|
1
|
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.
Collapse
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
| |
Collapse
|
|
2
|
Saito Y, Suzuki S, Sanomachi T, Kato K, Otake H, Nishise Y, Yamada Y, Saito K, Takahashi K, Kumanishi R, Fukui T, Yoshioka T. Pancreatic Mixed Acinar-neuroendocrine Carcinoma in a Patient With a Germline PTEN Variant: A Case Report and Genomic Literature Review. In Vivo 2025; 39:1173-1181. [PMID: 40010976 PMCID: PMC11884457 DOI: 10.21873/invivo.13921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/08/2025] [Accepted: 01/09/2025] [Indexed: 02/28/2025]
Abstract
BACKGROUND/AIM Cowden syndrome (CS)/PTEN hamartoma tumor syndrome (PHTS) is a hereditary disorder caused by germline PTEN variants. While patients with CS/PHTS have increased risk of various cancers, pancreatic cancer is not typically associated with this syndrome. We report a rare case of pancreatic mixed acinar-neuroendocrine carcinoma in a patient with a germline PTEN variant, aiming to understand its molecular characteristics and clinical implications. CASE REPORT A male in his late 40s presented with pancreatic cancer and hepatic metastases. His medical history included thyroid cancer and familial gastrointestinal malignancies. Liver biopsy revealed mixed acinar-endocrine carcinoma. Cancer genome profiling identified pathogenic variants in GNAS and TP53, along with a germline PTEN variant (V201fs*1), leading to a diagnosis of CS. Notably, KRAS mutations, commonly found in pancreatic cancer, were absent. The patient showed extreme resistance to multiple chemotherapy regimens, including FOLFIRINOX, gemcitabine plus nab-paclitaxel, and cisplatin plus etoposide, resulting in rapid clinical decline. CONCLUSION This case highlights a rare presentation of pancreatic cancer in CS/PHTS with distinct molecular and histological features. The absence of KRAS mutation and presence of germline PTEN variant may have contributed to the aggressive clinical course and treatment resistance. These findings underscore the need for further research into the molecular mechanisms of PTEN-associated pancreatic cancers and the development of targeted therapeutic strategies.
Collapse
Affiliation(s)
- Yosuke Saito
- Department of Clinical Oncology, Yamagata University Hospital, Yamagata, Japan
| | - Shuhei Suzuki
- Department of Clinical Oncology, Yamagata University Hospital, Yamagata, Japan;
- Yamagata Hereditary Tumor Research Center, Yamagata University, Yamagata, Japan
| | - Tomomi Sanomachi
- Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kaho Kato
- Master of Public Health, Human Genetics, University of Pittsburgh, Pittsburgh, PA, U.S.A
- Nihonkai General Hospital, Yamagata, Japan
| | - Hiroya Otake
- Department of Pathology, Yamagata City Hospital Saiseikan, Yamagata, Japan
| | - Yuko Nishise
- Department of Gastroenterology, Yamagata City Hospital Saiseikan, Yamagata, Japan
| | - Yuta Yamada
- Department of Clinical Oncology, Yamagata University Hospital, Yamagata, Japan
| | | | - Koshi Takahashi
- Department of Clinical Oncology, Yamagata University Hospital, Yamagata, Japan
| | - Ryosuke Kumanishi
- Department of Clinical Oncology, Yamagata University Hospital, Yamagata, Japan
| | - Tadahisa Fukui
- Department of Clinical Oncology, Yamagata University Hospital, Yamagata, Japan
| | - Takashi Yoshioka
- Department of Clinical Oncology, Yamagata University Hospital, Yamagata, Japan
| |
Collapse
|
|
3
|
Farshid G, Ibbetson SJ, Pradhan M, Henry L, Manton ND, Dubowsky A, Poplawski NK. Clinical, histological and receptor profiles of invasive breast cancer and ductal carcinoma in situ in females with germline pathogenic variants in PTEN and implications for germline testing. Pathology 2025; 57:72-80. [PMID: 39567325 DOI: 10.1016/j.pathol.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Revised: 07/31/2024] [Accepted: 08/07/2024] [Indexed: 11/22/2024]
Abstract
PTEN hamartoma tumour syndrome (PHTS) is an autosomal dominant hereditary cancer syndrome, caused mostly by germline pathogenic variants in PTEN. Female carriers have an up to 80% lifetime risk of breast cancer. Pathological features of breast cancer in PHTS have seldom been reported. In a collaboration between all histopathology laboratories in our state and our statewide familial cancer service, we tracked the breast biopsies of 12 females with known PTEN pathogenic or likely pathogenic (P/LP) variants (January 1990 to January 2018). Two further cases were added by a Victorian cancer genetics unit. Breast cancer, inclusive of invasive cancer or ductal carcinoma in situ (DCIS), was diagnosed in 12 of 14 cases (85.7%). One case had a family history of PHTS, and six had a family history of breast cancer. The mean age at first breast cancer diagnosis was 41.6 years (range 27-63). Six cases developed more than one breast cancer. Five (42%) developed contralateral breast cancer. Ten of the 12 invasive cancers were of no special type, and two were reported as lobular carcinomas. None were grade 1. When reported, all cancers were hormone-receptor positive and HER2 negative. All were associated with DCIS. The DCIS spanned all grades. The two cases without breast cancer still required surgery for exuberant benign changes, including papillomas, fibroadenomatoid change, florid ductal epithelial hyperplasia, adenosis and stromal fibrosis. We note that the morphology and receptor profiles of breast cancer in individuals with P/LP PTEN variants are not distinctive. Contrary to prevalent beliefs, these cancers do not conform to the contemporary definition of apocrine breast carcinoma. Greater familiarity of healthcare professionals with the overall clinical and pathological findings in PHTS and the validated Cleveland Clinic PTEN calculator (http://www.lerner.ccf.org/gmi/ccscore) would improve the recognition of female PHTS individuals with breast cancer. Earlier identification of their cancer predisposition syndrome would benefit these patients and their families who are at high risk of a range of cancers.
Collapse
MESH Headings
- Humans
- Female
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Breast Neoplasms/diagnosis
- PTEN Phosphohydrolase/genetics
- Adult
- Middle Aged
- Germ-Line Mutation
- Carcinoma, Intraductal, Noninfiltrating/pathology
- Carcinoma, Intraductal, Noninfiltrating/genetics
- Carcinoma, Intraductal, Noninfiltrating/diagnosis
- Genetic Testing
- Carcinoma, Ductal, Breast/genetics
- Carcinoma, Ductal, Breast/pathology
- Carcinoma, Ductal, Breast/diagnosis
- Carcinoma, Ductal, Breast/metabolism
- Hamartoma Syndrome, Multiple/genetics
- Hamartoma Syndrome, Multiple/pathology
- Hamartoma Syndrome, Multiple/diagnosis
Collapse
Affiliation(s)
- Gelareh Farshid
- Discipline of Medicine, Adelaide University and Directorate of Surgical Pathology, SA Pathology, Royal Adelaide Hospital, Adelaide, SA, Australia.
| | - S Jan Ibbetson
- SA Pathology and ClinPath Laboratories, Adelaide, SA, Australia
| | - Malcolm Pradhan
- School of Medical Sciences, Department of Digital Health, University of Sydney, Sydney, NSW, Australia
| | - Lachlan Henry
- Australian Clinical Laboratories, Woodville, SA, Australia
| | | | - Andrew Dubowsky
- Directorate of Genetics and Molecular Pathology, Flinders Medical Centre SA Pathology, Adelaide, SA, Australia
| | | |
Collapse
|
|
4
|
Maeda Y, Ikeda T, Sato A, Matsumoto A, Jinno H. Breast Cancer with a Newly Diagnosed Variant in the PTEN Gene: A Case Report. Surg Case Rep 2025; 11:24-0082. [PMID: 39974553 PMCID: PMC11835985 DOI: 10.70352/scrj.cr.24-0082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 12/29/2024] [Indexed: 02/21/2025] Open
Abstract
INTRODUCTION The phosphatase and tensin homolog hamartoma tumor syndrome (PHTS) refers to a spectrum of disorders caused by variants of the phosphatase and tensin homolog (PTEN) gene, including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, adult Lhermitte-Duclos disease, and autism spectrum disorders associated with macrocephaly. PHTS is characterized by hamartomas in multiple organs and is associated with an increased risk of developing malignant tumors including, breast, thyroid, endometrial, colorectal, and kidney tumors. Breast cancer is the most common malignancy associated with PHTS. CASE PRESENTATION We describe the case of a 44-year-old female patient with invasive ductal carcinoma of the right breast. Cobblestone papillomatosis was present in the gingiva. She had a medical history of bilateral adenomatous goiters for 10 years. Her mother had been diagnosed with breast cancer, thyroid and tongue tumors, gastric polyps, hepatic hemangioma, and collagen disease. Additionally, the patient's maternal grandmother had a history of colon cancer. Based on the patient's family history and physical findings, CS was suspected, and direct DNA sequencing analysis revealed a haplotype c.634del mutation in exon 7 of the PTEN gene. Although there is no clear evidence supporting risk-reducing surgery for PHTS, a right nipple-sparing mastectomy, sentinel lymph node biopsy, and tissue expander reconstruction were performed. CONCLUSIONS We report a case of breast cancer with a newly diagnosed c.634del mutation in the PTEN gene. We also reviewed the current literature on PTEN genetic variants and breast cancer subtypes.
