Akifumi Notsu
- Clinical Research Center, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Keiko Sasaki
- Division of Pathology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Takashi Sugino
- Division of Pathology, Shizuoka Cancer Center, Nagaizumi, Japan
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17
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Du X, Zhang C, Yin C, Wang W, Yan X, Xie D, Zheng X, Zheng Q, Li M, Song Z. High BLM Expression Predicts Poor Clinical Outcome and Contributes to Malignant Progression in Human Cholangiocarcinoma. Front Oncol 2021; 11:633899. [PMID: 33828983 PMCID: PMC8019910 DOI: 10.3389/fonc.2021.633899] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Accepted: 02/09/2021] [Indexed: 12/24/2022] Open
Abstract
Molecular mechanisms underlying the tumorigenesis of a highly malignant cancer, cholangiocarcinoma (CCA), are still obscure. In our study, the CCA expression profile data were acquired from The Cancer Genome Atlas (TCGA) database, and differentially expressed genes (DEGs) in the TCGA-Cholangiocarcinoma (TCGA-CHOL) data set were utilized to construct a co-expression network via weighted gene co-expression network analysis (WGCNA). The blue gene module associated with the histopathologic grade of CCA was screened. Then, five candidate hub genes were screened by combining the co-expression network with protein–protein interaction (PPI) network. After progression and survival analyses, bloom syndrome helicase (BLM) was ultimately identified as a real hub gene. Moreover, the receiver operating characteristic (ROC) curve analysis suggested that BLM had a favorable diagnostic and predictive recurrence value for CCA. The gene set enrichment analysis (GSEA) results for a single hub gene revealed the importance of cell cycle-related pathways in the CCA progression and prognosis. Furthermore, we detected the BLM expression in vitro, and the results demonstrated that the expression level of BLM was much higher in the CCA tissues and cells relative to adjacent non-tumor samples and normal bile duct epithelial cells. Additionally, after further silencing the BLM expression by small interfering RNA (siRNA), the proliferation and migration ability of CCA cells were all inhibited, and the cell cycle was arrested. Altogether, a real hub gene (BLM) and cell cycle-related pathways were identified in the present study, and the gene BLM may be involved in the CCA progression and could act as a reliable biomarker for potential diagnosis and prognostic evaluation.
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Affiliation(s)
- Xiaolong Du
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chen Zhang
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chuanzheng Yin
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjie Wang
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xueke Yan
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dawei Xie
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xichuan Zheng
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qichang Zheng
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Min Li
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zifang Song
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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18
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Takamura H, Gabata R, Obatake Y, Nakanuma S, Hayashi H, Kozaka K, Sasaki M, Okazaki M, Yamaguchi T, Shimbashi H, Terai S, Okamoto K, Makino I, Kinoshita J, Nakamura K, Miyashita T, Tajima H, Ninomiya I, Fushida S, Kitao A, Kitahara M, Arai K, Yamashita T, Yamashita T, Ikeda H, Satoh Y, Harada K, Kaneko S, Gabata T, Kosaka T, Ohta T. Clinical features and diagnostic imaging of cholangiolocellular carcinoma compared with other primary liver cancers: a surgical perspective. Technol Cancer Res Treat 2020; 19:1533033820948141. [PMID: 33073719 PMCID: PMC7592326 DOI: 10.1177/1533033820948141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background and Objectives: Although cholangiolocellular carcinoma is considered a combined hepatocellular and cholangiocarcinoma, we feel that this classification is not appropriate. Therefore, we compared the diagnostic imaging findings, surgical prognosis, and pathological features of cholangiolocellular carcinoma with those of other combined hepatocellular and cholangiocarcinoma subtypes, hepatocellular carcinoma, and cholangiocarcinoma. Methods: The study patients included 7 with classical type combined hepatocellular and cholangiocarcinoma; 8 with stem cell feature, intermediate type combined hepatocellular and cholangiocarcinoma; 13 with cholangiolocellular carcinoma; 58 with cholangiocarcinoma; and 359 with hepatocellular carcinoma. All patients underwent hepatectomy or living-related donor liver transplantation from 2001 to 2014. Results: cholangiolocellular carcinoma could be distinguished from hepatocellular carcinom, other combined hepatocellular and cholangiocarcinoma subtypes, and cholangiocarcinoma by the presence of intratumoral Glisson’s pedicle, hepatic vein penetration, and tumor-staining pattern on angiography-assisted CT. Cholangiolocellular carcinoma was associated with a significantly lower SUV-max than that of cholangiocarcinoma on FDG-PET. Hepatocellular carcinoma, classical type, and cholangiolocellular carcinoma had significantly better prognoses than stem cell feature, intermediate type and cholangiocarcinoma. A cholangiocarcinoma component was detected in cholangiolocellular carcinoma that progressed to the hepatic hilum, and the cholangiocarcinoma component was found in perineural invasion and lymph node metastases. Conclusions: From the viewpoint of surgeon, cholangiolocellular carcinoma should be classified as a good-prognosis subtype of biliary tract carcinoma because of its tendency to differentiate into cholangiocarcinoma during its progression, and its distinctive imaging and few recurrence rates different from other combined hepatocellular and cholangiocarcinoma subtypes.
