|
1
|
Tóth M, Kirchner M, Longerich T, Stenzinger A, Schirmacher P. Integrated genotype-phenotype analysis of familial adenomatous polyposis-associated hepatocellular adenomas. Virchows Arch 2024; 484:587-595. [PMID: 37872280 PMCID: PMC11062996 DOI: 10.1007/s00428-023-03680-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 09/25/2023] [Accepted: 10/10/2023] [Indexed: 10/25/2023]
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by a germline mutation in the adenomatous polyposis coli (APC) gene, characterized by numerous colorectal adenomas. In addition, FAP patients may develop extraintestinal manifestations. Several cases of hepatocellular adenomas (HCA) detected accidentally in FAP patients have raised the so-far unsolved question of whether they represent a specific manifestation of FAP or a mere coincidence. To investigate the incidence of liver tumors in FAP patients, we analyzed our diagnostic database from 1991 to 2021. Among the 58 hepatic mass lesions identified, five HCAs occurring in three patients with FAP were identified, and comprehensive morphological, immunohistological, and molecular analysis employing targeted next-generation sequencing was conducted for characterization. The HCAs in this study showed no cytological or histological atypia. They displayed a diffuse, strong positivity for glutamine synthetase but no nuclear beta-catenin immunostaining. In two patients, the adenomas showed moderate immunoreactivity against serum amyloid A. Consistent with the diagnosis of FAP, molecular profiling revealed a pathogenic germline mutation of the APC gene in all analyzed adenomas as well as deleterious somatic second hits. All somatic mutations were localized between codons 1345 and 1577. No mutations were found in the catenin beta 1 gene. HCA in FAP patients can be a specific, although rare, neoplastic manifestation of this inborn disease and represents a distinct subgroup of HCAs. These benign tumors represent an important differential diagnosis for hepatic metastases in FAP patients and require adequate clinical and molecular (diagnostic) assessments for optimal patient guidance.
Collapse
Affiliation(s)
- Marcell Tóth
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
| | - Martina Kirchner
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Thomas Longerich
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| |
Collapse
|
|
2
|
Espinoza AF, Vasudevan SA, Masand PM, Lòpez-Terrada DH, Patel KR. Pediatric Hepatocellular Adenomas: What Is Known and What Is New? Cancers (Basel) 2023; 15:4790. [PMID: 37835484 PMCID: PMC10571754 DOI: 10.3390/cancers15194790] [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: 08/31/2023] [Revised: 09/21/2023] [Accepted: 09/25/2023] [Indexed: 10/15/2023] Open
Abstract
Current understanding and classification of pediatric hepatocellular adenomas (HCA) are largely based on adult data. HCAs are rare in children and, unlike in adults, are often seen in the context of syndromes or abnormal background liver. Attempts to apply the adult classification to pediatric tumors have led to several "unclassifiable" lesions. Although typically considered benign, few can show atypical features and those with beta-catenin mutations have a risk for malignant transformation. Small lesions can be monitored while larger (>5.0 cm) lesions are excised due to symptoms or risk of bleeding/rupture, etc. Management depends on gender, age, underlying liver disease, multifocality, size of lesion, histologic subtype and presence of mutation, if any. In this review, we summarize the data on pediatric HCAs and highlight our experience with their diagnosis and management.
Collapse
Affiliation(s)
- Andres F. Espinoza
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; (A.F.E.); (S.A.V.)
| | - Sanjeev A. Vasudevan
- Divisions of Pediatric Surgery and Surgical Research, Michael E. DeBakey Department of Surgery, Pediatric Surgical Oncology Laboratory, Texas Children’s Surgical Oncology Program, Texas Children’s Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; (A.F.E.); (S.A.V.)
| | - Prakash M. Masand
- Department of Radiology, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX 77030, USA;
| | - Dolores H. Lòpez-Terrada
- Department of Pathology and Immunology, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX 77030, USA;
| | - Kalyani R. Patel
- Department of Pathology and Immunology, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX 77030, USA;
- Abercrombie B1, Texas Children’s Hospital, Baylor College of Medicine, 6621 Fannin St., Houston, TX 77030, USA
| |
Collapse
|
|
3
|
Li C, Furth EE, Rustgi AK, Klein PS. When You Come to a Fork in the Road, Take It: Wnt Signaling Activates Multiple Pathways through the APC/Axin/GSK-3 Complex. Cells 2023; 12:2256. [PMID: 37759479 PMCID: PMC10528086 DOI: 10.3390/cells12182256] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/02/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
The Wnt signaling pathway is a highly conserved regulator of metazoan development and stem cell maintenance. Activation of Wnt signaling is an early step in diverse malignancies. Work over the past four decades has defined a "canonical" Wnt pathway that is initiated by Wnt proteins, secreted glycoproteins that bind to a surface receptor complex and activate intracellular signal transduction by inhibiting a catalytic complex composed of the classical tumor suppressor Adenomatous Polyposis Coli (APC), Axin, and Glycogen Synthase Kinase-3 (GSK-3). The best characterized effector of this complex is β-catenin, which is stabilized by inhibition of GSK-3, allowing β-catenin entrance to the nucleus and activation of Wnt target gene transcription, leading to multiple cancers when inappropriately activated. However, canonical Wnt signaling through the APC/Axin/GSK-3 complex impinges on other effectors, independently of β-catenin, including the mechanistic Target of Rapamycin (mTOR), regulators of protein stability, mitotic spindle orientation, and Hippo signaling. This review focuses on these alternative effectors of the canonical Wnt pathway and how they may contribute to cancers.
Collapse
Affiliation(s)
- Chenchen Li
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Emma E. Furth
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Anil K. Rustgi
- Division of Digestive and Liver Diseases, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA
- Herbert Irving Comprehensive Cancer Center, 1130 St. Nicholas Avenue, New York, NY 10032, USA
| | - Peter S. Klein
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| |
Collapse
|
|
4
|
Colletti G, Ciniselli CM, Signoroni S, Cocco IMF, Magarotto A, Ricci MT, Brignola C, Bagatin C, Cattaneo L, Mancini A, Cavalcoli F, Milione M, Verderio P, Vitellaro M. Prevalence and Management of Cancer of the Rectal Stump after Total Colectomy and Rectal Sparing in Patients with Familial Polyposis: Results from a Registry-Based Study. Cancers (Basel) 2022; 14:298. [PMID: 35053462 PMCID: PMC8774025 DOI: 10.3390/cancers14020298] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The balance between quality of life and colorectal cancer risk in familial adenomatous polyposis (FAP) patients is of primary importance. A cut-off of less than 30 polyps under 1 cm of diameter in the rectum has been used as an indication for performing ileo-rectal anastomosis (IRA) in terms of lower rectal cancer risk. This study aimed to assess clinical and surgical features of FAP patients who developed cancer of the rectal stump. METHODS This retrospective study included all FAP patients who underwent total colectomy/IRA from 1977 to 2021 and developed subsequent rectal cancer. Patients' features were reported using descriptive statistics by considering the overall case series and within pre-specified classes of age (<20, 20-30, and >30 years) at first surgery. RESULTS Among the 715 FAP patients, 47 (6.57%, 95% confidence interval: 4.87; 8.65) developed cancer in the rectal stump during follow-up. In total, 57.45% of the population were male and 38.30% were proband. The median interval between surgery and the occurrence of rectal cancer was 13 years. This interval was wider in the youngest group (p-value: 0.012) than the oldest ones. Twelve patients (25.53%) received an endoscopic or minimally invasive resection. Amongst them, 61.70% were Dukes stage A cancers. CONCLUSIONS There is a definite risk of rectal cancer after total colectomy/IRA; however, the time interval from the index procedure to cancer developing is long. Minimally invasive and endoscopic treatments should be the procedures of choice in patients with early stage cancers.
