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Dhawan A, Baitamouni S, Liu D, Yehia L, Anthony K, McCarther A, Tischkowitz M, MacFarland SP, Ngeow J, Hoogerbrugge N, Eng C. Cancer and Overgrowth Manifestations of PTEN Hamartoma Tumor Syndrome: Management Recommendations from the International PHTS Consensus Guidelines Working Group. Clin Cancer Res 2025; 31:1754-1765. [PMID: 39937242 PMCID: PMC12010961 DOI: 10.1158/1078-0432.ccr-24-3819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/27/2024] [Accepted: 02/06/2025] [Indexed: 02/13/2025]
Abstract
PURPOSE PTEN hamartoma tumor syndrome (PHTS) is an autosomal dominant cancer predisposition and overgrowth syndrome caused by pathogenic germline variants in the PTEN gene, with an increased risk of both benign and malignant tumors involving the breast, colon, endometrium, thyroid, skin, and kidney. The objective of these clinical guidelines was to use the latest knowledge to generate an international consensus resource for providers, researchers, and individuals with PHTS on the best practices in the surveillance and management of cancer and overgrowth in PHTS. EXPERIMENTAL DESIGN The International PHTS Cancer and Overgrowth Guidelines Working Group was established, comprising a core group of six international experts in the diagnosis and management of PHTS. The working group held joint meetings with individuals with PHTS and their advocates. Informed by the literature, the working group met regularly between 2022 and 2024 to produce guideline statements, refined through iterative feedback. A modified Delphi approach was used with an independent external panel of PHTS, genetics, and cancer experts to establish final consensus guidelines. RESULTS Clinical consensus recommendations for the surveillance and management of cancer and overgrowth in individuals with PHTS were formed. The guidelines encompass the recommended practices in cases of breast, colon, endometrial, thyroid, and kidney cancers, as well as overgrowths. CONCLUSIONS The clinical management of individuals with PHTS is complex and necessitates a multidisciplinary approach. We generated international consensus guidelines for the surveillance and management of cancer and overgrowth in PHTS, aiming at improving care for affected individuals and families.
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Affiliation(s)
- Andrew Dhawan
- Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Sarah Baitamouni
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Darren Liu
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio
| | - Lamis Yehia
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Kristin Anthony
- PTEN Hamartoma Tumor Syndrome Foundation, Huntsville, Alabama
| | | | - Marc Tischkowitz
- Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom
| | - Suzanne P. MacFarland
- Division of Oncology, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joanne Ngeow
- Genomic Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
- Cancer Genetics Service, Division of Medical Oncology, National Cancer Centre, Singapore, Singapore
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands
| | - Charis Eng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
- Center for Personalized Genetic Healthcare, Medical Specialties Institute, Cleveland Clinic, Cleveland, Ohio
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio
- Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio
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Foda ZH, Dharwadkar P, Katona BW. Preventive strategies in familial and hereditary colorectal cancer. Best Pract Res Clin Gastroenterol 2023; 66:101840. [PMID: 37852714 DOI: 10.1016/j.bpg.2023.101840] [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: 04/14/2023] [Revised: 05/05/2023] [Accepted: 05/17/2023] [Indexed: 10/20/2023]
Abstract
Colorectal cancer is a leading cause of cancer-related deaths worldwide. While most cases are sporadic, a significant proportion of cases are associated with familial and hereditary syndromes. Individuals with a family history of colorectal cancer have an increased risk of developing the disease, and those with hereditary syndromes such as Lynch syndrome or familial adenomatous polyposis have a significantly higher risk. In these populations, preventive strategies are critical for reducing the incidence and mortality of colorectal cancer. This review provides an overview of current preventive strategies for individuals at increased risk of colorectal cancer due to familial or hereditary factors. The manuscript includes a discussion of risk assessment and genetic testing, highlighting the importance of identifying at-risk individuals and families. This review describes various preventive measures, including surveillance colonoscopy, chemoprevention, and prophylactic surgery, and their respective benefits and limitations. Together, this work highlights the importance of preventive strategies in familial and hereditary colorectal cancer.
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Affiliation(s)
- Zachariah H Foda
- The Sidney Kimmel Comprehensive Cancer Center and Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Pooja Dharwadkar
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA
| | - Bryson W Katona
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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Rahmatinejad Z, Goshayeshi L, Bergquist R, Goshayeshi L, Golabpour A, Hoseini B. PTEN hamartoma tumour syndrome: case report based on data from the Iranian hereditary colorectal cancer registry and literature review. Diagn Pathol 2023; 18:43. [PMID: 37016356 PMCID: PMC10071641 DOI: 10.1186/s13000-023-01331-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 03/22/2023] [Indexed: 04/06/2023] Open
Abstract
BACKGROUND PTEN hamartoma tumour syndrome (PHTS) is a rare hereditary disorder caused by germline pathogenic mutations in the PTEN gene. This study presents a case of PHTS referred for genetic evaluation due to multiple polyps in the rectosigmoid area, and provides a literature review of PHTS case reports published between March 2010 and March 2022. CASE PRESENTATION A 39-year-old Iranian female with a family history of gastric cancer in a first-degree relative presented with minimal bright red blood per rectum and resistant dyspepsia. Colonoscopy revealed the presence of over 20 polyps in the rectosigmoid area, while the rest of the colon appeared normal. Further upper endoscopy showed multiple small polyps in the stomach and duodenum, leading to a referral for genetic evaluation of hereditary colorectal polyposis. Whole-exome sequencing led to a PHTS diagnosis, even though the patient displayed no clinical or skin symptoms of the condition. Further screenings identified early-stage breast cancer and benign thyroid nodules through mammography and thyroid ultrasound. METHOD AND RESULTS OF LITERATURE REVIEW A search of PubMed using the search terms "Hamartoma syndrome, Multiple" [Mesh] AND "case report" OR "case series" yielded 43 case reports, predominantly in women with a median age of 39 years. The literature suggests that patients with PHTS often have a family history of breast, thyroid and endometrial neoplasms along with pathogenic variants in the PTEN/MMAC1 gene. Gastrointestinal polyps are one of the most common signs reported in the literature, and the presence of acral keratosis, trichilemmomas and mucocutaneous papillomas are pathognomonic characteristics of PHTS. CONCLUSION When a patient presents with more than 20 rectosigmoid polyps, PHTS should be considered. In such cases, it is recommended to conduct further investigations to identify other potential manifestations and the phenotype of PHTS. Women with PHTS should undergo annual mammography and magnetic resonance testing for breast cancer screening from the age of 30, in addition to annual transvaginal ultrasounds and blind suction endometrial biopsies.