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Affiliation(s)
- Hiroyuki Takamura
- General and Digestive Surgery, 12857Kanazawa Medical University, Kahoku, Ishikawa, Japan.,Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Ryousuke Gabata
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yoshinao Obatake
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Shinichi Nakanuma
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hironori Hayashi
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kazuto Kozaka
- Radiology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Motoko Sasaki
- Pathology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Mitsuyoshi Okazaki
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takahisa Yamaguchi
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hiroyuki Shimbashi
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Shiro Terai
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Koichi Okamoto
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Isamu Makino
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Jun Kinoshita
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Keishi Nakamura
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tomoharu Miyashita
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hidehiro Tajima
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Itasu Ninomiya
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Sachio Fushida
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Azusa Kitao
- Radiology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Masaaki Kitahara
- Gastroenterology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kuniaki Arai
- Gastroenterology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Taro Yamashita
- Gastroenterology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tatsuya Yamashita
- Gastroenterology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hiroko Ikeda
- Pathology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yasunori Satoh
- Pathology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kenichi Harada
- Pathology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Syuichi Kaneko
- Gastroenterology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | | | - Tateo Kosaka
- General and Digestive Surgery, 12857Kanazawa Medical University, Kahoku, Ishikawa, Japan
| | - Tetsuo Ohta
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
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19
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Sasaki M, Sato Y, Nakanuma Y. Bile duct adenoma may be a precursor lesion of small duct type intrahepatic cholangiocarcinoma. Histopathology 2020; 78:310-320. [PMID: 33405289 DOI: 10.1111/his.14222] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 07/23/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND/AIMS Precursor lesions of small duct type intrahepatic cholangiocarcinoma (small duct iCCA) have not been clarified so far. We hypothesised that precursor lesions may be frequently distributed in the background liver of small duct iCCA. METHODS AND RESULTS We determined by histology the presence of bile duct adenomas and von Meyenburg complexes as candidate precursor lesions in the background liver of small duct iCCA, with other primary liver carcinomas as control. Subjects included 28 patients with small duct iCCA, 29 with large duct iCCAs, 60 with combined hepatocellular-cholangiocarcinoma (Comb) and 40 with hepatocellular carcinoma (HCC). The prevalence of bile duct adenomas in the background liver was significantly higher in small duct iCCA (35.7%) compared to other primary liver carcinomas (Comb, 4.9%; 10%, HCC) (P < 0.01). The prevalence of bile duct adenomas was significantly associated with the presence of von Meyenburg complexes and ductal plate malformation-like patterns in small duct iCCAs and Combs. Von Meyenburg complexes were detected in 11 small duct iCCA (39.3%), five large duct iCCAs (17.2%), 10 Comb (16.4%) and 13 HCC (33.3%), respectively (P > 0.05). Small duct iCCAs showed altered expression of ARID1A (46.4%), p53 (39.3%), PBRM1 (14.3%), IMP3 (85.7%) and EZH2 (82.1%), whereas these markers were negative in bile duct adenomas. CONCLUSION Bile duct adenomas may be precursor lesions of small duct iCCAs. Alteration of ARID1A, p53 or PBRM1 may be involved in the carcinogenesis of small duct iCCAs.