Collapse
Affiliation(s)
- Gaia Colletti
- Department of Surgery, Colorectal Surgery Unit, Fondazione IRCSS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (G.C.); (M.V.)
- General Surgery Residency Program, University of Milan, Via Festa del Perdono 7, 20122 Milan, Italy
| | - Chiara Maura Ciniselli
- Unit of Bioinformatics and Biostatistics, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (C.M.C.); (C.B.); (P.V.)
| | - Stefano Signoroni
- Unit of Hereditary Digestive Tract Tumours, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (M.T.R.); (C.B.)
| | | | - Andrea Magarotto
- Diagnostic and Surgical Endoscopy Unit, Fondazione IRCSS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (A.M.); (A.M.); (F.C.)
| | - Maria Teresa Ricci
- Unit of Hereditary Digestive Tract Tumours, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (M.T.R.); (C.B.)
| | - Clorinda Brignola
- Unit of Hereditary Digestive Tract Tumours, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (M.T.R.); (C.B.)
| | - Clara Bagatin
- Unit of Bioinformatics and Biostatistics, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (C.M.C.); (C.B.); (P.V.)
| | - Laura Cattaneo
- First Pathology Division, Department of Diagnostic Pathology and Laboratory, Fondazione IRCSS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (L.C.); (M.M.)
| | - Andrea Mancini
- Diagnostic and Surgical Endoscopy Unit, Fondazione IRCSS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (A.M.); (A.M.); (F.C.)
| | - Federica Cavalcoli
- Diagnostic and Surgical Endoscopy Unit, Fondazione IRCSS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (A.M.); (A.M.); (F.C.)
| | - Massimo Milione
- First Pathology Division, Department of Diagnostic Pathology and Laboratory, Fondazione IRCSS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (L.C.); (M.M.)
| | - Paolo Verderio
- Unit of Bioinformatics and Biostatistics, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (C.M.C.); (C.B.); (P.V.)
| | - Marco Vitellaro
- Department of Surgery, Colorectal Surgery Unit, Fondazione IRCSS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (G.C.); (M.V.)
- Unit of Hereditary Digestive Tract Tumours, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; (M.T.R.); (C.B.)
| |
Collapse
|
|
5
|
Nuñez Bragayrac LA, Schwaab T. Adrenal Tumors. Urol Oncol 2019. [DOI: 10.1007/978-3-319-42623-5_41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
|
|
6
|
|
|
7
|
Yoneda N, Matsui O, Kitao A, Kozaka K, Kobayashi S, Sasaki M, Yoshida K, Inoue D, Minami T, Gabata T. Benign Hepatocellular Nodules: Hepatobiliary Phase of Gadoxetic Acid-enhanced MR Imaging Based on Molecular Background. Radiographics 2016; 36:2010-2027. [PMID: 27740898 DOI: 10.1148/rg.2016160037] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Gadoxetic acid is a contrast agent for magnetic resonance (MR) imaging with hepatocyte-specific properties and is becoming increasingly important in detection and characterization of hepatocellular carcinoma and benign hepatocellular nodules, including focal nodular hyperplasia (FNH), nodular regenerative hyperplasia (NRH), hepatocellular adenoma (HCA), and dysplastic nodule. In these hepatocellular nodules, a positive correlation between the grade of membranous uptake transporter organic anion-transporting polypeptide (OATP) 1B3 expression and signal intensity in the hepatobiliary (HB) phase has been verified. In addition, it has been clarified that OATP1B3 expression is regulated by activation of β-catenin and/or hepatocyte nuclear factor 4α. On the other hand, recent studies have also revealed some of the background molecular mechanisms of benign hepatocellular nodules. FNH commonly shows iso- or hyperintensity in the HB phase with equal or stronger OATP1B3 expression, with map-like distribution of glutamine synthetase (a target of Wnt/β-catenin signaling) and OATP1B3 expression. NRH shows doughnut-like enhancement with hypointensity in the central portion in the HB phase with OATP1B3 expression. The majority of HCAs show hypointensity in the HB phase, but β-catenin-activated HCA exclusively demonstrates iso- or hyperintensity with increased expression of nuclear β-catenin, glutamine synthetase, and OATP1B3. Dysplastic nodule commonly shows iso- or hyperintensity in the HB phase with similar to increased OATP1B3 expression, but one-third of high-grade dysplastic nodules can be demonstrated as a hypointense nodule with decreased OATP1B3 expression. Knowledge of these background molecular mechanisms of gadoxetic acid-enhanced MR imaging is important not only for precise imaging diagnosis but also understanding of the pathogenesis of benign hepatocellular nodules. ©RSNA, 2016.
Collapse
Affiliation(s)
- Norihide Yoneda
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Osamu Matsui
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Azusa Kitao
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Kazuto Kozaka
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Satoshi Kobayashi
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Motoko Sasaki
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Kotaro Yoshida
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Dai Inoue
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Tetsuya Minami
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Toshifumi Gabata
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| |
Collapse
|
|
8
|
Bhavanasi D, Klein PS. Wnt Signaling in Normal and Malignant Stem Cells. CURRENT STEM CELL REPORTS 2016; 2:379-387. [PMID: 28503404 DOI: 10.1007/s40778-016-0068-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Wnt signaling plays important roles in stem cell self-renewal and differentiation in adults as well as in embryonic development. Mutations that activate canonical Wnt/β-catenin signaling also initiate and maintain several cancer states, including colorectal cancer and leukemia, and hence Wnt inhibitors are currently being explored as therapeutic options. In this review, we summarize previous studies and update recent findings on canonical Wnt signaling and its components, as well as their roles in somatic stem cell homeostasis and maintenance of cancer initiating cells.
Collapse
Affiliation(s)
- Dheeraj Bhavanasi
- Department of Medicine (Hematology-Oncology), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| | - Peter S Klein
- Department of Medicine (Hematology-Oncology), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.,Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
| |
Collapse
|
|
9
|
Current Proceedings in the Molecular Dissection of Hepatocellular Adenomas: Review and Hands-on Guide for Diagnosis. Int J Mol Sci 2015; 16:20994-1007. [PMID: 26404250 PMCID: PMC4613237 DOI: 10.3390/ijms160920994] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Revised: 08/10/2015] [Accepted: 08/19/2015] [Indexed: 02/07/2023] Open
Abstract
Molecular dissection of hepatocellular adenomas has brought forward a diversity of well-defined entities. Their distinction is important for routine practice, since prognosis is tightly related to the individual subgroup. Very recent activity has generated new details on the molecular background of hepatocellular adenoma, which this article aims to integrate into the current concepts of taxonomy.