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Affiliation(s)
- Zahra Rahmatinejad
- Department of Medical Informatics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ladan Goshayeshi
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Robert Bergquist
- Ingerod, Brastad, SE-454 94, Sweden
- Formerly UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization, Geneva, Switzerland
| | - Lena Goshayeshi
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amin Golabpour
- School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Benyamin Hoseini
- Pharmaceutical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Hendricks LAJ, Hoogerbrugge N, Mensenkamp AR, Brunet J, Lleuger-Pujol R, Høberg-Vetti H, Tveit Haavind M, Innella G, Turchetti D, Aretz S, Spier I, Tischkowitz M, Jahn A, Links TP, Olderode-Berends MJW, Blatnik A, Leter EM, Evans DG, Woodward ER, Steinke-Lange V, Anastasiadou VC, Colas C, Villy MC, Benusiglio PR, Gerasimenko A, Barili V, Branchaud M, Houdayer C, Tesi B, Yazicioglu MO, van der Post RS, Schuurs-Hoeijmakers JHM, Vos JR. Cancer risks by sex and variant type in PTEN hamartoma tumor syndrome. J Natl Cancer Inst 2023; 115:93-103. [PMID: 36171661 DOI: 10.1093/jnci/djac188] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 07/26/2022] [Accepted: 09/23/2022] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND PTEN Hamartoma Tumor Syndrome (PHTS) is a rare syndrome with a broad phenotypic spectrum, including increased risks of breast (BC, 67%-78% at age 60 years), endometrial (EC, 19%-28%), and thyroid cancer (TC, 6%-38%). Current risks are likely overestimated due to ascertainment bias. We aimed to provide more accurate and personalized cancer risks. METHODS This was a European, adult PHTS cohort study with data from medical files, registries, and/or questionnaires. Cancer risks and hazard ratios were assessed with Kaplan-Meier and Cox regression analyses, and standardized incidence ratios were calculated. Bias correction consisted of excluding cancer index cases and incident case analyses. RESULTS A total of 455 patients were included, including 50.5% index cases, 372 with prospective follow-up (median 6 years, interquartile range = 3-10 years), and 159 of 281 females and 39 of 174 males with cancer. By age 60 years, PHTS-related cancer risk was higher in females (68.4% to 86.3%) than males (16.4% to 20.8%). Female BC risks ranged from 54.3% (95% confidence interval [CI] = 43.0% to 66.4%) to 75.8% (95% CI = 60.7% to 88.4%), with two- to threefold increased risks for PTEN truncating and approximately twofold for phosphatase domain variants. EC risks ranged from 6.4% (95% CI = 2.1% to 18.6%) to 22.1% (95% CI = 11.6% to 39.6%) and TC risks from 8.9% (95% CI = 5.1% to 15.3%) to 20.5% (95% CI = 11.3% to 35.4%). Colorectal cancer, renal cancer, and melanoma risks were each less than 10.0%. CONCLUSIONS Females have a different BC risk depending on their PTEN germline variant. PHTS patients are predominantly at risk of BC (females), EC, and TC. This should be the main focus of surveillance. These lower, more unbiased and personalized risks provide guidance for optimized cancer risk management.
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Affiliation(s)
- Linda A J Hendricks
- Department of Human Genetics, Radboudumc Expert Center for PHTS, Radboud university medical center, Nijmegen, the Netherlands.,Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboudumc Expert Center for PHTS, Radboud university medical center, Nijmegen, the Netherlands.,Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
| | - Arjen R Mensenkamp
- Department of Human Genetics, Radboudumc Expert Center for PHTS, Radboud university medical center, Nijmegen, the Netherlands.,Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
| | - Joan Brunet
- Hereditary Cancer Program, Catalan Institute of Oncology, ONCOBELL-IDIBELL-IDIBGI-IGTP, CIBERONC, Barcelona, Spain
| | - Roser Lleuger-Pujol
- Hereditary Cancer Program, Catalan Institute of Oncology, ONCOBELL-IDIBELL-IDIBGI-IGTP, CIBERONC, Barcelona, Spain
| | - Hildegunn Høberg-Vetti
- Western Norway Familial Cancer Center, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Marianne Tveit Haavind
- Western Norway Familial Cancer Center, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Giovanni Innella
- Department of Medical and Surgical Sciences, Center for Studies on Hereditary Cancer, University of Bologna and Unit of Medical Genetics, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Daniela Turchetti
- Department of Medical and Surgical Sciences, Center for Studies on Hereditary Cancer, University of Bologna and Unit of Medical Genetics, IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Stefan Aretz
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Isabel Spier
- Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Marc Tischkowitz
- Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Arne Jahn
- Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,Hereditary Cancer Syndrome Center Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Dresden, Germany.,National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany
| | - Thera P Links
- Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Maran J W Olderode-Berends
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ana Blatnik
- Department of Clinical Cancer Genetics, Institute of Oncology Ljubljana, Ljubljana, Slovenia
| | - Edward M Leter
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands
| | - D Gareth Evans
- Manchester Centre for Genomic Medicine, St Mary's Hospital, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK
| | - Emma R Woodward
- Manchester Centre for Genomic Medicine, St Mary's Hospital, Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, UK
| | - Verena Steinke-Lange
- Medical Genetics Center, Munich, Germany.,Arbeitsgruppe Erbliche Gastrointestinale Tumore, Medizinische Klinik und Poliklinik IV-Campus Innenstadt, Klinikum der Universität München, Munich, Germany
| | - Violetta C Anastasiadou
- Karaiskakio Foundation, Nicosia Cyprus and Archbishop Makarios III Children's Hospital, Nicosia, Cyprus
| | - Chrystelle Colas
- Institut Curie, Service de Génétique, Paris, France.,Inserm U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe Labellisée Par la Ligue Nationale Contre le Cancer, Paris, France
| | - Marie-Charlotte Villy
- Inserm U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe Labellisée Par la Ligue Nationale Contre le Cancer, Paris, France
| | - Patrick R Benusiglio
- UF d'oncogénétique Clinique, Department de Génétique, Hôspital Pitié-Salpêtrière, AP-HP, Sorbonne Université, Paris, France
| | - Anna Gerasimenko
- UF d'oncogénétique Clinique, Department de Génétique, Hôspital Pitié-Salpêtrière, AP-HP, Sorbonne Université, Paris, France
| | - Valeria Barili
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Maud Branchaud
- Department of Genetics, Normandy Center for Genomic and Personalized Medicine, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France
| | - Claude Houdayer
- Department of Genetics, Normandy Center for Genomic and Personalized Medicine, Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France
| | - Bianca Tesi
- Department of Clinical Genetics, Karolinska University Hospital and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - M Omer Yazicioglu
- Department of Endocrine Tumors and Sarcoma, Karolinska University Hospital and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Rachel S van der Post
- Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands.,Department of Pathology, Radboud university medical center, Nijmegen, the Netherlands
| | - Janneke H M Schuurs-Hoeijmakers
- Department of Human Genetics, Radboudumc Expert Center for PHTS, Radboud university medical center, Nijmegen, the Netherlands
| | | | - Janet R Vos
- Department of Human Genetics, Radboudumc Expert Center for PHTS, Radboud university medical center, Nijmegen, the Netherlands.,Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, the Netherlands
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Boland CR, Idos GE, Durno C, Giardiello FM, Anderson JC, Burke CA, Dominitz JA, Gross S, Gupta S, Jacobson BC, Patel SG, Shaukat A, Syngal S, Robertson DJ. Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2022; 162:2063-2085. [PMID: 35487791 DOI: 10.1053/j.gastro.2022.02.021] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.