Collapse
Affiliation(s)
- Yuka Maeda
- Department of Surgery, School of Medicine, Teikyo University, Tokyo, Japan
| | - Tatsuhiko Ikeda
- Department of Surgery, School of Medicine, Teikyo University, Tokyo, Japan
| | - Ayana Sato
- Department of Surgery, School of Medicine, Teikyo University, Tokyo, Japan
| | - Akiko Matsumoto
- Department of Surgery, School of Medicine, Teikyo University, Tokyo, Japan
| | - Hiromitsu Jinno
- Department of Surgery, School of Medicine, Teikyo University, Tokyo, Japan
| |
Collapse
|
|
5
|
Schultz KAP, MacFarland SP, Perrino MR, Mitchell SG, Kamihara J, Nelson AT, Mallinger PHR, Brzezinski JJ, Maxwell KN, Woodward ER, Gallinger B, Kim SY, Greer MLC, Schneider KW, Scollon SR, Das A, Wasserman JD, Eng C, Malkin D, Foulkes WD, Michaeli O, Bauer AJ, Stewart DR. Update on Pediatric Surveillance Recommendations for PTEN Hamartoma Tumor Syndrome, DICER1-Related Tumor Predisposition, and Tuberous Sclerosis Complex. Clin Cancer Res 2025; 31:234-244. [PMID: 39540884 PMCID: PMC11747828 DOI: 10.1158/1078-0432.ccr-24-1947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/04/2024] [Accepted: 11/13/2024] [Indexed: 11/16/2024]
Abstract
Phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex are rare conditions, which each increases risk for distinct spectra of benign and malignant neoplasms throughout childhood and adulthood. Surveillance considerations for each of these conditions focus on patient and family education, early detection, and multidisciplinary care. In this article, we present updated surveillance recommendations and considerations for children and adolescents with phosphate and tensin homolog hamartoma tumor syndrome, DICER1-related tumor predisposition, and tuberous sclerosis complex and provide suggestions for further research in each of these conditions.
Collapse
Affiliation(s)
- Kris Ann P. Schultz
- International Pleuropulmonary Blastoma/DICER1 Registry, Cancer and Blood Disorders, Children’s Minnesota, Minneapolis, MN
| | - Suzanne P. MacFarland
- Division of Oncology, The Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Melissa R. Perrino
- Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN
| | - Sarah G. Mitchell
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA
| | - Junne Kamihara
- Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA
| | - Alexander T. Nelson
- International Pleuropulmonary Blastoma/DICER1 Registry, Cancer and Blood Disorders, Children’s Minnesota, Minneapolis, MN
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
| | - Paige H. R. Mallinger
- International Pleuropulmonary Blastoma/DICER1 Registry, Cancer and Blood Disorders, Children’s Minnesota, Minneapolis, MN
| | - Jack J. Brzezinski
- Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON
| | - Kara N. Maxwell
- Department of Medicine, Division of Hematology/Oncology and Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Emma R. Woodward
- Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Bailey Gallinger
- Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON
- Department of Molecular Genetics, The University of Toronto, Toronto, ON
| | - Sun Young Kim
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH
| | - Mary-Louise C. Greer
- Department of Diagnostic and Interventional Radiology, The Hospital for Sick Children, Department of Medical Imaging, University of Toronto, Toronto, ON
| | - Kami Wolfe Schneider
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Sarah R. Scollon
- Department of Pediatrics, Texas Children’s Cancer and Hematology Center, Baylor College of Medicine, Houston, TX
| | - Anirban Das
- Division of Haematology/Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON
| | - Jonathan D. Wasserman
- Division of Endocrinology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON
| | - Charis Eng
- Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
| | - David Malkin
- Division of Haematology/Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON
| | | | - Orli Michaeli
- Division of Hematology and Oncology, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel
| | - Andrew J. Bauer
- Division of Endocrinology and Diabetes, The Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Douglas R. Stewart
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD
| |
Collapse
|
|
6
|
Бричева ЭБ, Нагаева ЕВ, Бровин ДН, Бондаренко ЕВ, Шеремета МС, Безлепкина ОБ, Олина ТС, Коваленко ТВ. [Thyroid cancer in a child with Cowden syndrome]. PROBLEMY ENDOKRINOLOGII 2024; 70:84-90. [PMID: 39509640 PMCID: PMC11610633 DOI: 10.14341/probl13445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 04/02/2024] [Indexed: 11/15/2024]
Abstract
Cowden disease (Cowden syndrome) refers to PTEN-associated hamartoma tumor syndromes. It arises due to a mutation in the phosphatase and tensin homolog gene, one of the main functions of which is cell cycle regulation. The presence of a mutation in the gene leads to uncontrolled cell growth, and patients have a lifelong increased risk of neoplasms of various degrees of malignancy. This article presents a clinical case of Cowden syndrome with an early debut at the age of 7 years. The combination of macrocephaly (SDS of head circumference >2) with various skin manifestations (facial trichilemmomas, acral keratosis, papillomatous papules) and the presence of benign and/or malignant neoplasms are pathognomonic for Cowden syndrome. Of the malignancies, breast and thyroid cancer, colorectal cancer, renal cell carcinoma, and endometrial cancer are the most common. Thyroid carcinoma has been shown to have an earlier age of manifestation and often occurs already in childhood. This determines the need to screen patients with a proven mutation in the PTEN gene for nodal neoplasms from an early age. If surgical treatment is necessary, thyroidectomy remains preferable due to the frequent recurrence of nodules, as well as the uncertain potential for malignancy due to the low study of thyroid nodules in patients with mutations in the PTEN gene.
Collapse
Affiliation(s)
- Э. Б. Бричева
- Национальный медицинский исследовательский центр эндокринологии
| | - Е. В. Нагаева
- Национальный медицинский исследовательский центр эндокринологии
| | - Д. Н. Бровин
- Национальный медицинский исследовательский центр эндокринологии
| | | | - М. С. Шеремета
- Национальный медицинский исследовательский центр эндокринологии
| | | | - Т. С. Олина
- Республиканская детская клиническая больница
| | | |
Collapse
|
|
7
|
Schei-Andersen AJ, Hendricks LAJ, van der Post RS, Mensenkamp AR, Schieving J, Schuurs-Hoeijmakers JHM, Hoogerbrugge N, Vos JR. Histopathological phenotyping of cancers in PTEN Hamartoma Tumor Syndrome for improved recognition: A single-center study. Int J Cancer 2024; 155:1567-1576. [PMID: 38861330 DOI: 10.1002/ijc.35049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 03/20/2024] [Accepted: 04/18/2024] [Indexed: 06/13/2024]
Abstract
PTEN hamartoma tumor syndrome (PHTS) has a broad clinical spectrum including various benign and malignant tumors at varying age of diagnosis. Many patients remain unrecognized, unaware of their increased cancer risk. We aimed to describe the cancer spectrum, age of onset and histopathological cancer characteristics to assess whether specific cancer characteristics could improve PHTS recognition. Genetic testing results and pathology reports were collected for patients tested for germline PTEN variants between 1997 and 2020 from the diagnostic laboratory and the Dutch nationwide pathology databank (Palga). The cancer spectrum and age of onset were assessed in patients with (PTENpos) and without (PTENneg) a germline PTEN variant. Histopathological cancer characteristics were assessed in a nested cohort. 341 PTENpos patients (56% females) and 2882 PTENneg patients (66% females) were included. PTENpos patients presented mostly with female breast (BC, 30%), endometrial (EC, 6%), thyroid (TC, 4%) or colorectal cancer (4%). PTENpos were significantly younger at cancer onset (43 vs. 47 years) and had more often (46% vs. 18%) a second BC than PTENneg. PTEN detection rates were highest for BC <40 years (9%), TC <20 years (15%) and EC <50 years (28%), and dropped to 6%, 4%, and 15% by age 60. Histopathological characteristics were similar between groups. No histopathological cancer characteristics were distinctive for PHTS. However, PTENpos were significantly younger at cancer onset. Therefore early-onset BC, EC, or TC warrants consideration of PHTS diagnostics either through a pre-screen for other PHTS features or direct germline testing.