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Affiliation(s)
- Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Yasunori Sato
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Yasuni Nakanuma
- Division of Pathology, Fukui Saiseikai Hospital, Fukui, Japan
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20
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Lendvai G, Szekerczés T, Illyés I, Dóra R, Kontsek E, Gógl A, Kiss A, Werling K, Kovalszky I, Schaff Z, Borka K. Cholangiocarcinoma: Classification, Histopathology and Molecular Carcinogenesis. Pathol Oncol Res 2020; 26:3-15. [PMID: 30448973 DOI: 10.1007/s12253-018-0491-8] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 10/10/2018] [Indexed: 02/06/2023]
Abstract
Cholangiocarcinoma (CC) is the second most common tumor of the liver, originating from the biliary system with increasing incidence and mortality worldwide. Several new classifications review the significance of tumor localization, site of origin, proliferation and biomarkers in the intrahepatic, perihilar and distal forms of the lesion. Based on growth pattern mass-forming, periductal-infiltrating, intraductal, undefined and mixed types are differentiated. There are further subclassifications which are applied for the histological features, in particular for intrahepatic CC. Recognition of the precursors and early lesions of CC including biliary intraepithelial neoplasia (BilIN), intraductal papillary neoplasm of the bile ducts (IPNB), biliary mucinous cystic neoplasm (MCNB) and the candidate precursors, such as bile duct adenoma and von Meyenburg complex is of increasing significance. In addition to the previously used biliary markers detected by immunohistochemistry, several new markers have been added to the differentiation of both the benign and malignant lesions, which can be used to aid in the subclassification in association with the outcome of CC. Major aspects of biliary carcinogenesis have been revealed, yet, the exact way of this diverse process is still unclear. The factors contributing to molecular cholangiocarcinogenesis include various risk factors, different anatomical localizations, multiple cellular origins, genetic and epigenetic alterations, tumor microenvironment, heterogeneity and clonal evolution. Driver mutations have been identified, implying that they are optimal candidates for targeted therapy. The most promising therapeutic candidates have entered clinical trials.
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Affiliation(s)
- Gábor Lendvai
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Tímea Szekerczés
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Idikó Illyés
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Réka Dóra
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Endre Kontsek
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Alíz Gógl
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - András Kiss
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
| | - Klára Werling
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, 1085, Hungary
| | - Ilona Kovalszky
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, 1085, Hungary
| | - Zsuzsa Schaff
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary.
| | - Katalin Borka
- 2nd Department of Pathology, Semmelweis University, Üllői út 93, Budapest, H-1091, Hungary
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21
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Overexpression of polycomb repressive complex 2 key components EZH2/SUZ12/EED as an unfavorable prognostic marker in cholangiocarcinoma. Pathol Res Pract 2019; 215:152451. [PMID: 31126817 DOI: 10.1016/j.prp.2019.152451] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 04/29/2019] [Accepted: 05/12/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Cholangiocarcinoma (CCA) is a fatal liver cancer arising from bile duct epithelium. Polycomb repressive complex 2 (PRC2) is a histone methyltransferase enzyme that catalyzes trimethylation of histone H3 on lysine 27, resulting transcriptional gene silencing. The key components of PRC2 are EZH2, SUZ12 and EED, which EZH2 is a catalytic subunit. The defect of individual PRC2 components has been shown to enhance carcinogenesis and cancer progression. The aim of this study was to determine the expression of individual PRC2 components and evaluate its association with clinicopathological data in CCA patients. METHODS The expression of PRC2 components including EZH2, SUZ12 and EED was determined by immunohistochemistry in 40 CCA tissue samples. RESULTS The expression of EZH2 and SUZ12 in CCA tissue was significantly higher than that in adjacent non-cancerous tissue (P < 0.001). The high cytoplasmic EZH2 expression was significantly associated with short overall survival in CCA (P = 0.030). Interestingly, a combined high nuclear and cytoplasmic expression of EZH2 was found to be a worse prognostic marker for overall survival (P = 0.015). Moreover, combined high expression of EZH2 and SUZ12/EED was also associated with short overall survival (P < 0.05). CONCLUSIONS Our findings suggest that overexpression of the PRC2 key components especially EZH2 in both nucleus and cytoplasm can be potentially used as a prognostic marker for CCA.