Collapse
|
|
10
|
Lee SH, Koh YW, Roh HJ, Cha HJ, Kwon Y. Ovarian microcystic stromal tumor: A novel extracolonic tumor in familial adenomatous polyposis. Genes Chromosomes Cancer 2015; 54:353-60. [DOI: 10.1002/gcc.22233] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 11/25/2014] [Indexed: 11/10/2022] Open
Affiliation(s)
- Sang Hun Lee
- Department of Obstetrics and GynecologyUniversity of Ulsan College of Medicine, Ulsan University Hospital Ulsan Korea
| | - Young Wha Koh
- Department of PathologyAjou University School of Medicine Suwon Korea
| | - Hyun Jin Roh
- Department of Obstetrics and GynecologyUniversity of Ulsan College of Medicine, Ulsan University Hospital Ulsan Korea
| | - Hee Jeong Cha
- Department of PathologyUniversity of Ulsan College of Medicine, Ulsan University Hospital Ulsan Korea
| | - Yong‐Soon Kwon
- Department of Obstetrics and GynecologyUniversity of Ulsan College of Medicine, Ulsan University Hospital Ulsan Korea
| |
Collapse
|
|
11
|
Abstract
The adrenal gland consists of two distinct parts, the cortex and the medulla. Molecular mechanisms controlling differentiation and growth of the adrenal gland have been studied in detail using mouse models. Knowledge also came from investigations of genetic disorders altering adrenal development and/or function. During embryonic development, the adrenal cortex acquires a structural and functional zonation in which the adrenal cortex is divided into three different steroidogenic zones. Significant progress has been made in understanding adrenal zonation. Recent lineage tracing experiments have accumulated evidence for a centripetal differentiation of adrenocortical cells from the subcapsular area to the inner part of the adrenal cortex. Understanding of the mechanism of adrenocortical cancer (ACC) development was stimulated by knowledge of adrenal gland development. ACC is a rare cancer with a very poor overall prognosis. Abnormal activation of the Wnt/β-catenin as well as the IGF2 signaling plays an important role in ACC development. Studies examining rare genetic syndromes responsible for familial ACT have played an important role in identifying genetic alterations in these tumors (like TP53 or CTNNB1 mutations as well as IGF2 overexpression). Recently, genomic analyses of ACT have shown gene expression profiles associated with malignancy as well as chromosomal and methylation alterations in ACT and exome sequencing allowed to describe the mutational landscape of these tumors. This progress leads to a new classification of these tumors, opening new perspectives for the diagnosis and prognostication of ACT. This review summarizes current knowledge of adrenocortical development, growth, and tumorigenesis.
Collapse
Affiliation(s)
- Lucile Lefèvre
- Inserm, U1016, Institut Cochin, Paris, France Cnrs, UMR8104, Paris, France Université Paris Descartes, Sorbonne Paris Cité, France Department of Endocrinology, Referral Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
| | | | | |
Collapse
|
|
12
|
Fragoso MCBV, Alencar GA, Lerario AM, Bourdeau I, Almeida MQ, Mendonca BB, Lacroix A. Genetics of primary macronodular adrenal hyperplasia. J Endocrinol 2015; 224:R31-43. [PMID: 25472909 DOI: 10.1530/joe-14-0568] [Citation(s) in RCA: 31] [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: 11/08/2022]
Abstract
ACTH-independent macronodular adrenal hyperplasia is a rare cause of Cushing's syndrome (CS), accounting for <2% of all endogenous CS cases; however it is more frequently identified incidentally with sub-clinical cortisol secretion. Recently, cortisol secretion has been shown to be regulated by ectopic corticotropin, which is in turn produced by clusters of steroidogenic cells of the hyperplastic adrenal nodules. Hence, the term 'ACTH-independent' is not entirely appropriate for this disorder. Accordingly, the disease is designated primary macronodular adrenal hyperplasia (PMAH) in this review article. The means by which cortisol production is regulated in PMAH despite the suppressed levels of ACTH of pituitary origin is exceedingly complex. Several molecular events have been proposed to explain the enhanced cortisol secretion, increased cell proliferation, and nodule formation in PMAH. Nonetheless, the precise sequence of events and the molecular mechanisms underlying this condition remain unclear. The purpose of this review is therefore to present new insights on the molecular and genetic profile of PMAH pathophysiology, and to discuss the implications for disease progression.
Collapse
Affiliation(s)
- Maria Candida Barisson Villares Fragoso
- Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Guilherme Asmar Alencar
- Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Antonio Marcondes Lerario
- Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Isabelle Bourdeau
- Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Madson Queiroz Almeida
- Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Berenice Bilharinho Mendonca
- Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - André Lacroix
- Unidade de SuprarrenalDisciplina de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, BrazilInstituto do Câncer de São Paulo ICESPSão Paulo, BrazilDépartement de MédecineCentre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| |
Collapse
|
|
13
|
Valvezan AJ, Huang J, Lengner CJ, Pack M, Klein PS. Oncogenic mutations in adenomatous polyposis coli (Apc) activate mechanistic target of rapamycin complex 1 (mTORC1) in mice and zebrafish. Dis Model Mech 2013; 7:63-71. [PMID: 24092877 PMCID: PMC3882049 DOI: 10.1242/dmm.012625] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Truncating mutations in adenomatous polyposis coli (APC) are strongly linked to colorectal cancers. APC is a negative regulator of the Wnt pathway and constitutive Wnt activation mediated by enhanced Wnt–β-catenin target gene activation is believed to be the predominant mechanism responsible for APC mutant phenotypes. However, recent evidence suggests that additional downstream effectors contribute to APC mutant phenotypes. We previously identified a mechanism in cultured human cells by which APC, acting through glycogen synthase kinase-3 (GSK-3), suppresses mTORC1, a nutrient sensor that regulates cell growth and proliferation. We hypothesized that truncating Apc mutations should activate mTORC1 in vivo and that mTORC1 plays an important role in Apc mutant phenotypes. We find that mTORC1 is strongly activated in apc mutant zebrafish and in intestinal polyps in Apc mutant mice. Furthermore, mTORC1 activation is essential downstream of APC as mTORC1 inhibition partially rescues Apc mutant phenotypes including early lethality, reduced circulation and liver hyperplasia. Importantly, combining mTORC1 and Wnt inhibition rescues defects in morphogenesis of the anterior-posterior axis that are not rescued by inhibition of either pathway alone. These data establish mTORC1 as a crucial, β-catenin independent effector of oncogenic Apc mutations and highlight the importance of mTORC1 regulation by APC during embryonic development. Our findings also suggest a new model of colorectal cancer pathogenesis in which mTORC1 is activated in parallel with Wnt/β-catenin signaling.