Collapse
Affiliation(s)
- Ane J Schei-Andersen
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
- Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Linda A J Hendricks
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
- Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Rachel S van der Post
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Arjen R Mensenkamp
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
- Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jolanda Schieving
- Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Pediatric Neurology, Radboud University Medical Center, Amalia Children's Hospital, Nijmegen, The Netherlands
| | | | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
- Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network Genetic Tumour Risk Syndromes (ERN GENTURIS)
| | - Janet R Vos
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
- Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands
- European Reference Network Genetic Tumour Risk Syndromes (ERN GENTURIS)
| |
Collapse
|
|
8
|
Rajeswarie RT, Mallik D, Gopal S. Lhermitte-Duclos Disease: A Rare Entity With Typical Histology but Ambiguous Histogenesis. Int J Surg Pathol 2024; 32:1113-1116. [PMID: 38073095 DOI: 10.1177/10668969231215816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2023]
Affiliation(s)
- R T Rajeswarie
- Department of Laboratory Medicine - Histopathology, Sakra World Hospital, Bengaluru, Karnataka, India
| | - Dattatraya Mallik
- Departments of Laboratory Medicine and Neurosurgery, Sakra World Hospital, Bangalore, Karnataka, India
- Department of Neuroscience, Sakra World Hospital, Bengaluru, Karnataka, India
| | - Swaroop Gopal
- Departments of Laboratory Medicine and Neurosurgery, Sakra World Hospital, Bangalore, Karnataka, India
| |
Collapse
|
|
9
|
García-Iturbide R, Velázquez JA, Lozano Guzmán I, Falcon-Molina JE, Rodríguez MA, Sánchez-Gómez A, Heras Lorenzana JR, Estrada Estrada EM. Treatment and Diagnostic Approach for Lhermitte-Duclos Disease and Suspected Cowden Syndrome. Cureus 2024; 16:e62968. [PMID: 39044874 PMCID: PMC11265621 DOI: 10.7759/cureus.62968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/22/2024] [Indexed: 07/25/2024] Open
Abstract
Lhermitte-Duclos disease (LDD) is a rare entity, which may or may not be associated with Cowden syndrome (CS). The authors present a 26-year-old male with a history of emergency treatment due to acute obstructive hydrocephalus and apparent Chiari malformation. In posterior evaluation, mild cerebellar symptoms, mucocutaneous lesions, and a left hemispheric cerebellar lesion were evident. Initially, with the clinical evidence and the radiological study report of a cerebellar tiger-striped lesion, LDD with associated CS was suspected, and a genetic protocol was performed. The protocol included an endoscopy and thyroid ultrasound, and with symptom progression, a new neurosurgical procedure was performed. To complete the approach, we used the clinical criteria for PTEN hamartoma tumor syndrome established in 2013, and CS was diagnosed in the patient. In patients with radiological and clinical suspicion of LDD and CS, it should be mandatory to investigate the presence of other types of tumors due to their association with PTEN hamartomatous tumor syndrome, and in the absence of genetic study, the clinical criteria previously established in the literature should be sufficient to establish the diagnosis.
Collapse
Affiliation(s)
- Ricardo García-Iturbide
- Neurological Surgery, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, MEX
| | - Joel A Velázquez
- Neurological Surgery, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, MEX
| | - Isauro Lozano Guzmán
- Neurological Surgery, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, MEX
| | - Jesus E Falcon-Molina
- Neurological Surgery, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, MEX
| | - Marco A Rodríguez
- Pathology, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, MEX
| | - Adrian Sánchez-Gómez
- Neurological Surgery, Hospital Regional 1ro de Octubre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE), Mexico City, MEX
| | - Jesùs R Heras Lorenzana
- Neurological Surgery, Hospital Regional de Alta Especialidad Bicentenario de la Independencia, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE), Tultitlán de Mariano Escobedo, MEX
| | - Eric M Estrada Estrada
- Neurological Surgery, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, MEX
| |
Collapse
|
|
10
|
Fazelpour S, Deverapalli SC, Nguyen B. Skin cancer-associated genodermatoses in skin of color patients: a review. Arch Dermatol Res 2024; 316:282. [PMID: 38796611 DOI: 10.1007/s00403-024-03087-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 10/22/2023] [Accepted: 04/26/2024] [Indexed: 05/28/2024]
Abstract
Skin cancers are associated with a large number of genodermatoses. Existing knowledge and guidelines on the presentations of these genodermatoses focus disproportionately on White patients. Our goal is to identify notable characteristics in location, frequency, and severity of cutaneous findings along with the median age of skin cancers in skin-of-color (SOC) patients with skin-cancer-associated genodermatoses to improve diagnosis rates. We searched for genodermatoses on six databases. Each case report or case series was reviewed, including reports, published in English, containing adult patient descriptions. Duplicate manuscripts were removed using EndNote. The following case-level data were collected from the manuscripts: age, gender, patient country or region of origin, author country/continent of residence, skin cancer-related, and other key dermatologic features. 381 published articles, with a total of 578 SOC patients, met criteria for inclusion. SOC patients can present with fewer classic findings, such as a lower incidence of basal cell carcinomas (44%) in SOC Gorlin syndrome patients than palmar pits (66%) and mandibular cysts (66%). Differences between SOC populations were also noted, such as leukoplakia being more common in Asian dyskeratosis congenita patients (80%) in comparison to African dyskeratosis congenita patients (44%). SOC patients also have varying onset of skin cancer depending on the genodermatosis, from a median of 25 years of age in Rothmund-Thomson syndrome to 53 in Muir-Torre syndrome. In this review, SOC patients with genodermatoses can have varying presentations. Being cognizant of these characteristics may lead to earlier diagnosis and interventions to mitigate skin-cancer-related morbidity in SOC patients.
Collapse
Affiliation(s)
- Sherwin Fazelpour
- Boston University School of Medicine, 72 E Concord St, Boston, MA, 02118, USA.
| | | | - Bichchau Nguyen
- Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA
| |
Collapse
|
|
11
|
Rosty C, Brosens LAA. Pathology of Gastrointestinal Polyposis Disorders. Gastroenterol Clin North Am 2024; 53:179-200. [PMID: 38280747 DOI: 10.1016/j.gtc.2023.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2024]
Abstract
Gastrointestinal polyposis disorders are a group of syndromes defined by clinicopathologic features that include the predominant histologic type of colorectal polyp and specific inherited gene mutations. Adenomatous polyposis syndromes comprise the prototypical familial adenomatous polyposis syndrome and other recently identified genetic conditions inherited in a dominant or recessive manner. Serrated polyposis syndrome is defined by arbitrary clinical criteria. The diagnosis of hamartomatous polyposis syndromes can be suggested from the histologic characteristics of colorectal polyps and the association with various extraintestinal manifestations. Proper identification of affected individuals is important due to an increased risk of gastrointestinal and extragastrointestinal cancers.
Collapse
Affiliation(s)
- Christophe Rosty
- Envoi Specialist Pathologists, Brisbane, Queensland 4059, Australia; University of Queensland, Brisbane, Queensland 4072, Australia; Department of Clinical Pathology, Colorectal Oncogenomics Group, Victorian Comprehensive Cancer Centre, The University of Melbourne, Victoria 3051, Australia.
| | - Lodewijk A A Brosens
- Department of Pathology University Medical Center Utrecht, Utrecht University, Postbus 85500, 3508, Utrecht, Galgenwaad, The Netherlands
| |
Collapse
|
|
12
|
Watanabe T, Soeda S, Okoshi C, Fukuda T, Yasuda S, Fujimori K. Landscape of somatic mutated genes and inherited susceptibility genes in gynecological cancer. J Obstet Gynaecol Res 2023; 49:2629-2643. [PMID: 37632362 DOI: 10.1111/jog.15766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/26/2023] [Indexed: 08/28/2023]
Abstract
Traditionally, gynecological cancers have been classified based on histology. Since remarkable advancements in next-generation sequencing technology have enabled the exploration of somatic mutations in various cancer types, comprehensive sequencing efforts have revealed the genomic landscapes of some common forms of human cancer. The genomic features of various gynecological malignancies have been reported by several studies of large-scale genomic cohorts, including The Cancer Genome Atlas. Although recent comprehensive genomic profiling tests, which can detect hundreds of genetic mutations at a time from cancer tissues or blood samples, have been increasingly used as diagnostic clinical biomarkers and in therapeutic management decisions, germline pathogenic variants associated with hereditary cancers can also be detected using this test. Gynecological cancers are closely related to genetic factors, with approximately 5% of endometrial cancer cases and 20% of ovarian cancer cases being caused by germline pathogenic variants. Hereditary breast and ovarian cancer syndrome and Lynch syndrome are the two major cancer susceptibility syndromes among gynecological cancers. In addition, several other hereditary syndromes have been reported to be associated with gynecological cancers. In this review, we highlight the genes for somatic mutation and germline pathogenic variants commonly seen in gynecological cancers. We first describe the relationship between clinicopathological attributes and somatic mutated genes. Subsequently, we discuss the characteristics and clinical management of inherited cancer syndromes resulting from pathogenic germline variants in gynecological malignancies.