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Affiliation(s)
- C Richard Boland
- Division of Gastroenterology, University of California-San Diego School of Medicine, San Diego, California
| | - Gregory E Idos
- Divisions of Gastroenterology and Clinical Cancer Genomics, Center for Precision Medicine, City of Hope National Medical Center, Duarte, California
| | - Carol Durno
- The Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Francis M Giardiello
- Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Joseph C Anderson
- Veterans Affairs Medical Center, White River Junction, Vermont; Geisel School of Medicine at Dartmouth, Hanover, New Hampshire; University of Connecticut, Farmington, Connecticut
| | - Carol A Burke
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, Ohio
| | - Jason A Dominitz
- Veterans Affairs Puget Sound Health Care System, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington
| | - Seth Gross
- Division of Gastroenterology and Hepatology, New York University Langone Health, New York, New York
| | - Samir Gupta
- Veterans Affairs Medical Center, San Diego, California; University of California San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California
| | - Brian C Jacobson
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Swati G Patel
- University of Colorado School of Medicine, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado
| | - Aasma Shaukat
- Minneapolis Veterans Affairs Health Care System, Minneapolis, Minnesota; University of Minnesota, Minneapolis, Minnesota
| | - Sapna Syngal
- Brigham and Women's Hospital, Boston Massachusetts; Dana-Farber Cancer Institute, Boston Massachusetts; Harvard Medical School, Boston Massachusetts
| | - Douglas J Robertson
- Veterans Affairs Medical Center, White River Junction, Vermont; Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
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6
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Boland CR, Idos GE, Durno C, Giardiello FM, Anderson JC, Burke CA, Dominitz JA, Gross S, Gupta S, Jacobson BC, Patel SG, Shaukat A, Syngal S, Robertson DJ. Diagnosis and management of cancer risk in the gastrointestinal hamartomatous polyposis syndromes: recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc 2022; 95:1025-1047. [PMID: 35487765 DOI: 10.1016/j.gie.2022.02.044] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S. Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.
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Affiliation(s)
- C Richard Boland
- Division of Gastroenterology, University of California-San Diego School of Medicine, San Diego, California.
| | - Gregory E Idos
- Divisions of Gastroenterology and Clinical Cancer Genomics, Center for Precision Medicine, City of Hope National Medical Center, Duarte, California
| | - Carol Durno
- The Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology and Nutrition, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Francis M Giardiello
- Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Joseph C Anderson
- Veterans Affairs Medical Center, White River Junction, Vermont; Geisel School of Medicine at Dartmouth, Hanover, New Hampshire; University of Connecticut, Farmington, Connecticut
| | - Carol A Burke
- Department of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, Ohio
| | - Jason A Dominitz
- Veterans Affairs Puget Sound Health Care System, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington
| | - Seth Gross
- Division of Gastroenterology and Hepatology, New York University Langone Health, New York, New York
| | - Samir Gupta
- Veterans Affairs Medical Center, San Diego, California; University of California San Diego, La Jolla, California; Veterans Affairs San Diego Healthcare System, San Diego, California
| | - Brian C Jacobson
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Swati G Patel
- University of Colorado School of Medicine, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado
| | - Aasma Shaukat
- Minneapolis Veterans Affairs Health Care System, Minneapolis, Minnesota; University of Minnesota, Minneapolis, Minnesota
| | - Sapna Syngal
- Brigham and Women's Hospital, Boston Massachusetts; Dana-Farber Cancer Institute, Boston Massachusetts; Harvard Medical School, Boston Massachusetts
| | - Douglas J Robertson
- Veterans Affairs Medical Center, White River Junction, Vermont; Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
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7
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Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol 2022; 117:846-864. [PMID: 35471415 DOI: 10.14309/ajg.0000000000001755] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 12/11/2022]
Abstract
The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This US Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.
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8
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D'Ermo G, Genuardi M. Gastrointestinal manifestations in PTEN hamartoma tumor syndrome. Best Pract Res Clin Gastroenterol 2022; 58-59:101792. [PMID: 35988965 DOI: 10.1016/j.bpg.2022.101792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/04/2022] [Accepted: 03/08/2022] [Indexed: 02/07/2023]
Abstract
The PTEN hamartoma tumor syndrome (PHTS) is a heterogeneous set of multisystem disorders caused by germline pathogenic variants in the PTEN tumor suppressor gene. Manifestations include developmental anomalies and proliferative lesions. Evidence of involvement of the GI tract has accrued over time, leading to the incorporation of GI manifestations (multiple hamartomas, glycogenic acanthosis and colorectal cancer) into the diagnostic criteria. Polyps of the upper and lower GI tract are found in most adult patients and in a significant fraction of children. Polyps tend to be of mixed histology, with a predominance of hamartomas and ganglioneuromas. PHTS patients are also at increased risk of colorectal cancer, and surveillance by colonoscopy is advised starting at the age of 35-40 years. A number of additional manifestations, including eosinophilic gastrointestinal disorders, have been observed in few or single cases, and their association with PHTS has yet to be determined.
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Affiliation(s)
- Giuseppe D'Ermo
- Dipartimento di Chirurgia "Pietro Valdoni", Università La Sapienza, Rome, Italy
| | - Maurizio Genuardi
- Fondazione Policlinico Universitario A. Gemelli IRCCS, UOC Genetica Medica, Rome, Italy; Sezione di Medicina Genomica, Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy.