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22
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Prachayakul V, Kanchanapermpoon J, Thuwajit C, Boonyaarunnate T, Pongpaibul A, Chobson P, Thuwajit P. DNA Methylation Markers Improve the Sensitivity of Endoscopic Retrograde Cholangiopancreatography-Based Brushing Cytology in Extrahepatic Cholangiocarcinoma. Technol Cancer Res Treat 2017; 16:1252-1258. [PMID: 29484968 PMCID: PMC5762100 DOI: 10.1177/1533034617748090] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 10/15/2017] [Accepted: 11/17/2017] [Indexed: 12/17/2022] Open
Abstract
Endoscopic retrograde cholangiopancreatography with brushed cytology is still the standard method for the diagnosis of extrahepatic cholangiocarcinoma in obstructive jaundice; however, the diagnostic yield is limited. To improve the diagnostic sensitivity, DNA methylation analysis is an attractive candidate, since this may constitute a stable marker in brushed specimens. Therefore, this study aims to evaluate the importance of such epigenetic markers in brushed biliary cells from patients with obstructive jaundice for the diagnosis of extrahepatic cholangiocarcinoma. The cells examined were those that were left over from brushed cytology done during routine endoscopic retrograde cholangiopancreatography of patients with extrahepatic cholangiocarcinoma. The methylation states of HOXA1, RASSF1A, P16, and NEUROG1 genes in extrahepatic cholangiocarcinoma were measured by quantitative methylation-specific polymerase chain reaction and compared between brushed biliary cells and normal gall bladder epithelial cells. The results showed that the sensitivity of the methylation index measurements of HOXA1 and NEUROG1 genes from brushed samples was markedly superior to that of standard cytology. In conclusion, measurement of the DNA methylation status of HOXA1 and NEUROG1 genes in leftover brushed biliary cells might serve as a useful supplement in the detection of malignant biliary obstruction by increasing the sensitivity of diagnosis by routine cytology.
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Affiliation(s)
- Varayu Prachayakul
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Jiraporn Kanchanapermpoon
- Graduate Program in Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Chanitra Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Thiraphon Boonyaarunnate
- Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Ananya Pongpaibul
- Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Pornpimol Chobson
- NANOTEC-Mahidol University Center of Excellence in Nanotechnology for Cancer Diagnosis and Treatment, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Peti Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
- NANOTEC-Mahidol University Center of Excellence in Nanotechnology for Cancer Diagnosis and Treatment, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
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23
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Verlingue L, Hollebecque A, Boige V, Ducreux M, Malka D, Ferté C. Matching genomic molecular aberrations with molecular targeted agents: Are biliary tract cancers an ideal playground? Eur J Cancer 2017. [PMID: 28628842 DOI: 10.1016/j.ejca.2017.05.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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24
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Immunohistochemical Antibody Panel for the Differential Diagnosis of Pancreatic Ductal Carcinoma From Gastrointestinal Contamination and Benign Pancreatic Duct Epithelium in Endoscopic Ultrasound-Guided Fine-Needle Aspiration. Pancreas 2017; 46:531-538. [PMID: 28099249 DOI: 10.1097/mpa.0000000000000774] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES The diagnosis of pancreatic ductal adenocarcinoma (PDAC) by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) can be challenging to distinguish tumor cells from benign epithelium (BE). The aim of the present study was to set a minimal antibody panel to differentiate PDAC from contaminated BE in EUS-FNA specimens. METHODS Immunohistochemistry using claudin 4, EZH2, Ki-67, maspin, p53, and S100P was performed on tissue microarray sections containing 53 PDACs and 33 BE as well as cell blocks of EUS-FNA including 53 PDACs and 22 BE. The positive rate was scored as 0 to 4+. The receiver operating characteristic curve was applied to determine a cutoff point, and the Classification And Regression Trees method was used to obtain a classification tree of the best panel. RESULTS The cutoff point was 1+ for claudin 4, EZH2, Ki-67, p53, and S100P and 2+ for maspin. All BE scored 0 for p53. The classification tree revealed using p53, S100P, and claudin 4 was the most powerful. The sensitivity and specificity of the tree were 96.2% and 100% in tissue microarrays and 100% and 95.5% in EUS-FNA, respectively. CONCLUSIONS The classification tree using p53, S100P, and claudin 4 seems to successfully distinguish PDAC from the accompanying BE.