Collapse
Affiliation(s)
- Takafumi Watanabe
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima, Japan
| | - Shu Soeda
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima, Japan
| | - Chihiro Okoshi
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima, Japan
| | - Toma Fukuda
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima, Japan
| | - Shun Yasuda
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima, Japan
| | - Keiya Fujimori
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima, Japan
| |
Collapse
|
|
13
|
Takayama T, Muguruma N, Igarashi M, Ohsumi S, Oka S, Kakuta F, Kubo Y, Kumagai H, Sasaki M, Sugai T, Sugano K, Takeda Y, Doyama H, Banno K, Fukahori S, Furukawa Y, Horimatsu T, Ishikawa H, Iwama T, Okazaki Y, Saito Y, Matsuura N, Mutoh M, Tomita N, Akiyama T, Yamamoto T, Ishida H, Nakayama Y. Clinical Guidelines for Diagnosis and Management of Cowden Syndrome/PTEN Hamartoma Tumor Syndrome in Children and Adults-Secondary Publication. J Anus Rectum Colon 2023; 7:284-300. [PMID: 37900693 PMCID: PMC10600266 DOI: 10.23922/jarc.2023-028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 05/30/2023] [Indexed: 10/31/2023] Open
Abstract
Cowden syndrome (CS)/PTEN hamartoma tumor syndrome (PHTS) is a rare autosomal dominantly inherited condition caused by germline pathogenesis. It is associated with multiple hamartomatous lesions occurring in various organs and tissues, including the gastrointestinal tract, skin, mucous membranes, breast, thyroid, endometrium, and brain. Macrocephaly or multiple characteristic mucocutaneous lesions commonly develop in individuals in their 20s. This syndrome is occasionally diagnosed in childhood due to the occurrence of multiple gastrointestinal polyps, autism spectrum disorders, and intellectual disability. CS/PHTS can be diagnosed taking the opportunity of multigene panel testing in patients with cancer. Appropriate surveillance for early diagnosis of associated cancers is required because patients have a high risk of cancers including breast, thyroid, colorectal, endometrial, and renal cancers. Under these circumstances, there is growing concern regarding the management of CS/PHTS in Japan, but there are no available practice guidelines. To address this situation, the guideline committee, which included specialists from multiple academic societies, was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour, and Welfare, Japan. The present clinical guidelines explain the principles in the diagnosis and management of CS/PHTS, together with four clinical questions and the corresponding recommendations, incorporating the concept of the Grading of Recommendations Assessment, Development, and Evaluation system. Herein, we present an English version of the guideline, some of which have been updated, to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with CS/PHTS.
Collapse
Affiliation(s)
- Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Masahiro Igarashi
- Department of Lower GI Medicine, Cancer Institute Hospital of JFCR, Tokyo, Japan
| | - Shozo Ohsumi
- Department of Breast Oncology, NHO Shikoku Cancer Center, Matsuyama, Japan
| | - Shiro Oka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Fumihiko Kakuta
- Division of General Pediatrics and Gastroenterology, Miyagi Children's Hospital, Sendai, Japan
| | - Yoshiaki Kubo
- Department of Dermatology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hideki Kumagai
- Department of Pediatrics, Jichi Medical University, Shimotsuke, Japan
| | - Mika Sasaki
- Department of Pediatrics, National Hospital Organization Morioka Medical Center, Morioka, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan
| | - Kokichi Sugano
- Oncogene Res Unit, Cancer Prevention Unit Tochigi Cancer Center Research Institute, Cancer Prevention, Genetic Counseling Clinic, Genome Center, Tochigi Cancer Center, Utsunomiya, Japan
- Department of Genetic Medicine, Sasaki Foundation, Kyoundo Hospital, Tokyo, Japan
| | - Yuko Takeda
- Faculty of Nursing and Medical Care, Graduate School of Health Management, Keio University, Tokyo, Japan
| | - Hisashi Doyama
- Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan
| | - Kouji Banno
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Suguru Fukahori
- Department of Pediatric Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Yoichi Furukawa
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takahiro Horimatsu
- Department of Real World Data Research and Development, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hideki Ishikawa
- Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Ishikawa Gastroenterology Clinic, Osaka, Japan
| | - Takeo Iwama
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Yasushi Okazaki
- Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | | | - Michihiro Mutoh
- Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Naohiro Tomita
- Cancer Treatment Center, Toyonaka Municipal Hospital, Toyonaka, Japan
| | - Takashi Akiyama
- Department of Pediatric Surgery, Chuden Hospital, Hiroshima, Japan
| | - Toshiki Yamamoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Japan
| | - Yoshiko Nakayama
- Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
| |
Collapse
|
|
14
|
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.
Collapse
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.
| |
Collapse
|
|
15
|
McCarthy RL, Copson E, Tapper W, Bolton H, Mirnezami AH, O'Neill JR, Patel NN, Tischkowitz M, Cutress RI. Risk-reducing surgery for individuals with cancer-predisposing germline pathogenic variants and no personal cancer history: a review of current UK guidelines. Br J Cancer 2023; 129:383-392. [PMID: 37258796 PMCID: PMC10403612 DOI: 10.1038/s41416-023-02296-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 04/18/2023] [Accepted: 04/21/2023] [Indexed: 06/02/2023] Open
Abstract
Identifying healthy carriers of germline pathogenic variants in high penetrance cancer susceptibility genes offers the potential for risk-reducing surgery. The NHS England National Genomic Test Directory offers germline and somatic testing to patients with certain cancers or rare and inherited diseases, or, in some cases, to their relatives. This review summarises current UK guidelines for risk-reducing surgical interventions available for individuals with no personal history of cancer, who are determined to carry germline pathogenic variants. An electronic literature search of NICE guidelines and PubMed citable articles was performed. NICE guidelines are available for bilateral mastectomy and are currently in development for risk-reducing bilateral salpingo-oophorectomy. Guidelines developed with affiliation to, or through relevant British Surgical Societies or international consensus, are available for risk-reducing hysterectomy, polypectomy, gastrectomy, and thyroidectomy. There is a disparity in the development and distribution of national guidelines for interventions amongst tumour types. Whilst we are focusing on UK guidelines, we anticipate they will be relevant much more generally and so of interest to a wider audience including where there are no national guidelines to refer to. We suggest that, as genetic testing becomes rapidly more accessible, guideline development for interventions should be more closely aligned to those for testing.
Collapse
Affiliation(s)
- Rebecca L McCarthy
- University Hospital Southampton NHS Trust, Southampton, UK.