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9
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Khare A, Burke CA, Heald B, O'Malley M, LaGuardia L, Milicia S, Cruise M, Eng C, Mankaney G. Endoscopic Findings in Patients With PTEN Hamartoma Tumor Syndrome Undergoing Surveillance. J Clin Gastroenterol 2022; 56:e183-e188. [PMID: 34231499 DOI: 10.1097/mcg.0000000000001580] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 05/28/2021] [Indexed: 12/30/2022]
Abstract
GOALS AND BACKGROUND Phosphatase and tensin homolog hamartoma tumor syndrome (PHTS) is an inherited disorder that increases the risk for cancer in multiple organ systems, including breast, endometrial, thyroid, and the gastrointestinal tract. Surveillance is recommended however there lacks data to describe the change in polyposis phenotype and cancer incidence over surveillance. Our aim is to describe the polyposis phenotype and cancer incidence in PHTS patients undergoing endoscopic surveillance. STUDY PHTS patients, ages 17 through 89, who underwent at least 2 esophagogastroduodenoscopy (EGDs) or colonoscopies were identified. Number and sizes of polyps were noted, from which 5 categories were recreated. Incidence of colorectal and gastric cancer was evaluated. RESULTS Seventy patients were included. Patients were clustered and classified into 1 of 5 categories: no polyps, few small polyps (<1 cm, < 10 polyps), few large polyps (≥1 cm, < 10 polyps), many small polyps (<1 cm, ≥10 polyps), many large polyps (≥1 cm, ≥10 polyps). There was no significant difference in polyp number or size on EGD (P=0.47 and 0.83, respectively) or colonoscopy (P=0.49 and 0.10, respectively) over the surveillance period (4.8±3.9 y for stomach and 5.6±4.4 y for colon). The average interval between endoscopies was 28±24 months for EGDs and 29±23 months for colonoscopies. A stage II transverse colon adenocarcinoma and stage IV gastric adenocarcinoma were identified. Standardized incidence rates for gastric and colon cancers were 5427 (P=0.0002) and 353 (P=0.002), respectively. CONCLUSIONS PTHS individuals can be classified into polyposis phenotypes which do not change over an endoscopic surveillance period. Two cancers were associated with a large size polyp phenotype. Surveillance intervals should be determined by polyp size ≥1 cm and pathology.
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Affiliation(s)
| | - Carol A Burke
- Gastroenterology, Hepatology, and Nutrition
- Colorectal Surgery
- Pathology and Laboratory Medicine Institute
| | - Brandie Heald
- Center for Personalized Genetic Healthcare
- Sanford R. Weiss, M.D. Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic, Cleveland, OH
| | - Margaret O'Malley
- Colorectal Surgery
- Sanford R. Weiss, M.D. Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic, Cleveland, OH
| | - Lisa LaGuardia
- Colorectal Surgery
- Sanford R. Weiss, M.D. Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic, Cleveland, OH
| | - Susan Milicia
- Colorectal Surgery
- Sanford R. Weiss, M.D. Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic, Cleveland, OH
| | - Michael Cruise
- Pathology and Laboratory Medicine Institute
- Sanford R. Weiss, M.D. Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic, Cleveland, OH
| | - Charis Eng
- Genomic Medicine Institute
- Center for Personalized Genetic Healthcare
- Sanford R. Weiss, M.D. Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic, Cleveland, OH
| | - Gautam Mankaney
- Gastroenterology, Hepatology, and Nutrition
- Sanford R. Weiss, M.D. Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgical Institute, Cleveland Clinic, Cleveland, OH
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10
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Liu S, Ma Y, You W, Li J, Li JN, Qian JM. Hamartomatous polyposis syndrome associated malignancies: Risk, pathogenesis and endoscopic surveillance. J Dig Dis 2021; 22:444-451. [PMID: 34145757 DOI: 10.1111/1751-2980.13029] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/20/2021] [Accepted: 06/16/2021] [Indexed: 12/11/2022]
Abstract
Hamartomatous polyposis syndromes (HPS) are a heterogeneous spectrum of diseases that are characterized by diffuse hamartomatous polyps lining the gastrointestinal (GI) tract together with extra-GI manifestations. Classical HPS includes juvenile polyposis syndrome, Peutz-Jeghers syndrome, PTEN hamartoma tumor syndrome and hereditary mixed polyposis syndrome. Patients with HPS have a higher risk of GI and extra-GI malignancies than the general population, although the underlying mechanisms remain unclear and are obviously different from the carcinogenesis of classical adenocarcinoma and colitis-associated malignancy. In this review we aimed to clarify the risks, possible mechanism and endoscopic surveillance of HPS-associated GI malignancies.
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Affiliation(s)
- Shuang Liu
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Ye Ma
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Wen You
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Ji Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Jing Nan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Jia Ming Qian
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
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11
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Innella G, Miccoli S, Colussi D, Pradella LM, Amato LB, Zuntini R, Salfi NCM, Collina G, Ferrara F, Ricciardiello L, Turchetti D. Colorectal polyposis as a clue to the diagnosis of Cowden syndrome: Report of two cases and literature review. Pathol Res Pract 2021; 218:153339. [PMID: 33482532 DOI: 10.1016/j.prp.2020.153339] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 12/30/2020] [Accepted: 12/30/2020] [Indexed: 11/26/2022]
Abstract
Cowden Syndrome (CS) is an autosomal dominant disorder characterized by hamartomatous growth in several organs and by an increased risk of malignancies, which makes its recognition essential to undertake risk reduction measures. Although the involvement of gastrointestinal tract is extremely common, awareness of this entity among gastroenterologists appears limited. We report on two unrelated patients: a 46-year-old male and a 38-year-old woman, who were referred to the Genetic Clinic because of the endoscopic finding of multiple colorectal polyps. Despite both displayed striking clinical (and, in the first case, familial) manifestations of Cowden Syndrome (PTEN Hamartoma Tumor Syndrome-PHTS), they had not been recognized before. Diagnosis of PHTS was confirmed by the detection of causative PTEN variants. Pathological examination of the polyps showed multiple histology types: hyperplastic, juvenile, serrated and lymphoid. Hyperplastic polyps analyzed from both patients failed to show BRAF V600E and KRAS codon 12/13 mutations, which provides evidence against their potential to evolve to colorectal cancer through the serrated pathway. We then reviewed the literature on gastrointestinal polyps detected in patients with Cowden Syndrome, in order to provide a comprehensive scenario of presentations: among a total of 568 patients reported in the literature, 91.7 % presented with colon polyps, with 63.0 % having two or more different histological types of polyps; besides, 58.5 % had extra-colonic polyps (located either in stomach and/or in small intestine). Finding multiple polyps with mixed and/or unusual histology should alert gastroenterologists and pathologists about the possible diagnosis of Cowden Syndrome and prompt the search for other manifestations of this condition in the patient.