Collapse
Affiliation(s)
- Alexander J Valvezan
- Cell and Molecular Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | | | | | | | | |
Collapse
|
|
14
|
Pathological Diagnosis of Hepatocellular Cellular Adenoma according to the Clinical Context. Int J Hepatol 2013; 2013:253261. [PMID: 23691330 PMCID: PMC3652210 DOI: 10.1155/2013/253261] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2012] [Accepted: 03/01/2013] [Indexed: 02/07/2023] Open
Abstract
In Europe and North America, hepatocellular adenomas (HCA) occur, classically, in middle-aged woman taking oral contraceptives. Twenty percent of women, however, are not exposed to oral contraceptives; HCA can more rarely occur in men, children, and women over 65 years. HCA have been observed in many pathological conditions such as glycogenosis, familial adenomatous polyposis, MODY3, after male hormone administration, and in vascular diseases. Obesity is frequent particularly in inflammatory HCA. The background liver is often normal, but steatosis is a frequent finding particularly in inflammatory HCA. The diagnosis of HCA is more difficult when the background liver is fibrotic, notably in vascular diseases. HCA can be solitary, or multiple or in great number (adenomatosis). When nodules are multiple, they are usually of the same subtype. HNF1 α -inactivated HCA occur almost exclusively in woman. The most important point of the classification is the identification of β -catenin mutated HCA, a strong argument to identify patients at risk of malignant transformation. Some HCA already present criteria indicating malignant transformation. When the whole nodule is a hepatocellular carcinoma, it is extremely difficult to prove that it is the consequence of a former HCA. It is occasionally difficult to identify HCA remodeled by necrosis or hemorrhage.
Collapse
|
|
15
|
Liau SS, Qureshi MS, Praseedom R, Huguet E. Molecular pathogenesis of hepatic adenomas and its implications for surgical management. J Gastrointest Surg 2013; 17:1869-82. [PMID: 23835731 PMCID: PMC3782654 DOI: 10.1007/s11605-013-2274-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2013] [Accepted: 06/18/2013] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Hepatic adenomas (HAs) are benign tumors of the liver, which can be solitary or multiple, and have a definite risk of malignant degeneration. DISCUSSION The pathogenesis and natural history of this disease entity were previously unknown. Recent research into the molecular pathogenesis of this condition has provided evidence for the malignant transformation of some of these adenomas. In the current article, we discuss the current evidence on the molecular biology underlying malignant transformation of hepatic adenomas and the implications for the surgical management of this disease.
Collapse
Affiliation(s)
- Siong-Seng Liau
- />Hepatopancreatobiliary Unit, Department of Surgery, Addenbrooke’s Hospital, Cambridge, UK , />Medical Research Council (MRC) Cancer Cell Unit, Hutchison-MRC Research Centre, Cambridge, UK
| | - M. Saeed Qureshi
- />Hepatopancreatobiliary Unit, Department of Surgery, Addenbrooke’s Hospital, Cambridge, UK
| | - Raaj Praseedom
- />Hepatopancreatobiliary Unit, Department of Surgery, Addenbrooke’s Hospital, Cambridge, UK
| | - Emmanuel Huguet
- />Hepatopancreatobiliary Unit, Department of Surgery, Addenbrooke’s Hospital, Cambridge, UK
| |
Collapse
|
|
16
|
Inaba K, Sakaguchi T, Kurachi K, Mori H, Tao H, Nakamura T, Takehara Y, Baba S, Maekawa M, Sugimura H, Konno H. Hepatocellular adenoma associated with familial adenomatous polyposis coli. World J Hepatol 2012; 4:322-326. [PMID: 23293720 PMCID: PMC3536841 DOI: 10.4254/wjh.v4.i11.322] [Citation(s) in RCA: 7] [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: 02/21/2012] [Revised: 08/27/2012] [Accepted: 10/22/2012] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular adenoma (HCA) is a benign liver tumor that most frequently occurs in young women using oral contraceptives. We report a rare case of HCA in a 29 years old female with familial adenomatous polyposis (FAP). The first proband was her sister, who underwent a total colectomy and was genetically diagnosed as FAP. A tumor, 3.0 cm in diameter, was detected in the right lobe of the liver during a screening study for FAP. A colonoscopy and gastroendoscopy revealed numerous adenomatous polyps without carcinoma. The patient underwent a total colectomy and ileo-anal anastomosis and hepatic posterior sectoriectomy. The pathological findings of the liver tumor were compatible with HCA. The resected specimen of the colon revealed multiple colonic adenomatous polyps. Examination of genetic alteration revealed a germ-line mutation of the adenomatous polyposis coli (APC) gene. Inactivation of the second APC allele was not found. Other genetic alterations in the hepatocyte nuclear factor 1 alpha and β-catenin gene, which are reported to be associated with HCA, were not detected. Although FAP is reported to be complicated with various neoplasias in extracolic organs, only six cases of HCA associated with FAP, including the present case, have been reported. Additional reports will establish the precise mechanisms of HCA development in FAP patients.
Collapse
Affiliation(s)
- Keisuke Inaba
- Keisuke Inaba, Department of Surgery, Iwata City Hospital, Iwata 438-8500, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Current and emerging therapeutic options in adrenocortical cancer treatment. JOURNAL OF ONCOLOGY 2012; 2012:408131. [PMID: 22934112 PMCID: PMC3425859 DOI: 10.1155/2012/408131] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/23/2012] [Revised: 06/26/2012] [Accepted: 06/27/2012] [Indexed: 12/14/2022]
Abstract
Adrenocortical carcinoma (ACC) is a very rare endocrine tumour, with variable prognosis, depending on tumour stage and time of diagnosis. The overall survival is five years from detection. Radical surgery is considered the therapy of choice in the first stages of ACC. However postoperative disease-free survival at 5 years is only around 30% and recurrence rates are frequent. o,p'DDD (ortho-, para'-, dichloro-, diphenyl-, dichloroethane, or mitotane), an adrenolytic drug with significant toxicity and unpredictable therapeutic response, is used in the treatment of ACC. Unfortunately, treatment for this aggressive cancer is still ineffective. Over the past years, the growing interest in ACC has contributed to the development of therapeutic strategies in order to contrast the neoplastic spread. In this paper we discuss the most promising therapies which can be used in this endocrine neoplasia.
Collapse
|
|
18
|
Hu PJ, Knoepp SM, Wu R, Cho KR. Ovarian steroid cell tumor with biallelic adenomatous polyposis coli inactivation in a patient with familial adenomatous polyposis. Genes Chromosomes Cancer 2011; 51:283-9. [PMID: 22120905 DOI: 10.1002/gcc.20953] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2011] [Revised: 10/17/2011] [Accepted: 10/18/2011] [Indexed: 01/09/2023] Open
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant cancer predisposition syndrome that accounts for approximately 0.5-1% of all colorectal cancer cases. It is caused by germline mutations in the gene encoding the adenomatous polyposis coli (APC) tumor suppressor. Somatic APC inactivation due to mutation or loss of heterozygosity (LOH) promotes the development of adenomatous polyps by stabilizing the transcriptional coactivator β-catenin. Although colorectal cancer is by far the most common malignancy seen in FAP patients, the widespread use of prophylactic colectomy in these patients has increased the clinical importance of extracolonic tumors that are part of the neoplastic spectrum in FAP. Many of these tumors exhibit LOH or somatic APC mutation, strongly supporting a causative role of APC inactivation in their pathogenesis. Here we describe a 47-year-old female FAP patient with clinical manifestations of virilization who was found to have an ovarian steroid cell tumor, a rare neoplasm not known to be associated with FAP. Immunohistochemical analysis of the ovarian tumor demonstrated strong nuclear β-catenin staining consistent with somatic APC inactivation, and molecular analysis confirmed biallelic APC inactivation in the tumor. Our findings provide the first evidence that ovarian steroid cell tumors may be an extracolonic manifestation of FAP and implicate β-catenin activation as an oncogenic mechanism in ovarian steroid cell tumorigenesis.