- Faculty of Medicine, University of Southampton, Southampton, UK.
| | - Ellen Copson
- University Hospital Southampton NHS Trust, Southampton, UK
- Cancer Sciences Academic Unit, University of Southampton, Southampton, UK
| | - William Tapper
- University of Southampton Faculty of Medicine Health and Life Sciences, Southampton, UK
| | - Helen Bolton
- Department of Gynaecological Oncology, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, Cambridgeshire, UK
| | - Alex H Mirnezami
- University Hospital Southampton NHS Trust, Southampton, UK
- Cancer Sciences Academic Unit, University of Southampton, Southampton, UK
| | - J Robert O'Neill
- Cambridge Oesophagogastric Centre, Addenbrooke's Hospital, Cambridge, Cambridgeshire, UK
| | - Nimesh N Patel
- Department of Otolaryngology, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - Marc Tischkowitz
- Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Ramsey I Cutress
- University Hospital Southampton NHS Trust, Southampton, UK
- Cancer Sciences Academic Unit, University of Southampton, Southampton, UK
| |
Collapse
|
|
16
|
Emons G, Steiner E, Vordermark D, Uleer C, Paradies K, Tempfer C, Aretz S, Cremer W, Hanf V, Mallmann P, Ortmann O, Römer T, Schmutzler RK, Horn LC, Kommoss S, Lax S, Schmoeckel E, Mokry T, Grab D, Reinhardt M, Steinke-Lange V, Brucker SY, Kiesel L, Witteler R, Fleisch MC, Heinrich Prömpeler † 25, Friedrich M, Höcht S, Lichtenegger W, Mueller M, Runnebaum I, Feyer P, Hagen V, Juhasz-Böss I, Letsch A, Niehoff P, Zeimet AG, Battista MJ, Petru E, Widhalm S, van Oorschot B, Panke JE, Weis J, Dauelsberg T, Haase H, Beckmann MW, Jud S, Wight E, Prott FJ, Micke O, Bader W, Reents N, Henscher U, Reina Tholen † 52, Schallenberg M, Rahner N, Mayr D, Kreißl M, Lindel K, Mustea A, Strnad V, Goerling U, Bauerschmitz GJ, Langrehr J, Neulen J, Ulrich UA, Nothacker MJ, Blödt S, Follmann M, Langer T, Wenzel G, Weber S, Erdogan S. Endometrial Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry Number 032/034-OL, September 2022). Part 1 with Recommendations on the Epidemiology, Screening, Diagnosis and Hereditary Factors of Endometrial Cancer, Geriatric Assessment and Supply Structures. Geburtshilfe Frauenheilkd 2023; 83:919-962. [PMID: 37588260 PMCID: PMC10427205 DOI: 10.1055/a-2066-2051] [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: 03/17/2023] [Accepted: 06/22/2023] [Indexed: 08/18/2023] Open
Abstract
Summary The S3-guideline on endometrial cancer, first published in April 2018, was reviewed in its entirety between April 2020 and January 2022 and updated. The review was carried out at the request of German Cancer Aid as part of the Oncology Guidelines Program and the lead coordinators were the German Society for Gynecology and Obstetrics (DGGG), the Gynecology Oncology Working Group (AGO) of the German Cancer Society (DKG) and the German Cancer Aid (DKH). The guideline update was based on a systematic search and assessment of the literature published between 2016 and 2020. All statements, recommendations and background texts were reviewed and either confirmed or amended. New statements and recommendations were included where necessary. Aim The use of evidence-based risk-adapted therapies to treat women with endometrial cancer of low risk prevents unnecessarily radical surgery and avoids non-beneficial adjuvant radiation therapy and/or chemotherapy. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimum level of radical surgery and indicates whether chemotherapy and/or adjuvant radiation therapy is necessary. This should improve the survival rates and quality of life of these patients. The S3-guideline on endometrial cancer and the quality indicators based on the guideline aim to provide the basis for the work of certified gynecological cancer centers. Methods The guideline was first compiled in 2018 in accordance with the requirements for S3-level guidelines and was updated in 2022. The update included an adaptation of the source guidelines identified using the German Instrument for Methodological Guideline Appraisal (DELBI). The update also used evidence reviews which were created based on selected literature obtained from systematic searches in selected literature databases using the PICO process. The Clinical Guidelines Service Group was tasked with carrying out a systematic search and assessment of the literature. Their results were used by interdisciplinary working groups as a basis for developing suggestions for recommendations and statements which were then modified during structured online consensus conferences and/or additionally amended online using the DELPHI process to achieve a consensus. Recommendations Part 1 of this short version of the guideline provides recommendations on epidemiology, screening, diagnosis, and hereditary factors. The epidemiology of endometrial cancer and the risk factors for developing endometrial cancer are presented. The options for screening and the methods used to diagnose endometrial cancer are outlined. Recommendations are given for the prevention, diagnosis, and therapy of hereditary forms of endometrial cancer. The use of geriatric assessment is considered and existing structures of care are presented.
Collapse
Affiliation(s)
- Günter Emons
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
| | - Eric Steiner
- Frauenklinik GPR Klinikum Rüsselsheim am Main, Rüsselsheim, Germany
| | - Dirk Vordermark
- Universität Halle (Saale), Radiotherapie, Halle (Saale), Germany
| | - Christoph Uleer
- Facharzt für Frauenheilkunde und Geburtshilfe, Hildesheim, Germany
| | - Kerstin Paradies
- Konferenz onkologischer Kranken- und Kinderkrankenpfleger (KOK), Hamburg, Germany
| | - Clemens Tempfer
- Frauenklinik der Ruhr-Universität Bochum, Bochum/Herne, Germany
| | - Stefan Aretz
- Institut für Humangenetik, Universität Bonn, Zentrum für erbliche Tumorerkrankungen, Bonn, Germany
| | | | - Volker Hanf
- Frauenklinik Nathanstift – Klinikum Fürth, Fürth, Germany
| | | | - Olaf Ortmann
- Universität Regensburg, Fakultät für Medizin, Klinik für Frauenheilkunde und Geburtshilfe, Regensburg, Germany
| | - Thomas Römer
- Evangelisches Klinikum Köln Weyertal, Gynäkologie Köln, Köln, Germany
| | - Rita K. Schmutzler
- Universitätsklinikum Köln, Zentrum Familiärer Brust- und Eierstockkrebs, Köln, Germany
| | | | - Stefan Kommoss
- Universitätsklinikum Tübingen, Universitätsfrauenklinik Tübingen, Tübingen, Germany
| | - Sigurd Lax
- Institut für Pathologie, LKH Graz Süd-West, Graz, Austria
| | | | - Theresa Mokry
- Universitätsklinikum Heidelberg, Diagnostische und Interventionelle Radiologie, Heidelberg, Germany
| | - Dieter Grab
- Universitätsklinikum Ulm, Frauenheilkunde und Geburtshilfe, Ulm, Germany
| | - Michael Reinhardt
- Klinik für Nuklearmedizin, Pius Hospital Oldenburg, Oldenburg, Germany
| | - Verena Steinke-Lange
- MGZ – Medizinisch Genetisches Zentrum München, München, Germany
- Medizinische Klinik und Poliklinik IV, LMU München, München, Germany
| | - Sara Y. Brucker
- Universitätsklinikum Tübingen, Universitätsfrauenklinik Tübingen, Tübingen, Germany
| | - Ludwig Kiesel
- Universitätsklinikum Münster, Frauenklinik A Schweitzer Campus 1, Münster, Germany
| | - Ralf Witteler
- Universitätsklinikum Münster, Frauenklinik A Schweitzer Campus 1, Münster, Germany
| | - Markus C. Fleisch
- Helios, Universitätsklinikum Wuppertal, Landesfrauenklinik, Wuppertal, Germany
| | | | - Michael Friedrich
- Helios Klinikum Krefeld, Klinik für Frauenheilkunde und Geburtshilfe, Krefeld, Germany
| | - Stefan Höcht
- XCare, Praxis für Strahlentherapie Saarlouis, Saarlouis, Germany
| | - Werner Lichtenegger
- Universitätsmedizin Berlin, Frauenklinik Charité, Campus Virchow-Klinikum, Berlin, Germany
| | - Michael Mueller
- Universitätsklinik für Frauenheilkunde, Inselspital Bern, Bern, Switzerland
| | | | - Petra Feyer
- Vivantes Klinikum Neukölln, Klinik für Strahlentherapie und Radioonkologie, Berlin, Germany
| | - Volker Hagen
- Klinik für Innere Medizin II, St.-Johannes-Hospital Dortmund, Dortmund, Germany
| | | | - Anne Letsch
- Universitätsklinikum Schleswig Holstein, Campus Kiel, Innere Medizin, Kiel, Germany
| | - Peter Niehoff
- Strahlenklinik, Sana Klinikum Offenbach, Offenbach, Germany
| | - Alain Gustave Zeimet
- Medizinische Universität Innsbruck, Universitätsklinik für Gynäkologie und Geburtshilfe, Innsbruck, Austria
| | | | - Edgar Petru
- Med. Univ. Graz, Frauenheilkunde, Graz, Austria
| | | | - Birgitt van Oorschot
- Universitätsklinikum Würzburg, Interdisziplinäres Zentrum Palliativmedizin, Würzburg, Germany
| | - Joan Elisabeth Panke
- Medizinischer Dienst des Spitzenverbandes Bund der Krankenkassen e. V. Essen, Essen, Germany
| | - Joachim Weis
- Albert-Ludwigs-Universität Freiburg, Medizinische Fakultät, Tumorzentrum Freiburg – CCCF, Freiburg, Germany