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Affiliation(s)
- Giovanni Innella
- Dipartimento di Scienze Mediche e Chirurgiche: Centro di Ricerca sui Tumori Ereditari, Università di Bologna, Italy; UO Genetica Medica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Sara Miccoli
- Dipartimento di Scienze Mediche e Chirurgiche: Centro di Ricerca sui Tumori Ereditari, Università di Bologna, Italy; UO Genetica Medica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Dora Colussi
- UO Gastroenterologia, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Laura Maria Pradella
- Dipartimento di Scienze Mediche e Chirurgiche: Centro di Ricerca sui Tumori Ereditari, Università di Bologna, Italy; UO Genetica Medica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Laura Benedetta Amato
- Dipartimento di Scienze Mediche e Chirurgiche: Centro di Ricerca sui Tumori Ereditari, Università di Bologna, Italy; UO Genetica Medica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Roberta Zuntini
- Dipartimento di Scienze Mediche e Chirurgiche: Centro di Ricerca sui Tumori Ereditari, Università di Bologna, Italy; UO Genetica Medica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Nunzio Cosimo Mario Salfi
- UO Anatomia e Istologia Patologica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Guido Collina
- UOC Anatomia Patologica, Ospedale "C e G. Mazzoni", Ascoli Piceno, Italy.
| | - Francesco Ferrara
- UO Gastroenterologia ed Endoscopia Digestiva, AUSL di Bologna, Ospedale Bellaria, Bologna, Italy.
| | - Luigi Ricciardiello
- Dipartimento di Scienze Mediche e Chirurgiche: Centro di Ricerca sui Tumori Ereditari, Università di Bologna, Italy; UO Gastroenterologia, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
| | - Daniela Turchetti
- Dipartimento di Scienze Mediche e Chirurgiche: Centro di Ricerca sui Tumori Ereditari, Università di Bologna, Italy; UO Genetica Medica, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Bologna, Italy.
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12
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Hendricks LAJ, Hoogerbrugge N, Schuurs-Hoeijmakers JHM, Vos JR. A review on age-related cancer risks in PTEN hamartoma tumor syndrome. Clin Genet 2020; 99:219-225. [PMID: 33140411 PMCID: PMC7839546 DOI: 10.1111/cge.13875] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/29/2020] [Accepted: 10/30/2020] [Indexed: 12/18/2022]
Abstract
Patients with PTEN hamartoma tumor syndrome (PHTS, comprising Cowden, Bannayan‐Riley‐Ruvalcaba, and Proteus‐like syndromes) are at increased risk of developing cancer due to pathogenic PTEN germline variants. This review summarizes age‐, sex‐, and type‐specific malignant cancer risks for PHTS patients, which is urgently needed for clinical management. A PubMed literature search for Standardized Incidence Ratios or Cumulative Lifetime cancer risks (CLTRs) resulted in nine cohort studies comprising four independent PHTS cohorts, including mainly index cases and prevalent cancer cases. The median age at diagnosis was 36 years. Reported CLTRs for any cancer varied from 81% to 90%. The tumor spectrum included female breast cancer (CLTRs including sex‐specific estimates at age 60‐70: 67% to 85%), endometrium cancer (19% to 28%), thyroid cancer (6% to 38%), renal cancer (2% to 24%), colorectal cancer (9% to 32%), and melanoma (0% to 6%). Although these estimates provide guidance for clinical care, discrepancies between studies, sample sizes, retrospective designs, strongly ascertained cases, and lack of pediatric research emphasizes that data should be interpreted with great caution. Therefore, more accurate and more personalized age‐, sex‐, and cancer‐specific risk estimates are needed to enable counseling of all PHTS patients irrespective of ascertainment, and improvement of cancer surveillance guidelines.
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Affiliation(s)
- Linda A J Hendricks
- Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.,Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.,Radboud university medical center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands
| | | | - Janet R Vos
- Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands.,Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
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13
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Smerdel MP, Skytte AB, Jelsig AM, Ebbehøj E, Stochholm K. Revised Danish guidelines for the cancer surveillance of patients with Cowden Syndrome. Eur J Med Genet 2020; 63:103873. [PMID: 32058060 DOI: 10.1016/j.ejmg.2020.103873] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 11/05/2019] [Accepted: 02/01/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Cowden syndrome is a cancer predisposition syndrome caused by pathogenic variants in PTEN. The affected patients possess an increased risk of breast, thyroid, renal, colorectal, endometrial cancers as well as malignant melanoma. Thus prophylactic surveillance and follow up is crucial for these patients. METHODS A review of the literature including existing guidelines from the years 1996 until 2017 was carried out. In total, 2078 scientific papers were identified through database searches on Cowden syndrome. Among these, 11 manuscripts were included based on scientific relevance and quality. Expert consensus was reached to define management guidelines. RESULTS The literature revealed a high risk of cancer in specific organs for patients diagnosed with Cowden Syndrome. Alternative management guidelines were proposed and discussed. CONCLUSIONS Here we propose a revised set of management guidelines for patients with Cowden syndrome in Denmark to address the increased risk of various cancer types.
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Affiliation(s)
- Maja Patricia Smerdel
- Department of Clinical Genetics, Lillebaelt Hospital - University Hospital of Southern Denmark, Vejle, Denmark.
| | - Anne-Bine Skytte
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
| | - Anne Marie Jelsig
- Clinical Genetic Clinic, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
| | - Eva Ebbehøj
- Department of Internal Medicine and Diabetes, Aarhus University Hospital, Aarhus, Denmark.
| | - Kirstine Stochholm
- Department of Pediatrics, Center of Rare Diseases, Aarhus University Hospital and Department of Internal Medicine and Diabetes, Aarhus University Hospital, Aarhus, Denmark.
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14
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Griff JR, Duffy KA, Kalish JM. Characterization and Childhood Tumor Risk Assessment of Genetic and Epigenetic Syndromes Associated With Lateralized Overgrowth. Front Pediatr 2020; 8:613260. [PMID: 33392121 PMCID: PMC7773942 DOI: 10.3389/fped.2020.613260] [Citation(s) in RCA: 12] [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: 10/01/2020] [Accepted: 11/03/2020] [Indexed: 12/26/2022] Open
Abstract
Lateralized overgrowth (LO), or segmental overgrowth, is defined as an increase in growth of tissue (bone, muscle, connective tissue, vasculature, etc.) in any region of the body. Some overgrowth syndromes, characterized by both generalized and lateralized overgrowth, have been associated with an increased risk of tumor development. This may be due to the underlying genetic and epigenetic defects that lead to disrupted cell growth and proliferation pathways resulting in the overgrowth and tumor phenotypes. This chapter focuses on the four most common syndromes characterized by LO: Beckwith-Wiedemann spectrum (BWSp), PIK3CA-related overgrowth spectrum (PROS), Proteus syndrome (PS), and PTEN hamartoma tumor syndrome (PHTS). These syndromes demonstrate variable risks for tumor development in patients affected by LO, and we provide a comprehensive literature review of all common tumors reported in patients diagnosed with an LO-related disorder. This review summarizes the current data on tumor risk among these disorders and their associated tumor screening guidelines. Furthermore, this chapter highlights the importance of an accurate diagnosis when a patient presents with LO as similar phenotypes are associated with different tumor risks, thereby altering preventative screening protocols.