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25
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Misumi K, Hayashi A, Shibahara J, Arita J, Sakamoto Y, Hasegawa K, Kokudo N, Fukayama M. Intrahepatic cholangiocarcinoma frequently shows loss of BAP1 and PBRM1 expression, and demonstrates specific clinicopathological and genetic characteristics with BAP1 loss. Histopathology 2017; 70:766-774. [PMID: 27864835 DOI: 10.1111/his.13127] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 11/16/2016] [Indexed: 12/15/2022]
Abstract
AIMS BAP1 and PBRM1 expression loss has been observed in multiple cancers, including intrahepatic cholangiocarcinoma (ICC). We investigated BAP1 and PBRM1 expression in ICC using immunohistochemistry, and analysed its association with clinicopathological and genetic features, including two histological subtypes. METHODS AND RESULTS Whole-section slides of 108 consecutive primary ICC cases were immunostained against BAP1 and PBRM1. Complete loss of BAP1 and PBRM1 was observed in 21 (19.4%) and 25 (23.1%) cases, respectively, and partial loss was identified in four (3.7%) and nine (8.4%) cases. In all cases, normal bile ducts were strongly and diffusely positive for both BAP1 and PBRM1. ICC with BAP1 loss showed lower serum CA19-9 levels, less perineural invasion, rare mucin production, weaker immunoreactivity against S-100P and stronger immunoreactivity against N-cadherin and NCAM. IDH mutations were identified more frequently in ICCs with BAP1 loss. All ICC with BAP1 loss corresponded to small-duct type ICC. Multivariate Cox regression analysis showed that BAP1 loss was an independent prognostic factor for both overall and recurrence-free survival (P < 0.05). Conversely, PBRM1 loss was found in both small-duct type and large-duct type ICC, and was not associated significantly with any specific characteristics, including prognosis. CONCLUSION BAP1 and PBRM1 loss is seen frequently in ICC. ICC with BAP1 loss shares features of small-duct type ICC.
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Affiliation(s)
- Kento Misumi
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Akimasa Hayashi
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Junji Shibahara
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Junichi Arita
- Hepato-Biliary-Pancreatic Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshihiro Sakamoto
- Hepato-Biliary-Pancreatic Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Hepato-Biliary-Pancreatic Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masashi Fukayama
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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26
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Sasaki M, Nakanuma Y. New concept: cellular senescence in pathophysiology of cholangiocarcinoma. Expert Rev Gastroenterol Hepatol 2017; 10:625-38. [PMID: 26680649 DOI: 10.1586/17474124.2016.1133291] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cholangiocarcinoma, a malignant tumor arising in the hepatobiliary system, presents with poor prognosis because of difficulty in its early detection/diagnosis. Recent progress revealed that cellular senescence may be involved in the pathophysiology of cholangiocarcinoma. Cellular senescence is defined as permanent growth arrest caused by several cellular injuries, such as oncogenic mutations and oxidative stress. "Oncogene-induced" and/or stress-induced senescence may occur in the process of multi-step cholangiocarcinogenesis, and overexpression of a polycomb group protein EZH2 may play a role in the escape from, and/or bypassing of, senescence. Furthermore, senescent cells may play important roles in tumor development and progression via the production of senescence-associated secretory phenotypes. Cellular senescence may be a new target for the prevention, early diagnosis, and therapy of cholangiocarcinoma in the near future.