Collapse
Affiliation(s)
- Patrick J Hu
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
| | | | | | | |
Collapse
|
|
19
|
Toiyama Y, Inoue Y, Yasuda H, Yoshiyama S, Araki T, Miki C, Kusunoki M. Hepatocellular adenoma containing hepatocellular carcinoma in a male patient with familial adenomatous polyposis coli: Report of a case. Surg Today 2011; 41:1442-6. [PMID: 21922375 DOI: 10.1007/s00595-010-4451-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2010] [Accepted: 10/20/2010] [Indexed: 01/13/2023]
Abstract
Hepatocellular adenoma (HCA) is a benign condition occurring most frequently in young women using oral contraceptives. We herein report the first case of a 28-year-old man with familial adenomatous polyposis (FAP) who experienced hepatocellular carcinoma (HCC) within HCA. A preoperative computed tomography scan of the abdomen disclosed a tumor measuring 5.8 cm in diameter in the left lobe of the liver. A total proctocolectomy with construction of a linear stapled J-pouch, a hand-sewn ileoanal anastomosis and a liver tumor resection were performed. The pathology of the resected specimen confirmed the diagnosis of HCA containing HCC. Five cases of HCA have been reported that developed in patients with FAP, but this is the first case of HCA containing HCC. Hepatocellular adenomas occur due to the inactivation of hepatic nuclear factor 1α, but the mechanism underlying the malignant transformation from HCA to HCC could not be identified in this case.
Collapse
Affiliation(s)
- Yuji Toiyama
- Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | | | | | | | | | | | | |
Collapse
|
|
20
|
Gaujoux S, Pinson S, Gimenez-Roqueplo AP, Amar L, Ragazzon B, Launay P, Meatchi T, Libé R, Bertagna X, Audebourg A, Zucman-Rossi J, Tissier F, Bertherat J. Inactivation of the APC gene is constant in adrenocortical tumors from patients with familial adenomatous polyposis but not frequent in sporadic adrenocortical cancers. Clin Cancer Res 2010; 16:5133-41. [PMID: 20978149 DOI: 10.1158/1078-0432.ccr-10-1497] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE In adrenocortical tumors (ACT), Wnt/β-catenin pathway activation can be explained by β-catenin somatic mutations only in a subset of tumors. ACT is observed in patients with familial adenomatous polyposis (FAP) with germline APC mutations, as well as in patients with Beckwith-Wiedemann syndrome with Wilms' tumors reported to have WTX somatic mutations. Both APC and WTX are involved in Wnt/β-catenin pathway regulation and may play a role in ACT tumorigenesis. The aim of this study was to report if APC and WTX may be associated with FAP-associated and sporadic ACT. EXPERIMENTAL DESIGN ACTs from patients with FAP and sporadic adrenocortical carcinomas (ACC) with abnormal β-catenin localization on immunohistochemistry but no somatic β-catenin mutations were studied. APC was analyzed by denaturing high-performance liquid chromatography followed by direct sequencing and by multiplex ligation-dependent probe amplification when allelic loss was suspected. WTX was studied by direct sequencing. RESULTS Four ACTs were observed in three patients with FAP and were ACC, adrenocortical adenoma, and bilateral macronodular adrenocortical hyperplasia, all with abnormal β-catenin localization. Biallelic inactivation of APC was strongly suggested by the simultaneous existence of somatic and germline alterations in all ACTs. In the 20 sporadic ACCs, a silent heterozygous somatic mutation as well as a rare heterozygous polymorphism in APC was found. No WTX mutations were observed. CONCLUSIONS ACT should be considered a FAP tumor. Biallelic APC inactivation mediates activation of the Wnt/β-catenin pathway in the ACTs of patients with FAP. In contrast, APC and WTX genetic alterations do not play a significant role in sporadic ACC.
Collapse
Affiliation(s)
- Sébastien Gaujoux
- Institut Cochin, Université Paris Descartes-Faculté de médecine, CNRS (UMR 8104), Paris, France
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Will OCC, Hansmann A, Phillips RKS, Palazzo FF, Meeran K, Marshall M, Clark SK. Adrenal incidentaloma in familial adenomatous polyposis: a long-term follow-up study and schema for management. Dis Colon Rectum 2009; 52:1637-44. [PMID: 19690494 DOI: 10.1007/dcr.0b013e3181a876d6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE Adrenal incidentaloma is often diagnosed in patients with familial adenomatous polyposis, because they frequently undergo abdominal imaging and have a raised incidence of adrenal incidentaloma. This study investigates the natural history of adrenal incidentaloma in familial adenomatous polyposis, and suggests a schema for management. METHODS An original cohort of 14 familial adenomatous polyposis patients with adrenal incidentaloma, identified prospectively 12 years ago, was followed up clinically and radiologically. A further group of 16 patients was also identified. All had lesions >1 cm. For both cohorts, characteristics of patients (genotype, age at diagnosis, concomitant diagnoses) and incidentaloma (size, laterality, rate of growth, outcome) are described. RESULTS Overall, 3 of 30 patients underwent adrenalectomy; one patient had pheochromocytoma and another had an adenoma of borderline malignancy. A further three lesions were radiologically suspicious for malignancy at the time of diagnosis; one was in a patient who was unfit for surgery but died of nonadrenal causes after nine years. None of the lesions radiologically benign at diagnosis showed an aggressive course, but one patient required referral for surgery after 12 years because of a slow increase in size of the lesion. There were no associations with genotype. CONCLUSIONS Familial adenomatous polyposis-associated adrenal incidentaloma may warrant long-term follow-up. Although the natural history is similar to lesions occurring sporadically, these patients have concomitant familial adenomatous polyposis-associated manifestations under radiologic surveillance. In this rare condition, development of a robust protocol will require evidence from worldwide patient cohorts. However, a tailored schema is suggested as a consistent basis for future modification.