| | - Timm Dauelsberg
- Universitätsklinikum Freiburg, Klinik für Onkologische Rehabilitation, Freiburg, Germany
| | | | | | | | - Edward Wight
- Frauenklinik des Universitätsspitals Basel, Basel, Switzerland
| | - Franz-Josef Prott
- Facharzt für Radiologie und Strahlentherapie, Wiesbaden, Wiesbaden, Germany
| | - Oliver Micke
- Franziskus Hospital Bielefeld, Klinik für Strahlentherapie und Radioonkologie, Bielefeld, Germany
| | - Werner Bader
- Klinikum Bielefeld Mitte, Zentrum für Frauenheilkunde, Bielefeld, Germany
| | | | | | | | | | | | - Doris Mayr
- LMU München, Pathologisches Institut, München, Germany
| | - Michael Kreißl
- Universität Magdeburg, Medizinische Fakultät, Universitätsklinik für Radiologie und Nuklearmedizin, Germany
| | - Katja Lindel
- Städtisches Klinikum Karlsruhe, Karlsruhe, Germany
| | - Alexander Mustea
- Universitätsklinikum Bonn, Zentrum Gynäkologie und gynäkologische Onkologie, Bonn, Germany
| | - Vratislav Strnad
- Universitätsklinikum Erlangen, Brustzentrum Franken, Erlangen, Germany
| | - Ute Goerling
- Universitätsmedizin Berlin, Campus Charité Mitte, Charité Comprehensive Cancer Center, Berlin, Germany
| | - Gerd J. Bauerschmitz
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
| | - Jan Langrehr
- Martin-Luther-Krankenhaus, Klinik für Allgemein-, Gefäß- und Viszeralchirurgie, Berlin, Germany
| | - Joseph Neulen
- Uniklinik RWTH Aachen, Klinik für Gynäkologische Endokrinologie und Reproduktionsmedizin, Aachen, Germany
| | - Uwe Andreas Ulrich
- Martin-Luther-Krankenhaus, Johannesstift Diakonie, Gynäkologie, Berlin, Germany
| | | | | | - Markus Follmann
- Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
| | - Thomas Langer
- Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
| | - Gregor Wenzel
- Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
| | - Sylvia Weber
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
| | - Saskia Erdogan
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
| |
Collapse
|
|
17
|
Asare B, Panigrahi B. Synchronous and metachronous thyroid cancer, breast cancer, and melanoma in a premenopausal patient with Cowden syndrome. Radiol Case Rep 2023; 18:1918-1923. [PMID: 36942005 PMCID: PMC10024037 DOI: 10.1016/j.radcr.2023.02.023] [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: 02/04/2023] [Accepted: 02/08/2023] [Indexed: 03/14/2023] Open
Abstract
Cowden syndrome is a rare autosomal dominant genetic disorder characterized by a germline mutation in the phosphatase and tensin homolog gene, leading to multiple hamartomas, neurodevelopmental disorders, and an increased lifetime risk of multiple cancers. Malignancy is the most common cause of mortality in Cowden syndrome, with breast cancer being the most common malignancy encountered in females with the disorder. Screening guidelines for this population should address this risk at an early age. We present a case of metachronous thyroid cancer followed by synchronous breast cancer and melanoma in a young female with Cowden syndrome, highlighting diagnostic imaging, management, and screening considerations.
Collapse
Affiliation(s)
- Belinda Asare
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medicine, 601 N. Caroline St, Baltimore, MD 21287, USA
| | - Babita Panigrahi
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medicine, 601 N. Caroline St, Baltimore, MD 21287, USA
| |
Collapse
|
|
18
|
Cummings S, Alfonso A, Hughes E, Kucera M, Mabey B, Singh N, Eng C. Cancer Risk Associated With PTEN Pathogenic Variants Identified Using Multigene Hereditary Cancer Panel Testing. JCO Precis Oncol 2023; 7:e2200415. [PMID: 36634299 PMCID: PMC9928870 DOI: 10.1200/po.22.00415] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
PURPOSE PTEN-associated clinical syndromes such as Cowden syndrome (CS) increase cancer risk and have historically been diagnosed based upon phenotypic criteria. Because not all patients clinically diagnosed with CS have PTEN pathogenic variants (PVs), and not all patients with PTEN PVs have been clinically diagnosed with CS, the cancer risk conferred by PTEN PVs calculated from cohorts of patients with clinical diagnoses of CS/CS-like phenotypes may be inaccurate. METHODS We assessed a consecutive cohort of 727,091 individuals tested clinically for hereditary cancer risk, with a multigene panel between September 2013 and February 2022. Multivariable logistic regression models accounting for personal and family cancer history, age, sex, and ancestry were used to quantify disease risks associated with PTEN PVs. RESULTS PTEN PVs were detected in 0.027% (193/727,091) of the study population, and were associated with a high risk of female breast cancer (odds ratio [OR], 7.88; 95% CI, 5.57 to 11.16; P = 2.3 × 10-31), endometrial cancer (OR, 13.51; 95% CI, 8.77 to 20.83; P = 4.2 × 10-32), thyroid cancer (OR, 4.88; 95% CI, 2.64 to 9.01; P = 4.0 × 10-7), and colon polyposis (OR, 31.60; CI, 15.60 to 64.02; P = 9.0 × 10-22). We observed modest evidence suggesting that PTEN PVs may be associated with ovarian cancer risk (OR, 3.77; 95% CI, 1.71 to 8.32; P = 9.9 × 10-4). Among patients with similar personal/family history and ancestry, every 5-year increase in age of diagnosis decreased the likelihood of detecting a PTEN PV by roughly 60%. CONCLUSION We demonstrate that PTEN PVs are associated with significantly increased risk for a range of cancers. Together with the observation that PTEN PV carriers had earlier disease onset relative to otherwise comparable noncarriers, our results may guide screening protocols, inform risk-management strategies, and warrant enhanced surveillance approaches that improve clinical outcomes for PTEN PV carriers, regardless of their clinical presentation.
Collapse
Affiliation(s)
- Shelly Cummings
- Myriad Genetics Inc, Salt Lake City, UT,Shelly Cummings, MS, 320 Wakara Way, Salt Lake City, UT 84108; e-mail:
| | | | | | | | | | | | - Charis Eng
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH,Center for Personalized Genetic Healthcare, Cleveland Clinic Community Care, Cleveland, OH,Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH,Department of Genetics and Genome Sciences, and CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH
| |
Collapse
|
|
19
|
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: 20] [Impact Index Per Article: 10.0] [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.
Collapse
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
| |
Collapse
|
|
20
|
Long-Term Outcome of Patients with Stage II and III Muscle-Invasive Urothelial Bladder Cancer after Multimodality Approach. Which Is the Best Option? Medicina (B Aires) 2022; 59:medicina59010050. [PMID: 36676675 PMCID: PMC9865683 DOI: 10.3390/medicina59010050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/18/2022] [Accepted: 12/22/2022] [Indexed: 12/29/2022] Open
Abstract
Background and Objectives: There is no consensus regarding the optimal therapy sequence in stage II and III bladder cancer. The study aimed to evaluate the long-term oncologic outcomes in patients with bladder cancer after a multimodality approach. Materials and methods: Medical files of 231 consecutive patients identified with stage II (46.8%), IIIA (30.3%), and IIIB (22.9%) transitional cell carcinoma of the bladder (BC) treated with a multimodality approach were retrospectively reviewed. The treatment consisted of transurethral resections or cystectomy, radiotherapy alone or concurrent chemoradiotherapy as definitive treatment, or neoadjuvant chemotherapy using platinum salt regimens. Results: Median age at diagnosis was 65 ± 10.98 years. Radical or partial cystectomy was performed in 88 patients (37.1%), and trans-urethral resection of bladder tumor (TURBT) alone was performed in 143 (61.9%) patients. Overall, 40 patients (17.3%) received neoadjuvant chemotherapy and 82 (35.5%) received definitive chemoradiotherapy. After a median follow-up of 30.6 months (range 3-146 months), the median disease-free survival (DFS) for an entire lot of patients was 32 months, and the percentage of patients without recurrence at 12, 24, and 36 months was 86%, 58%, and 45%, respectively. Patients receiving neoadjuvant chemotherapy had a better oncologic outcome compared to patients without neoadjuvant chemotherapy (median DFS not reached vs. 31 months, p = 0.038, HR = 0.55, 95% CI 0.310-0.951). There was a trend for better 3-year DFS with radical cystectomy vs. TURBT (60 months vs. 31 months, p = 0.064). Definitive chemoradiotherapy 3-year DFS was 58% compared to 44% in patients who received radiotherapy or chemotherapy alone. Conclusions: In patients with stages II and III, both neoadjuvant chemotherapy and concurrent radio-chemotherapy are valid options for treatment and must be part of a multidisciplinary approach.