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Affiliation(s)
- Motoko Sasaki
- a Human Pathology , Kanazawa University Graduate School of Medical Sciences , Kanzawa , Japan
| | - Yasuni Nakanuma
- b Department of Diagnostic Pathology , Shizuoka Cancer Center , Shizuoka , Japan
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27
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Kim SK, Kim SR, Imoto S, Kim CW, Matsuoka T, Nakashima O, Sasaki M, Kumabe T, Kudo M, Fukusato T, Kondo F. Bile duct adenoma in patient with chronic hepatitis C: As a benign neoplasm by pathological and imaging studies. Pathol Int 2016; 66:640-642. [PMID: 27663997 DOI: 10.1111/pin.12457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 07/15/2016] [Accepted: 08/12/2016] [Indexed: 11/28/2022]
Affiliation(s)
- Soo Ki Kim
- Department of Gastroenterology, Kobe Asahi Hospital, Kobe, Japan
| | - Soo Ryang Kim
- Department of Gastroenterology, Kobe Asahi Hospital, Kobe, Japan
| | - Susumu Imoto
- Department of Gastroenterology, Kobe Asahi Hospital, Kobe, Japan
| | - Chi Wan Kim
- Department of Gastroenterology, Kobe Asahi Hospital, Kobe, Japan
| | - Toshiyuki Matsuoka
- Department of Radiology, Osaka City University Medical School, Osaka, Japan
| | - Osamu Nakashima
- Kurume University Hospital Department of Clinical Laboratory Medicine, Fukuoka, Japan
| | - Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | | | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osakasayama, Japan
| | - Toshio Fukusato
- Department of Pathology, Teikyo University School of Medicine, Japan
| | - Fukuo Kondo
- Department of Pathology, Teikyo University Hospital, Japan
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28
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Kim SK, Kim SR, Imoto S, Kim CW, Matsuoka T, Sasaki M, Nakashima O, Kumabe T, Hayashi Y. Confluent hepatic fibrosis in alcohol liver cirrhosis with elevated pivkaii value - usefulness of immunostaining for EZH2 and p16INK4ain differentiating it from cholangiolocellular carcinoma - Confluent hepatic fibrosis. Pathol Int 2016; 66:543-5. [DOI: 10.1111/pin.12435] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 06/15/2016] [Accepted: 06/17/2016] [Indexed: 11/28/2022]
Affiliation(s)
- Soo Ki Kim
- Department of Gastroenterology; Kobe Asahi Hospital; Kobe Japan
| | - Soo Ryang Kim
- Department of Gastroenterology; Kobe Asahi Hospital; Kobe Japan
| | - Susumu Imoto
- Department of Gastroenterology; Kobe Asahi Hospital; Kobe Japan
| | - Chi Wan Kim
- Department of Gastroenterology; Kobe Asahi Hospital; Kobe Japan
| | - Toshiyuki Matsuoka
- Department of Radiology; Osaka City University Medical School; Osaka Japan
| | - Motoko Sasaki
- Department of Human Pathology; Kanazawa University Graduate School of Medicine; Kanazawa Japan
| | - Osamu Nakashima
- Kurume University Hospital Department of Clinical Laboratory Medicine; Fukuoka Japan
| | | | - Yoshitake Hayashi
- Division of Molecular Medicine & Medical Genetics, Department of Pathology; Kobe University Graduate School of Medicine; Kobe Japan
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Mayr C, Neureiter D, Wagner A, Pichler M, Kiesslich T. The role of polycomb repressive complexes in biliary tract cancer. Expert Opin Ther Targets 2014; 19:363-75. [PMID: 25424424 DOI: 10.1517/14728222.2014.986460] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Polycomb group proteins are major epigenetic regulators that modify histone tails. They are organized in two multi-protein complexes called polycomb repressive complex (PRC) 1 and 2. Aberrant PRC activity is known to contribute to the development and aggressiveness of many cancers. Biliary tract cancer (BTC) is a rare malignancy associated with high chemoresistance and poor clinical outcome. Here we review the role of the PRC complexes and the effects of RNAi and drug-mediated inhibition of PRC1 and PRC2 in BTC. AREAS COVERED This review gives a short overview of the composition, biochemical functions and oncogenic role of PRC complexes. We then focus on and summarize the results of current studies that address the role of PRC in BTC. Finally, we discuss options and results of therapeutic targeting of PRC in BTC. EXPERT OPINION Pharmacological inhibition of the two PRC complexes seems to be a promising strategy for treatment of BTC. To date, only few studies have addressed the therapeutic effect of PRC inhibition in BTC. Therefore, it will be important to test established PRC inhibitors, such as DZNep, as well as newly developed drugs, for example, PTC209, to gain more insight into the role of the PRC complexes in BTC and potentially to develop new therapeutic strategies.