Collapse
Affiliation(s)
- O C C Will
- The Polyposis Registry, St. Mark's Hospital, Harrow, United Kingdom.
| | | | | | | | | | | | | |
Collapse
|
|
22
|
Tissier F. Anatomie pathologique des tumeurs corticosurrénaliennes de l’adulte : état des lieux et données récentes. ANNALES D'ENDOCRINOLOGIE 2009; 70:179-85. [DOI: 10.1016/j.ando.2009.02.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
|
|
23
|
Bielinska M, Parviainen H, Kiiveri S, Heikinheimo M, Wilson DB. Review paper: origin and molecular pathology of adrenocortical neoplasms. Vet Pathol 2009; 46:194-210. [PMID: 19261630 DOI: 10.1354/vp.46-2-194] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Neoplastic adrenocortical lesions are common in humans and several species of domestic animals. Although there are unanswered questions about the origin and evolution of adrenocortical neoplasms, analysis of human tumor specimens and animal models indicates that adrenocortical tumorigenesis involves both genetic and epigenetic alterations. Chromosomal changes accumulate during tumor progression, and aberrant telomere function is one of the key mechanisms underlying chromosome instability during this process. Epigenetic changes serve to expand the size of the uncommitted adrenal progenitor population, modulate their phenotypic plasticity (i.e., responsiveness to extracellular signals), and increase the likelihood of subsequent genetic alterations. Analyses of heritable and spontaneous types of human adrenocortical tumors documented alterations in either cell surface receptors or their downstream effectors that impact neoplastic transformation. Many of the mutations associated with benign human adrenocortical tumors result in dysregulated cyclic adenosine monophosphate signaling, whereas key factors and/or signaling pathways associated with adrenocortical carcinomas include dysregulated expression of the IGF2 gene cluster, activation of the Wnt/beta-catenin pathway, and inactivation of the p53 tumor suppressor. A better understanding of the factors and signaling pathways involved in adrenal tumorigenesis is necessary to develop targeted pharmacologic and genetic therapies.
Collapse
Affiliation(s)
- M Bielinska
- Box 8208, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA.
| | | | | | | | | |
Collapse
|
|
24
|
Abstract
The study of the clonality of adrenocortical tumours (ACTs) has shown that adrenocortical cancers (ACCs) are of monoclonal origin. Numerous chromosomal alterations have been observed in ACCs, and they are much more frequent than in adrenocortical adenomas. Progress in the genetics of familial syndromes associated with ACTs helped to identify significant somatic molecular alterations in sporadic adult ACCs. Somatic mutations of the tumour suppressor gene TP53 are observed in a third of ACCs. Interestingly, allelic losses (LOH) at the TP53 locus (17p13) are very frequent, observed in more than 85% of ACCs. The insulin-like growth factor II (IGF-II) locus (11p15) is imprinted. IGF-II is over-expressed in 90% of ACCs. Transcriptome studies have identified an IGF-II cluster of genes significantly over-expressed in ACCs. Transcriptome analysis suggests also that the Wnt/beta-catenin signalling pathway is activated in ACT. About a third of ACCs harbours somatic activating mutations of the beta-catenin gene. This recent progress in the molecular genetics of ACC has led to the development of new molecular markers for the diagnosis of malignancy; these might also help to identify prognostic markers of ACC and may ultimately lead to novel therapeutic approaches.
Collapse
Affiliation(s)
- Jérôme Bertherat
- Endocrinology, Metabolism & Cancer Department, INSERM U567, CNRS UMR8104, Institut Cochin, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, INCa-COMETE Centre for Adrenal Cancer, Université Paris-Descartes, Paris, France.
| | | |
Collapse
|
|
25
|
Hepatocellular adenoma in a male with familial adenomatous polyposis coli. ACTA ACUST UNITED AC 2009; 16:571-4. [PMID: 19288049 DOI: 10.1007/s00534-009-0050-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2008] [Accepted: 03/17/2008] [Indexed: 02/07/2023]
Abstract
Hepatocellular adenoma (HA) is a benign liver tumor most frequently occurring in young women using oral contraceptives. We report a rare case of HA in a 27-year-old male patient with familial adenomatous polyposis (FAP). The patient underwent a total colectomy and ileo-rectal anastomosis for FAP in 2003. A preoperative computed tomography scan of the abdomen disclosed a tumor in the left-lobe of the liver, 5.8 cm in diameter. Pathologic examination of a needle biopsy disclosed HA, but he had never used anabolic steroids or other known inducers of HA. The size of the liver mass gradually increased to 8.5 cm during a follow-up period of 38 months, and a left hepatectomy was performed in 2006. Pathology of the resected specimen confirmed the diagnosis of HA. Although FAP is known to be complicated with neoplasia in various extracolonic organs, only five reported cases of HA have developed in patients with FAP, including this case. This is the first report of HA to develop in a male FAP patient.
Collapse
|
|
26
|
Tissier F. [Sporadic adrenocortical tumors: genetics and perspectives for the pathologist]. Ann Pathol 2008; 28:409-16. [PMID: 19068395 DOI: 10.1016/j.annpat.2008.07.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/30/2008] [Indexed: 11/24/2022]
Abstract
Most adrenocortical tumors are benign; adrenocortical carcinomas are rare but their prognosis is poor and few therapeutic options are available. In most adrenocortical tumors, the morphological approach provides enough elements to establish the differential diagnosis between a benign and a malignant tumor but in few cases, it is insufficient. Moreover, morphology is limited for predicting prognosis of adrenocortical carcinomas. These observations led to development of other approaches, in particular immunohistochemical and genetic approaches. The comprehension of the genetic syndromes associated with adrenocortical tumors led to progress in the identification of genetic abnormalities involved in sporadic adrenocortical tumorigenesis. Thus, in sporadic adrenocortical tumorigenesis, IGF-II overexpression and cyclin E overproduction have been associated with 11p15 alterations which are observed in Bethwith-Wiedemann syndrome and TP53 inactivating mutations and 17p13 locus abnormalities which are observed in Li-Fraumeni syndrome. Activation of the Wnt/ss-catenin signaling pathway which is observed in familial adenomatous polyposis has been found in adrenocortical adenomas and carcinomas associated to mutations of CTNNB1, the gene coding ss-catenin, suggesting a central role for this pathway in adrenocortical tumorigenesis. These genetics findings already have had repercussions for patients via the development of molecular markers for diagnosis and prognosis; in the future they should be helpful in the development of new therapeutics.
Collapse
Affiliation(s)
- Fréderique Tissier
- Service d'anatomie pathologique, hôpital Cochin, AP-HP, Paris, France; Faculté de médecine Paris-Descartes, université Paris-Descartes, Paris, France.
| |
Collapse
|
|
27
|
Rebouissou S, Couchy G, Libbrecht L, Balabaud C, Imbeaud S, Auffray C, Roskams T, Bioulac-Sage P, Zucman-Rossi J. The beta-catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules. J Hepatol 2008; 49:61-71. [PMID: 18466996 DOI: 10.1016/j.jhep.2008.03.013] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2007] [Revised: 02/25/2008] [Accepted: 03/03/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Focal nodular hyperplasias (FNHs) are benign liver lesions considered to be a hyperplastic response to increased blood flow in normal liver. In contrast, FNH-like lesions/nodules occur in cirrhotic liver but share similar histopathological features. We conducted a transcriptome analysis to identify biological pathways deregulated in FNH. METHODS Gene expression profiles obtained in FNH and normal livers were compared. Differentially-expressed genes were validated using quantitative-RT-PCR in 70 benign liver tumors including FNH-like lesions. RESULTS Among the deregulated genes in FNHs, 19 displayed physiological restricted distribution in the normal liver. All six perivenous genes were up-regulated in FNH, whereas 13 periportal genes were down-regulated. Almost all these genes are known to be regulated by beta-catenin. Glutamine synthetase was markedly overexpressed in anastomosed areas usually centered on visible veins. Moreover, activated hypophosphorylated beta-catenin protein accumulated in FNH in the absence of activating mutations. These results suggest the zonated activation of the beta-catenin pathway in FNH, whereas the other benign hepatocellular tumors, including FNH-like lesions, demonstrated an entirely different pattern of beta-catenin expression. CONCLUSIONS In FNH, increased activation of the beta-catenin pathway was found restricted to enlarged perivenous areas. FNH-like nodules may have a different pathogenetic origin.