Collapse
|
|
21
|
Leibowitz MS, Zelley K, Adams D, Brodeur GM, Fox E, Li MM, Mattei P, Pogoriler J, MacFarland SP. Neuroblastoma and cutaneous angiosarcoma in a child with PTEN hamartoma tumor syndrome. Pediatr Blood Cancer 2022; 69:e29656. [PMID: 35278038 DOI: 10.1002/pbc.29656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 02/26/2022] [Indexed: 11/10/2022]
Affiliation(s)
- Michael S Leibowitz
- Division of Oncology, Department of Pediatrics, Children's Hospital of Phialdelphia, Philadelphia, Pennsylvania, USA
| | - Kristin Zelley
- Division of Oncology, Department of Pediatrics, Children's Hospital of Phialdelphia, Philadelphia, Pennsylvania, USA
| | - Denise Adams
- Division of Oncology, Department of Pediatrics, Children's Hospital of Phialdelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Garrett M Brodeur
- Division of Oncology, Department of Pediatrics, Children's Hospital of Phialdelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Elizabeth Fox
- Department of Oncology, St. Jude's Children's Research Hospital, Memphis, Tennessee, USA
| | - Marilyn M Li
- Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.,Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelpiha, Philadelphia, Pennsylvania, USA
| | - Peter Mattei
- Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.,Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Jennifer Pogoriler
- Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.,Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelpiha, Philadelphia, Pennsylvania, USA
| | - Suzanne P MacFarland
- Division of Oncology, Department of Pediatrics, Children's Hospital of Phialdelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| |
Collapse
|
|
22
|
Plitt G, Brewer T, Yehia L, Jin J, Shin J, Eng C. Development and Progression of Thyroid Disease in PTEN Hamartoma Tumor Syndrome: Refined Surveillance Recommendations. Thyroid 2022; 32:1094-1100. [PMID: 35761794 DOI: 10.1089/thy.2022.0181] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Background: PTEN hamartoma tumor syndrome (PHTS) is associated with a high prevalence and early onset of differentiated thyroid cancer and benign thyroid disease. However, a consensus on the time of initiation and frequency of thyroid cancer surveillance has not yet been reached. Most commonly, guidelines recommend annual thyroid ultrasounds, but vary widely in the time of initiation, ranging from shortly after birth to 18 years of age. Minimal data are available on the development and progression of thyroid disease over time in this population. This study aimed to target this knowledge gap by investigating the time to develop thyroid nodules and thyroid cancer from an initial ultrasound in 76 PHTS patients. Methods: The electronic records of 281 prospectively accrued PHTS patients were retrospectively reviewed between 2005 and 2021, and 76 patients were identified as having at least two thyroid ultrasounds. Time-to-event analyses were performed, determining the probability of developing thyroid nodules and thyroid cancer over time. Results: We demonstrated that PHTS patients with an initial thyroid ultrasound without nodules (n = 41) had >90% likelihood of remaining free of a clinically actionable nodule at 3 years and an 85% likelihood at 6 years. None of these patients developed thyroid cancer over the entire follow-up period (mean 4.6 years). In patients with a clinically nonactionable nodule, defined as not meeting criteria for fine needle aspiration or thyroidectomy (n = 14), we demonstrated that 80% will not have an actionable nodule at 3 years, and none developed thyroid cancer over the entire follow-up period. Conclusions: Our observations suggest stratifying surveillance intervals based on thyroid ultrasound result, and support extending surveillance intervals in PHTS patients without nodules on ultrasound to 3-5 years, and patients with clinically nonactionable nodules to 2-3 years, in contrast to the current recommendation of annual ultrasounds. This change in practice would decrease the burden of frequent ultrasounds, especially in young children and adolescents who are more likely to have a normal or nonactionable ultrasound result.
Collapse
Affiliation(s)
- Gilman Plitt
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of General Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Takae Brewer
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Lamis Yehia
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Judy Jin
- Department of Endocrine Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| | - Joyce Shin
- Department of Endocrine Surgery, Cleveland Clinic, Cleveland, Ohio, USA
| | - Charis Eng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
- Germline High Risk Cancer Focus Group, CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA
| |
Collapse
|
|
23
|
Detection and Yield of Colorectal Cancer Surveillance in Adults with PTEN Hamartoma Tumour Syndrome. Cancers (Basel) 2022; 14:cancers14164005. [PMID: 36010998 PMCID: PMC9406787 DOI: 10.3390/cancers14164005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/12/2022] [Accepted: 08/16/2022] [Indexed: 11/17/2022] Open
Abstract
Colorectal cancer surveillance (CCS) with colonoscopy every five years is advised for PTEN Hamartoma Tumour Syndrome (PHTS) patients aged ≥40 due to an increased colorectal cancer (CRC) risk. However, data to support CCS guidelines are scarce and available CRC risks are low (0-5% at age 50) and likely overestimated. We aimed to assess the detection and yield of CCS for PHTS patients without a CRC history. A retrospective cohort study including PHTS patients aged ≥40 with CCS at a PHTS expertise centre between 2011 and 2022. Adenomas with a ≥10 mm size, (tubulo)villous histology, or high-grade dysplasia were considered advanced. During 67 follow-up years, 37 patients (median age 47 years) underwent 61 colonoscopies. CCS yielded no CRCs. Adenomas were diagnosed in 13/37 (35%) patients during 23/100 colonoscopies (95% CI: 14-36), including one advanced adenoma. Baseline adenoma detection rates were similar to follow-up and higher in patients aged above 50 (50/100, 95% CI: 24-76) vs. age 50 or below (11/100, 95% CI: 3-30; p = 0.021). The low CRC and advanced adenoma yield allow for a more personalised surveillance program. Following our findings combined with literature on CRC risk and progression, we suggest starting CCS at age 40 with variable follow-up intervals between 1 and 10 years depending on previous colonoscopy findings.
Collapse
|
|
24
|
Brewer T, Yehia L, Bazeley P, Eng C. Exome sequencing reveals a distinct somatic genomic landscape in breast cancer from women with germline PTEN variants. Am J Hum Genet 2022; 109:1520-1533. [PMID: 35931053 PMCID: PMC9388380 DOI: 10.1016/j.ajhg.2022.07.005] [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: 03/25/2022] [Accepted: 07/01/2022] [Indexed: 02/06/2023] Open
Abstract
Germline PTEN variants (PTEN hamartoma tumor syndrome [PHTS]) confer up to 85% lifetime risk of female breast cancer (BC). BCs arising in PHTS are clinically distinct from sporadic BCs, including younger age of onset, multifocality, and an increased risk of second primary BCs. Yet, there is no previous investigation into the underlying genomic landscape of this entity. We sought to address the hypothesis that BCs arising in PHTS have a distinct genomic landscape compared to sporadic counterparts. We performed and analyzed exome sequencing data from 44 women with germline PTEN variants who developed BCs. The control cohort comprised of 497 women with sporadic BCs from The Cancer Genome Atlas (TCGA) dataset. We demonstrate that PHTS-derived BCs have a distinct somatic mutational landscape compared to the sporadic counterparts, namely second somatic hits in PTEN, distinct mutational signatures, and increased genomic instability. The PHTS group had a significantly higher frequency of somatic PTEN variants compared to TCGA (22.7% versus 5.6%; odds ratio [OR] 4.93; 95% confidence interval [CI] 2.21 to 10.98; p < 0.001) and a lower mutational frequency in PIK3CA (22.7% versus 33.4%; OR 0.59; 95% CI 0.28 to 1.22; p = 0.15). Somatic variants in PTEN and PIK3CA were mutually exclusive in PHTS (p = 0.01) but not in TCGA. Our findings have important implications for the personalized management of PTEN-related BCs, especially in the context of more accessible genetic testing.