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Affiliation(s)
- Jessica R Griff
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Kelly A Duffy
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Jennifer M Kalish
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States.,Departments of Genetics and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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15
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Babcook MA, Akgul M, Margevicius S, MacLennan GT, Fu P, Abouassaly R, Gupta S. Ser-486/491 phosphorylation and inhibition of AMPKα activity is positively associated with Gleason score, metastasis, and castration-resistance in prostate cancer: A retrospective clinical study. Prostate 2018; 78:714-723. [PMID: 29577356 PMCID: PMC6591712 DOI: 10.1002/pros.23515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 03/09/2018] [Indexed: 11/06/2022]
Abstract
BACKGROUND We previously demonstrated that adenosine monophosphate-activated protein kinase (AMPKα) activity is significantly inhibited by Ser-486/491 phosphorylation in cell culture and in vivo models of metastatic and castration-resistant prostate cancer, and hypothesized these findings may translate to clinical specimens. METHODS In this retrospective, single-institution pilot study, 45 metastatic prostate cancer cases were identified within the University Hospitals Cleveland Medical Center Pathology Archive with both metastasis and matched primary prostate tumor specimens in formalin-fixed, paraffin-embedded blocks, and complete electronic medical records. Thirty non-metastatic, hormone-dependent prostate cancer controls, who were progression-free as defined by undetectable prostate specific antigen for at least 79.6 months (range 79.6-136.0 months), and matched metastatic cases based on age, race, and year of diagnosis. All specimens were collected from 1991 to 2014; primary tumor specimens were obtained via diagnostic biopsy or prostatectomy, and metastasis specimens obtained via surgery or perimortem. 5-μ sequential slides were processed for phospho-Ser-486/491 AMPKα1 /α2 , phospho-Thr-172 AMPKα, AMPKα1 /α2 , phospho-Ser-792 Raptor, phospho-Ser-79 acetyl-CoA carboxylase, and phospho-Ser-872, 3-hydroxy-3-methylglutaryl-CoA reductase immunohistochemistry to determine expression, phosphorylation pattern, and activity of AMPKα. RESULTS Increased inhibitory Ser-486/491 AMPKα1 /α2 phosphorylation, increased AMPKα protein expression, decreased AMPKα activity, and loss of nuclear AMPKα and p-AMPKα are associated with prostate cancer progression to metastasis. Increased p-Ser-486/491 AMPKα1 /α2 was also positively correlated with higher Gleason grade and progression to castration-resistance. CONCLUSIONS p-Ser-486/491 AMPKα1 /α2 is a novel marker of prostate cancer metastasis and castration-resistance. Ser-486/491 phosphokinases should be pursued as targets for metastatic and castration-resistant prostate cancer chemotherapy.
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Affiliation(s)
- Melissa A. Babcook
- Department of Urology, The James and Eilleen Dicke Laboratory, Case Western Reserve University, Cleveland, Ohio 44106
- The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio 44106
- Department of Medicine, The University of Toledo College of Medicine, Toledo, Ohio 43614
| | - Mahmut Akgul
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, Ohio 44106
| | - Seunghee Margevicius
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio 44106
| | - Gregory T. MacLennan
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, Ohio 44106
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106
| | - Pingfu Fu
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio 44106
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106
| | - Robert Abouassaly
- Department of Urology, The James and Eilleen Dicke Laboratory, Case Western Reserve University, Cleveland, Ohio 44106
- The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio 44106
| | - Sanjay Gupta
- Department of Urology, The James and Eilleen Dicke Laboratory, Case Western Reserve University, Cleveland, Ohio 44106
- The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio 44106
- Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, Ohio 44106
- Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
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16
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Abstract
Colorectal adenomatous polyposis syndromes encompass a diverse group of disorders with varying modes of inheritance and penetrance. Children may present with overt disease or within screening programs for families at high risk. We provide an overview of the array of pediatric polyposis syndromes, current screening recommendations, and surgical indications and technical considerations. Optimal disease management for these pediatric patients is still evolving and has implications for screening, surveillance, pediatric surgical management, and transition of care gastroenterologic neoplasia physicians and surgeons.
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Affiliation(s)
- Aodhnait S Fahy
- Division of Pediatric Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Christopher R Moir
- Division of Pediatric Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota
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17
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Lorans M, Dow E, Macrae FA, Winship IM, Buchanan DD. Update on Hereditary Colorectal Cancer: Improving the Clinical Utility of Multigene Panel Testing. Clin Colorectal Cancer 2018; 17:e293-e305. [PMID: 29454559 DOI: 10.1016/j.clcc.2018.01.001] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 12/17/2017] [Accepted: 01/09/2018] [Indexed: 12/30/2022]
Abstract
Colorectal cancer (CRC), one of the most common cancers, is a major public health issue globally, especially in Westernized countries. Up to 35% of CRCs are thought to be due to heritable factors, but currently only 5% to 10% of CRCs are attributable to high-risk mutations in known CRC susceptibility genes, predominantly the mismatch repair genes (Lynch syndrome) and adenomatous polyposis coli gene (APC; familial adenomatous polyposis). In this era of precision medicine, high-risk mutation carriers, when identified, can be offered various risk management options that prevent cancers and improve survival, including risk-reducing medication, screening for early detection, and surgery. The practice of clinical genetics is currently transitioning from phenotype-directed single gene testing to multigene panels, now offered by numerous providers. For CRC, the genes included across these panels vary, ranging from well established, clinically actionable susceptibility genes with quantified magnitude of risk, to genes that lack extensive validation or have less evidence of association with CRC and, therefore, have minimal clinical utility. The current lack of consensus regarding inclusion of genes in CRC panels presents challenges in patient counseling and management, particularly when a variant in a less validated gene is identified. Furthermore, there remain considerable challenges regarding variant interpretation even for the well established CRC susceptibility genes. Ironically though, only through more widespread testing and the accumulation of large international data sets will sufficient information be generated to (i) enable well powered studies to determine if a gene is associated with CRC susceptibility, (ii) to develop better models for variant interpretation and (iii) to facilitate clinical translation.
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Affiliation(s)
- Marie Lorans
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
| | - Eryn Dow
- Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Finlay A Macrae
- Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia; Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia; Colorectal Medicine and Genetics, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Ingrid M Winship
- Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia; Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia; Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Carlton, Victoria, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia.