Collapse
Affiliation(s)
- Sandra Rebouissou
- Inserm, U674, Génomique fonctionnelle des tumeurs solides, 27 rue Juliette Dodu, Paris F-75010, France
| | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Bioulac-Sage P, Balabaud C, Zucman-Rossi J. Les tumeurs hépatocytaires bénignes – des connaissances récentes : de la biologie moléculaire au diagnostic. ACTA ACUST UNITED AC 2008; 32:296-303; quiz 293, 314. [DOI: 10.1016/j.gcb.2008.02.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
|
|
29
|
Rebouissou S, Bioulac-Sage P, Zucman-Rossi J. Molecular pathogenesis of focal nodular hyperplasia and hepatocellular adenoma. J Hepatol 2008; 48:163-70. [PMID: 17997499 DOI: 10.1016/j.jhep.2007.10.003] [Citation(s) in RCA: 139] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2007] [Revised: 10/14/2007] [Accepted: 10/16/2007] [Indexed: 12/12/2022]
Abstract
Focal nodular hyperplasia (FNH) and hepatocellular adenomas (HCAs) are benign tumors that occur in otherwise normal liver parenchyma. FNH is considered to be the result of a hyperplastic response to increased blood flow secondary to vascular malformations. Most FNH are polyclonal and to date, the molecular pathway and mechanisms that are altered in FNH have yet to be elucidated. In contrast, HCAs are consistently monoclonal tumors, which have been divided up into three subtypes of tumors depending on the molecular alteration detected in the tumors: HNF1alpha inactivation, beta-catenin activation and/or an acute inflammatory response in the tumor. These molecular features are closely related to clinical and pathological characteristics, and one of the most critical correlations is the higher risk of malignant transformation for beta-catenin activated HCA cases. Moreover, various risk factors, such as oral contraception and obesity, are associated with HCA occurrence and may collaborate with constitutional genetic predisposition related to HNF1alpha or CYP1B1 germline mutations. Altogether, the recent identification of different molecular pathways that contribute to tumor development has significantly increased our knowledge of benign hepatocellular tumorigenesis. These findings may modify our clinical practice, particularly in the diagnosis and follow-up of HCA patients.
Collapse
Affiliation(s)
- Sandra Rebouissou
- Inserm, U674, Génomique fonctionnelle des tumeurs solides, Génétique des tumeurs hépatiques, Paris, France
| | | | | |
Collapse
|
|
30
|
Bioulac-Sage P, Blanc JF, Rebouissou S, Balabaud C, Zucman-Rossi J. Genotype phenotype classification of hepatocellular adenoma. World J Gastroenterol 2007; 13:2649-54. [PMID: 17569132 PMCID: PMC4147112 DOI: 10.3748/wjg.v13.i19.2649] [Citation(s) in RCA: 59] [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] [Indexed: 02/06/2023] Open
Abstract
Studies that compare tumor genotype with phenotype have provided the basis of a new histological/molecular classification of hepatocellular adenomas. Based on two molecular criteria (presence of a TCF1/HNF1α or β-catenin mutation), and an additional histological criterion (presence or absence of an inflammatory infiltrate), subgroups of hepatocellular adenoma can be defined and distinguished from focal nodular hyperplasia. Analysis of 96 hepatocellular adenomas performed by a French collaborative network showed that they can be divided into four broad subgroups: the first one is defined by the presence of mutations in TCF1 gene inactivating the hepatocyte nuclear factor 1 (HNF1α); the second by the presence of β-catenin activating mutations; the category without mutations of HNF1α or β-catenin is further divided into 2 subgroups depending on the presence or absence of inflammation. Therefore, the approach to the diagnosis of problematic benign hepatocytic nodules may be entering a new era directed by new molecular information. It is hoped that immunohistological tools will improve significantly diagnosis of liver biopsy in our ability to distinguish hepatocellular adenoma from focal nodular hyperplasia (FNH), and to delineate clinically meaningful entities within each group to define the best clinical management. The optimal care of patients with a liver nodule will benefit from the recent knowledge coming from molecular biology and the combined expertise of hepatologists, pathologists, radiologists, and surgeons.
Collapse
|
|
31
|
Jeannot E, Wendum D, Paye F, Mourra N, de Toma C, Fléjou JF, Zucman-Rossi J. Hepatocellular adenoma displaying a HNF1alpha inactivation in a patient with familial adenomatous polyposis coli. J Hepatol 2006; 45:883-6. [PMID: 17049664 PMCID: PMC2121664 DOI: 10.1016/j.jhep.2006.06.020] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2006] [Revised: 06/22/2006] [Accepted: 06/26/2006] [Indexed: 12/16/2022]
Abstract
Patients with familial adenomatous polyposis coli (FAP) may rarely develop hepatocellular adenoma. Here we report the case of a 37-year-old FAP woman presenting a hepatocellular adenoma after oestroprogestative oral contraception use. In this steatotic adenoma, we identified an inactivating biallelic mutation of HNF1alpha. In addition to the known germline APC mutation Q1062fs, we did not find an inactivation of the second APC allele nor an activation of the beta-catenin target genes GLUL and GPR49. Our findings contrast with two hepatocellular adenoma cases related to FAP, for which a biallelic inactivation of the APC gene was previously described. Altogether, these results suggest that benign hepatocellular carcinogenesis may be dependent on or independent of the Wnt/beta-catenin pathway in patients with FAP.