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Affiliation(s)
- Christian Mayr
- Department of Internal Medicine I, Paracelsus Medical University / Salzburger Landeskliniken and Laboratory for Tumor Biology and Experimental Therapies, Institute of Physiology and Pathophysiology, Paracelsus Medical University , Salzburg , Austria +43 662 4482 2795 ;
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30
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Padden J, Megger DA, Bracht T, Reis H, Ahrens M, Kohl M, Eisenacher M, Schlaak JF, Canbay AE, Weber F, Hoffmann AC, Kuhlmann K, Meyer HE, Baba HA, Sitek B. Identification of novel biomarker candidates for the immunohistochemical diagnosis of cholangiocellular carcinoma. Mol Cell Proteomics 2014; 13:2661-72. [PMID: 25034945 PMCID: PMC4188994 DOI: 10.1074/mcp.m113.034942] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
The aim of this study was the identification of novel biomarker candidates for the diagnosis of cholangiocellular carcinoma (CCC) and its immunohistochemical differentiation from benign liver and bile duct cells. CCC is a primary cancer that arises from the epithelial cells of bile ducts and is characterized by high mortality rates due to its late clinical presentation and limited treatment options. Tumorous tissue and adjacent non-tumorous liver tissue from eight CCC patients were analyzed by means of two-dimensional differential in-gel electrophoresis and mass-spectrometry-based label-free proteomics. After data analysis and statistical evaluation of the proteins found to be differentially regulated between the two experimental groups (fold change ≥ 1.5; p value ≤ 0.05), 14 candidate proteins were chosen for determination of the cell-type-specific expression profile via immunohistochemistry in a cohort of 14 patients. This confirmed the significant up-regulation of serpin H1, 14-3-3 protein sigma, and stress-induced phosphoprotein 1 in tumorous cholangiocytes relative to normal hepatocytes and non-tumorous cholangiocytes, whereas some proteins were detectable specifically in hepatocytes. Because stress-induced phosphoprotein 1 exhibited both sensitivity and specificity of 100%, an immunohistochemical verification examining tissue sections of 60 CCC patients was performed. This resulted in a specificity of 98% and a sensitivity of 64%. We therefore conclude that this protein should be considered as a potential diagnostic biomarker for CCC in an immunohistochemical application, possibly in combination with other candidates from this study in the form of a biomarker panel. This could improve the differential diagnosis of CCC and benign bile duct diseases, as well as metastatic malignancies in the liver.
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Affiliation(s)
- Juliet Padden
- From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany;
| | - Dominik A Megger
- From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Thilo Bracht
- From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Henning Reis
- ¶Institut für Pathologie, Universitätsklinikum Essen, Universität Duisburg-Essen, 45141 Essen, Germany
| | - Maike Ahrens
- From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Michael Kohl
- From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Martin Eisenacher
- From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Jörg F Schlaak
- ‖Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, 45141 Essen, Universität Duisburg-Essen, 45141 Essen, Germany
| | - Ali E Canbay
- ‖Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, 45141 Essen, Universität Duisburg-Essen, 45141 Essen, Germany
| | - Frank Weber
- **Klinik für Allgemeinchirurgie, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Universität Duisburg-Essen, 45141 Essen, Germany
| | - Andreas-Claudius Hoffmann
- ‡‡Innere Klinik (Tumorforschung), Westdeutsches Tumorzentrum, Universitätsklinikum Essen, Universität Duisburg-Essen, 45141 Essen, Germany
| | - Katja Kuhlmann
- From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany
| | - Helmut E Meyer
- From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany; §§Leibniz Institute for Analytical Sciences - ISAS, 44139 Dortmund, Germany
| | - Hideo A Baba
- ¶Institut für Pathologie, Universitätsklinikum Essen, Universität Duisburg-Essen, 45141 Essen, Germany
| | - Barbara Sitek
- From the ‡Medizinisches Proteom-Center, Ruhr-Universität Bochum, 44801 Bochum, Germany;
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