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18
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Hereditary Colorectal Polyposis and Cancer Syndromes: A Primer on Diagnosis and Management. Am J Gastroenterol 2017; 112:1509-1525. [PMID: 28786406 DOI: 10.1038/ajg.2017.212] [Citation(s) in RCA: 112] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 06/23/2017] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is the fourth most common cancer amongst men and women. Between 3 and 6% of all CRCs are attributed to well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), and several hamartomatous polyposis conditions. Identification of these patients through family history and appropriate genetic testing can provide estimates of cancer risk that inform appropriate cancer screening, surveillance and/or preventative interventions. This narrative review examines the hereditary colorectal cancer and polyposis syndromes, their genetic basis, clinical management, and evidence supporting cancer screening.
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19
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Adán Merino L, Aldeguer Martínez M, Álvarez Rodríguez F, Barceló López M, Plaza Santos R, Valentín Gómez F. Unusual presenting manifestation of a rare polyposis, Cowden syndrome. GASTROENTEROLOGIA Y HEPATOLOGIA 2017; 41:315-317. [PMID: 28716492 DOI: 10.1016/j.gastrohep.2017.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 06/05/2017] [Accepted: 06/07/2017] [Indexed: 11/28/2022]
Affiliation(s)
- Luisa Adán Merino
- Servicio de Aparato Digestivo, Hospital Universitario Infanta Leonor, Madrid, España.
| | | | | | - Marta Barceló López
- Servicio de Aparato Digestivo, Hospital Universitario Infanta Leonor, Madrid, España
| | - Rocío Plaza Santos
- Servicio de Aparato Digestivo, Hospital Universitario Infanta Leonor, Madrid, España
| | - Fátima Valentín Gómez
- Servicio de Aparato Digestivo, Hospital Universitario Infanta Leonor, Madrid, España
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Hawkins AT, Wise PE. Colon cancer in hereditary syndromes. SEMINARS IN COLON AND RECTAL SURGERY 2016. [DOI: 10.1053/j.scrs.2016.04.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Cowden Syndrome and Concomitant Pulmonary Neuroendocrine Tumor: A Presentation of Two Cases. Case Rep Med 2015; 2015:265786. [PMID: 26798346 PMCID: PMC4700167 DOI: 10.1155/2015/265786] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Accepted: 12/16/2015] [Indexed: 12/14/2022] Open
Abstract
Cowden Syndrome is a rare autosomal dominantly inherited disorder. Patients with Cowden Syndrome are at increased risk of various benign and malignant neoplasms in breast, endometrium, thyroid, gastrointestinal tract, and genitourinary system. Neuroendocrine tumors are ubiquitous neoplasms that may occur anywhere in the human body. Bronchopulmonary neuroendocrine tumors include four different histological subtypes, among these, typical and atypical pulmonary carcinoids. No association between Cowden Syndrome and neuroendocrine tumors has previously been described. We present two cases of Cowden Syndrome that were diagnosed with pulmonary carcinoids.
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ACG Guidelines on Management of PTEN-Hamartoma Tumor Syndrome: Does the Evidence Support so Much so Young? Am J Gastroenterol 2015; 110:1733-4. [PMID: 26673503 DOI: 10.1038/ajg.2015.368] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Cauchin E, Touchefeu Y, Matysiak-Budnik T. Hamartomatous Tumors in the Gastrointestinal Tract. Gastrointest Tumors 2015; 2:65-74. [PMID: 26672891 DOI: 10.1159/000437175] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Digestive hamartomatous polyps are a rare entity. They may be sporadic (solitary Peutz-Jeghers polyp or solitary juvenile polyp) or reveal genetic predisposition like Peutz-Jeghers syndrome, juvenile polyposis or Cowden disease. SUMMARY Diagnosis is based on personal and family history and on clinical data including physical signs (in particular dermatological), endoscopic findings (the number of polyps) and histological features of the polyps. The risk of complications and of digestive and extra-digestive cancers may be high, especially in case of genetic predisposition syndromes, and requires multidisciplinary management of the patients (oncogenetic counseling, gastroenterologist, pathologist, dermatologist, gynecologist and endocrinologist). Endoscopic evaluation is very helpful to establish the current situation, to perform polypectomy and to allow for good histological examination of the polyps, whose degeneration has been exceptionally described. The recent development of new molecular techniques (next-generation DNA sequencing) allows for rapid multiple gene sequencing and facilitates diagnosis. KEY MESSAGE Discovery of a hamartomatous polyp requires a rigorous work-up which should be performed by a multidisciplinary team, including a genetic oncologist, experienced in this pathology. PRACTICAL IMPLICATIONS The diagnostic procedure in hamartomatous polyps should be based on the number of polyps identified during endoscopy (solitary versus multiple) and on their histological characteristics. The clinical examination must search for mucosal and skin lesions. If a polyposis syndrome is identified, oncogenetic consultation is necessary in order to define screening modalities for family members, aiming at preventing cancer development. Endoscopic resection (polypectomy) of the lesions may prevent complications like bleeding and degeneration and also diminish the risk of surgery and subsequent short bowel syndrome.
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Affiliation(s)
- Estell Cauchin
- IMAD, Hepato-Gastroenterology and Digestive Oncology, Hôtel Dieu/CHU de Nantes, Nantes, France
| | - Yan Touchefeu
- IMAD, Hepato-Gastroenterology and Digestive Oncology, Hôtel Dieu/CHU de Nantes, Nantes, France
| | - Tamar Matysiak-Budnik
- IMAD, Hepato-Gastroenterology and Digestive Oncology, Hôtel Dieu/CHU de Nantes, Nantes, France
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Campos FG, Figueiredo MN, Martinez CAR. Colorectal cancer risk in hamartomatous polyposis syndromes. World J Gastrointest Surg 2015; 7:25-32. [PMID: 25848489 PMCID: PMC4381153 DOI: 10.4240/wjgs.v7.i3.25] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 01/06/2015] [Accepted: 02/09/2015] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a major cause of morbidity and mortality around the world, and approximately 5% of them develop in a context of inherited mutations leading to some form of familial colon cancer syndromes. Recognition and characterization of these patients have contributed to elucidate the genetic basis of CRC. Polyposis Syndromes may be categorized by the predominant histological structure found within the polyps. The aim of the present paper is to review the most important clinical features of the Hamartomatous Polyposis Syndromes, a rare group of genetic disorders formed by the peutz-Jeghers syndrome, juvenil polyposis syndrome and PTEN Hamartoma Tumor Syndrome (Bannayan-Riley-Ruvalacaba and Cowden Syndromes). A literature search was performed in order to retrieve the most recent and important papers (articles, reviews, clinical cases and clinical guidelines) regarding the studied subject. We searched for terms such as “hamartomatous polyposis syndromes”, “Peutz-Jeghers syndrome”, “juvenile polyposis syndrome”, “juvenile polyp”, and “PTEN hamartoma tumour syndrome” (Cowden syndrome, Bananyan-Riley-Ruvalcaba). The present article reports the wide spectrum of disease severity and extraintestinal manifestations, with a special focus on their potential to develop colorectal and other neoplasia. In the literature, the reported colorectal cancer risk for Juvenile Polyposis, Peutz-Jeghers and PTEN Hamartoma Tumor Syndromes are 39%-68%, 39%-57% and 18%, respectively. A review regarding cancer surveillance recommendations is also presented.