Collapse
Affiliation(s)
- Emmanuelle Jeannot
- Genomique Fonctionnelle des Tumeurs Solides
INSERM : U674Université Denis Diderot - Paris VIIHopital Saint-Louis - IFR 105 PARIS VII
27, Rue Juliette Dodu
75010 PARIS ,FR
| | - Dominique Wendum
- Service d'anatomie et cytologie pathologiques
AP-HP Hôpital Saint-AntoineUniversité Pierre et Marie Curie - Paris VI184, rue du Faubourg Saint-Antoine
75571 PARIS Cedex 12,FR
| | - François Paye
- Service de chirurgie générale et digestive
AP-HP Hôpital Saint-AntoineUniversité Pierre et Marie Curie - Paris VI184, rue du Faubourg Saint-Antoine
75571 PARIS Cedex 12,FR
| | - Najat Mourra
- Service d'anatomie et cytologie pathologiques
AP-HP Hôpital Saint-AntoineUniversité Pierre et Marie Curie - Paris VI184, rue du Faubourg Saint-Antoine
75571 PARIS Cedex 12,FR
| | - Claudia de Toma
- Centre d'Etude du Polymorphisme Humain
Fondation Jean DaussetFR
| | - Jean-François Fléjou
- Service d'anatomie et cytologie pathologiques
AP-HP Hôpital Saint-AntoineUniversité Pierre et Marie Curie - Paris VI184, rue du Faubourg Saint-Antoine
75571 PARIS Cedex 12,FR
| | - Jessica Zucman-Rossi
- Genomique Fonctionnelle des Tumeurs Solides
INSERM : U674Université Denis Diderot - Paris VIIHopital Saint-Louis - IFR 105 PARIS VII
27, Rue Juliette Dodu
75010 PARIS ,FR
- * Correspondence should be adressed to: Jessica Zucman-Rossi
| |
Collapse
|
|
32
|
|
|
33
|
Bertherat J, Groussin L, Bertagna X. Mechanisms of Disease: adrenocortical tumors—molecular advances and clinical perspectives. ACTA ACUST UNITED AC 2006; 2:632-41. [PMID: 17082810 DOI: 10.1038/ncpendmet0321] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2006] [Accepted: 07/10/2006] [Indexed: 12/17/2022]
Abstract
Most adrenocortical tumors are benign, unilateral, adrenocortical adenomas that are often discovered incidentally. Adrenocortical cancer is rare. Exceptionally, adrenocortical tumors can be bilateral. Although most adrenocortical tumors occur sporadically, they may also feature in congenital and/or familial disease. The identification of germline genetic defects in familial diseases associated with adrenocortical tumors helped to define the somatic alterations in sporadic disease: for example, overexpression of insulin-like growth factor 2 and alterations at the 11p15 locus (observed in Beckwith-Wiedemann syndrome) are also found in most adrenocortical cancers. Similarly, inactivating mutations of the TP53 gene, located at 17p13 (observed in Li-Fraumeni syndrome), can also be found at the somatic level in sporadic adrenocortical cancers, as can 17p13 allelic losses. Components of the cyclic AMP signaling pathway--for example, adrenocorticotropic hormone receptors and other membrane receptors, Gs proteins and protein kinase A--can be altered to various degrees in adrenocortical tumors. More recently, gene profiling and genetic studies have shown that the Wnt-beta-catenin signaling pathway is frequently activated in adrenocortical tumors. These research findings already have profound implications for clinical management of patients with adrenocortical tumors, for example in unraveling the genetic origin of the disease in some patients, and in the development of molecular markers for diagnosis and prognosis. The new findings should also help in the development of new therapeutic options.
Collapse
Affiliation(s)
- Jérôme Bertherat
- University of Paris 5, Cochin Hospital, Endocrinology Service, Paris, France.
| | | | | |
Collapse
|
|
34
|
Zucman-Rossi J, Jeannot E, Nhieu JTV, Scoazec JY, Guettier C, Rebouissou S, Bacq Y, Leteurtre E, Paradis V, Michalak S, Wendum D, Chiche L, Fabre M, Mellottee L, Laurent C, Partensky C, Castaing D, Zafrani ES, Laurent-Puig P, Balabaud C, Bioulac-Sage P. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology 2006; 43:515-24. [PMID: 16496320 DOI: 10.1002/hep.21068] [Citation(s) in RCA: 533] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Hepatocellular adenomas are benign tumors that can be difficult to diagnose. To refine their classification, we performed a comprehensive analysis of their genetic, pathological, and clinical features. A multicentric series of 96 liver tumors with a firm or possible diagnosis of hepatocellular adenoma was reviewed by liver pathologists. In all cases, the genes coding for hepatocyte nuclear factor 1alpha (HNF1alpha) and beta-catenin were sequenced. No tumors were mutated in both HNF1alpha and beta-catenin enabling tumors to be classified into 3 groups, according to genotype. Tumors with HNF1alpha mutations formed the most important group of adenomas (44 cases). They were phenotypically characterized by marked steatosis (P < 10(-4)), lack of cytological abnormalities (P < 10(-6)), and no inflammatory infiltrates (P < 10(-4)). In contrast, the group of tumors defined by beta-catenin activation included 13 lesions with frequent cytological abnormalities and pseudo-glandular formation (P < 10(-5)). The third group of tumors without mutation was divided into two subgroups based on the presence of inflammatory infiltrates. The subgroup of tumors consisting of 17 inflammatory lesions, resembled telangiectatic focal nodular hyperplasias, with frequent cytological abnormalities (P = 10(-3)), ductular reaction (P < 10(-2)), and dystrophic vessels (P = .02). In this classification, hepatocellular carcinoma associated with adenoma or borderline lesions between carcinoma and adenoma is found in 46% of the beta-catenin-mutated tumors whereas they are never observed in inflammatory lesions and are rarely found in HNF1alpha mutated tumors (P = .004). In conclusion, the molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype-phenotype correlations and suggests that adenomas with beta-catenin activation have a higher risk of malignant transformation.
Collapse
|
|
35
|
Tissier F, Cavard C, Groussin L, Perlemoine K, Fumey G, Hagneré AM, René-Corail F, Jullian E, Gicquel C, Bertagna X, Vacher-Lavenu MC, Perret C, Bertherat J. Mutations of beta-catenin in adrenocortical tumors: activation of the Wnt signaling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res 2005; 65:7622-7. [PMID: 16140927 DOI: 10.1158/0008-5472.can-05-0593] [Citation(s) in RCA: 323] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Adrenocortical cancer is a rare cancer with a very poor prognosis. The genetic alterations identified to date in adrenocortical tumors are limited. Activating mutations of the Wnt signaling pathway have been observed in more frequent cancers, particularly digestive tract tumors. We investigated whether Wnt pathway activation is involved in adrenocortical tumorigenesis. In a series of 39 adrenocortical tumors, immunohistochemistry revealed abnormal cytoplasmic and/or nuclear accumulation of beta-catenin in 10 of 26 adrenocortical adenomas and in 11 of 13 adrenocortical carcinomas. An activating somatic mutation of the beta-catenin gene was shown in 7 of 26 adrenocortical adenomas and in 4 of 13 adrenocortical carcinomas; these mutations were observed only in adrenocortical tumors with abnormal beta-catenin accumulation and most were point mutations altering the Ser45 of exon 3 (in the consensus GSK3-beta/CK1 phosphorylation site). Functional studies showed that the activating Ser45 beta-catenin mutation found in the adrenocortical cancer H295R cell line leads to constitutive activation of T-cell factor-dependent transcription. This is the first molecular defect to be reported with the same prevalence in both benign (27%) and malignant (31%) adrenocortical tumors. beta-Catenin mutations are also the most frequent genetic defect currently known in adrenocortical adenomas. In adrenocortical adenomas, beta-catenin alterations are more frequent in nonfunctioning tumors, suggesting that beta-catenin pathway activation might be mostly involved in the development of nonsecreting adrenocortical adenomas and adrenocortical carcinomas. The very frequent and substantial accumulation of beta-catenin in adrenocortical carcinomas suggests that other alterations might also be involved. This finding may contribute to new therapeutic approaches targeting the Wnt pathway in malignant adrenocortical tumors, for which limited medical therapy is available.
Collapse
Affiliation(s)
- Frédérique Tissier
- Department of Endocrinology, Institut National de la Santé et de la Recherche Médicale U567, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, IFR116, René Descartes-Paris 5 University, France
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|