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Abstract
Hereditary factors are involved in the development of a substantial proportion of all cases of colorectal cancer. Inherited forms of colorectal cancer are usually subdivided into polyposis syndromes characterized by the development of multiple colorectal polyps and nonpolyposis syndromes characterized by the development of few or no polyps. Timely identification of hereditary colorectal cancer syndromes is vital because patient participation in early detection programmes prevents premature death due to cancer. Polyposis syndromes are fairly easy to recognize, but some patients might have characteristics that overlap with other clinically defined syndromes. Comprehensive analysis of the genes known to be associated with polyposis syndromes helps to establish the final diagnosis in these patients. Recognizing Lynch syndrome is more difficult than other polyposis syndromes owing to the absence of pathognomonic features. Most investigators therefore recommend performing systematic molecular analysis of all newly diagnosed colorectal cancer using immunohistochemical methods. The implementation in clinical practice of new high-throughput methods for molecular analysis might further increase the identification of individuals at risk of hereditary colorectal cancer. This Review describes the clinical management of the various hereditary colorectal cancer syndromes and demonstrates the advantage of using a classification based on the underlying gene defects.
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Affiliation(s)
- Hans F A Vasen
- Department of Gastroenterology, Leiden University Medical Centre, Rijnsburgerweg 10, 2333 AA Leiden, Netherlands
| | - Ian Tomlinson
- Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
| | - Antoni Castells
- Department of Gastroenterology, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERehd, Villaroel 170, 08036 Barcelona, Catalonia, Spain
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Bendib M, Badescu A, Handra-Luca A. PTEN expression in colorectal adenomas: relationship to morphology and cell heterogeneity. Pathol Res Pract 2014; 211:248-51. [PMID: 25596996 DOI: 10.1016/j.prp.2014.12.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Revised: 10/28/2014] [Accepted: 12/05/2014] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Colorectal adenomas are the most frequent benign colorectal tumors. These tumors are characterized by dysplasia, low and high grade, the latter having the potential to evolve to adenocarcinoma. The aim of this study was to study the expression patterns of PTEN protein in a series of colorectal adenomas and the relationships to cell proliferation and CD133, marker of stem phenotype. METHODS Colorectal adenomas were studied for the immunohistochemical expression of PTEN on tissue microarrays. PTEN expression was analysed with regard to morphological features and with regard to the Ki67 and CD133-positive cell compartments by using the Kendall rank-correlation test. RESULTS PTEN was expressed in 92% adenomas, either in a cytoplasmic or nuclear pattern. Cytoplasmic PTEN was correlated to cytoplasmic CD133 (p = 0.02, tau 0.191) while nuclear PTEN to decreased adenoma size and to tubular architecture (p = 0.01, τ-0.184 and p = 0.01, τ-0.183). Nuclear PTEN was also correlated to low grade intraepithelial neoplasia, while global PTEN (nuclear or cytoplasmic) was correlated to the presence of a decreased Ki67-positive component but with marginal significance (p = 0.06, τ-0.144 and p = 0.07, τ-0.213). CONCLUSION The results of this study suggest a role for PTEN in colorectal adenoma morphogenesis and cell protein heterogeneity, being correlated to decreased size, tubular architecture and a high CD133-positive component.
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Affiliation(s)
- Mouna Bendib
- Service d'Anatomie pathologique, APHP Université Paris Nord Sorbonne Cité, 125 rue Stalingrad, 93009 Bobigny, France
| | - Alina Badescu
- Service d'Anatomie pathologique, APHP Université Paris Nord Sorbonne Cité, 125 rue Stalingrad, 93009 Bobigny, France; Universitatea de Medicina Craiova, Strada Petru Rareş 2-4, 200349 Craiova, Romania
| | - Adriana Handra-Luca
- Service d'Anatomie pathologique, APHP Université Paris Nord Sorbonne Cité, 125 rue Stalingrad, 93009 Bobigny, France.
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Stanich PP, Pilarski R, Rock J, Frankel WL, El-Dika S, Meyer MM. Colonic manifestations of PTEN hamartoma tumor syndrome: Case series and systematic review. World J Gastroenterol 2014; 20:1833-1838. [PMID: 24587660 PMCID: PMC3930981 DOI: 10.3748/wjg.v20.i7.1833] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Revised: 09/12/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate our clinical experience with the colonic manifestations of phosphatase and tensin homolog on chromosome ten (PTEN) hamartoma tumor syndrome (PHTS) and to perform a systematic literature review regarding the same.
METHODS: This study was approved by the appropriate institutional review board prior to initiation. A clinical genetics database was searched for patients with PHTS or a component syndrome that received gastrointestinal endoscopy or pathology interpretation at our center. These patient’s records were retrospectively reviewed for clinical characteristics (including family history and genetic testing), endoscopy results and pathology findings. We also performed a systematic review of the literature for case series of PHTS or component syndromes that reported gastrointestinal manifestations and investigations published after consensus diagnostic criteria were established in 1996. These results were compiled and reported.
RESULTS: Eight patients from our institution met initial inclusion criteria. Of these, 5 patients underwent 4.2 colonoscopies at mean age 45.8 ± 10.8 years. All were found to have colon polyps during their clinical course and polyp histology included adenoma, hyperplastic, ganglioneuroma and juvenile. No malignant lesions were identified. Two had multiple histologic types. One patient underwent colectomy due to innumerable polyps and concern for future malignant potential. Systematic literature review of PHTS patients undergoing endoscopy revealed 107 patients receiving colonoscopy at mean age 37.4 years. Colon polyps were noted in 92.5% and multiple colon polyp histologies were reported in 53.6%. Common polyp histologies included hyperplastic (43.6%), adenoma (40.4%), hamartoma (38.3%), ganglioneuroma (33%) and inflammatory (24.5%) polyps. Twelve (11.2%) patients had colorectal cancer at mean age 46.7 years (range 35-62). Clinical outcomes secondary to colon polyposis and malignancy were not commonly reported.
CONCLUSION: PHTS has a high prevalence of colon polyposis with multiple histologic types. It should be considered a mixed polyposis syndrome. Systematic review found an increased prevalence of colorectal cancer and we recommend initiating colonoscopy for colorectal cancer surveillance at age 35 years.
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