Collapse
Affiliation(s)
- Takae Brewer
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
| | - Lamis Yehia
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Peter Bazeley
- Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Charis Eng
- Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA,Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA,Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA,Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA,Corresponding author
| |
Collapse
|
|
25
|
Donato UM, Donato SA, Otto K. A Case of Medullary Microcarcinoma in the Setting of Cowden’s Syndrome. Cureus 2022; 14:e26947. [PMID: 35989785 PMCID: PMC9380963 DOI: 10.7759/cureus.26947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2022] [Indexed: 11/24/2022] Open
Abstract
Cowden’s syndrome (CS) is a rare inherited condition characterized by hamartomas in various organs including the thyroid and mucocutaneous tissues as one of the most distinctive features. We present a rare case of Cowden’s syndrome with medullary microcarcinoma of the thyroid, in a 56 year old male with a history of hamartomatous colon polyps, papillomas of the tongue, skin tags, learning disability in the spectrum of autism and macrocephaly. This was evident on immunohistochemical examination of a nodule in the right thyroid lobe. Calcitonin and carcinoembryonic antigen (CEA) positivity along with C-cell hyperplasia were consistent with a medullary microcarcinoma. Total thyroidectomy was performed. Post-operatively margins were uninvolved by carcinoma. Perineural and lymphatic invasion was not identified. Considering the rarity of this condition and the unique presentation of our patient we believe that reporting this case would add more information to the existing fund of knowledge.
Collapse
|
|
26
|
Dawson H, Smrke A, Ellery PM, Wilkinson N, Rosenthal AN, McVeigh TP. Fibroadenoma in vulval ectopic breast tissue in a patient with PTEN Hamartoma Tumour Syndrome. Fam Cancer 2022; 21:363-368. [PMID: 34524588 DOI: 10.1007/s10689-021-00275-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 09/08/2021] [Indexed: 10/20/2022]
Abstract
PTEN is a tumour suppressor gene involved in regulating cell division. Pathogenic germline variants in PTEN predispose to benign and malignant growths of numerous organs, including of the breast. In the following report, we describe the first documented case of a fibroadenoma developing in ectopic breast tissue of the vulva in a patient with a germline pathogenic variant in PTEN. This highlights the risk of hyperplasia developing in any breast tissue, including rare ectopic sites, particularly in patients with underlying germline variants in cancer susceptibility genes.
Collapse
Affiliation(s)
- Hannah Dawson
- The Royal Marsden Hospital NHS Foundation Trust, 203 Fulham Road, London, SW3 6JJ, UK
| | - Alannah Smrke
- The Royal Marsden Hospital NHS Foundation Trust, 203 Fulham Road, London, SW3 6JJ, UK
| | - Peter M Ellery
- Department of Cellular Pathology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Nafisa Wilkinson
- Department of Cellular Pathology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Adam N Rosenthal
- Department of Women's Cancer, Institute for Women's Health, University College London, London, UK
| | - Terri P McVeigh
- The Royal Marsden Hospital NHS Foundation Trust, 203 Fulham Road, London, SW3 6JJ, UK.
| |
Collapse
|
|
27
|
Halaseh SA, Halaseh S, Alali Y, Ashour ME, Alharayzah MJ. A Review of the Etiology and Epidemiology of Bladder Cancer: All You Need To Know. Cureus 2022; 14:e27330. [PMID: 36042998 PMCID: PMC9411696 DOI: 10.7759/cureus.27330] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/27/2022] [Indexed: 11/05/2022] Open
Abstract
Bladder cancer is any tumor that originates in the urinary bladder. It is the most prevalent tumor of the urinary system, with urothelial carcinoma being the most prevalent histologic subtype. It impacts both men and women. The development of bladder cancer was influenced by several risk factors, including advanced age, male sex, cigarette smoking, and occupational and environmental toxin exposure. Bladder tumors may manifest as gross or microscopic hematuria, which is assessed using cystoscopy, urine analysis, and other specialized tests. Due to the large number of cases related to environmental causes, bladder cancer is an appropriate target for public health preventative interventions. Cessation of smoking, adequate occupational safety procedures, diet, weight loss, and schistosomiasis prevention may mitigate the rising global incidence.
Collapse
Affiliation(s)
- Sattam A Halaseh
- General and Colorectal Surgery, Torbay and South Devon NHS Foundation Trust, Torbay Hospital, Torquay, GBR
| | | | - Yaman Alali
- Oncology, University of Nebraska Medical Center, Omaha, USA
| | | | | |
Collapse
|
|
28
|
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.
Collapse
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
| |
Collapse
|
|
29
|
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.
Collapse
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
| |
Collapse
|
|
30
|
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.
Collapse
|
|
31
|
Teramae S, Muguruma N, Okamoto K, Oseto K, Nishikawa R, Tanoue T, Hirata K, Yanai S, Matsumoto T, Shimizu S, Miwa J, Sasaki Y, Yashima K, Ohnuma H, Sato Y, Kitayama Y, Ohda Y, Yamauchi A, Sanomura Y, Tanaka K, Kubo Y, Ishikawa H, Bando Y, Sonoda T, Takayama T. Cancer risk and genotype-phenotype correlation in Japanese patients with Cowden syndrome. Int J Clin Oncol 2022; 27:639-647. [PMID: 35106660 DOI: 10.1007/s10147-022-02116-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 12/26/2021] [Indexed: 01/25/2023]
Abstract
BACKGROUND Cowden syndrome (CS) is an autosomal-dominant hereditary disorder caused by a germline PTEN variant and characterized by multiple hamartomas and a high risk of cancers. However, no detailed data on CS in Asian patients nor genotype-phenotype correlation have been reported. METHODS We performed the first Japanese nationwide questionnaire survey on CS and obtained questionnaire response data on 49 CS patients. RESULTS Patients included 26 females (median age 48 years). The incidence of breast, thyroid, endometrium, and colorectal cancer was 32.7%, 12.2%, 19.2% (among females), and 6.1%, respectively. The incidence of any cancers was relatively high among all patients (46.9%, 23/49), and particularly female patients (73.1%, 19/26), compared with previous reports from Western countries. Gastrointestinal (GI) polyps were more frequently found throughout the GI tract compared with previous studies. PTEN variants were detected in 95.6% (22/23) of patients; 12 in the N-terminal region (11 in phosphatase domain) and 10 in the C-terminal (C2 domain) region. The incidence of cancer in the C2 domain group was significantly higher than in the N-terminal region (phosphatase) group. All female patients with C2 domain variant had breast cancer. CONCLUSION Our data suggest that Japanese patients with CS, particularly female patients and patients with C2 domain variant may have a high risk of cancers.
Collapse
Affiliation(s)
- Satoshi Teramae
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Kumiko Oseto
- Department of Obstetrics and Gynecology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Ryutaro Nishikawa
- Department of Obstetrics and Gynecology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Takayuki Tanoue
- Department of Surgery I, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Keiji Hirata
- Department of Surgery I, School of Medicine, University of Occupational and Environmental Health, Fukuoka, Japan
| | - Shunichi Yanai
- Division of Gastroenterology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Seiji Shimizu
- Department of Gastroenterology, Osaka General Hospital of West Japan Railway Company, Osaka, Japan
| | - Jun Miwa
- Department of Gastroenterology, Toshiba Hospital, Tokyo, Japan
| | - Yu Sasaki
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | - Kazuo Yashima
- Department of Gastroenterology, Tottori University Hospital, Tottori, Japan
| | - Hiroyuki Ohnuma
- Department of Medical Oncology, Sapporo Medical University, Hokkaido, Japan
| | - Yasushi Sato
- Department of Medical Oncology, Sapporo Medical University, Hokkaido, Japan
| | - Yoshitaka Kitayama
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Hyogo College of Medicine, Hyogo, Japan
| | - Yoshio Ohda
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Hyogo College of Medicine, Hyogo, Japan
| | - Atsushi Yamauchi
- Department of Gastroenterology and Hepatology, Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan
| | - Yoji Sanomura
- Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan
| | - Kumiko Tanaka
- The Post-Graduate Education Center, Tokushima University Hospital, Tokushima University, Tokushima, Japan
| | - Yoshiaki Kubo
- Department of Dermatology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hideki Ishikawa
- Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yoshimi Bando
- Division of Pathology, Tokushima University Graduate School, Tokushima, Japan
| | - Tomoko Sonoda
- Department of Public Health, Sapporo Medical University School of Medicine, Hokkaido, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan.
| |
Collapse
|
|
32
|
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.
Collapse
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.
| |
Collapse
|
|
33
|
Plamper M, Gohlke B, Woelfle J. PTEN hamartoma tumor syndrome in childhood and adolescence-a comprehensive review and presentation of the German pediatric guideline. Mol Cell Pediatr 2022; 9:3. [PMID: 35187600 PMCID: PMC8859017 DOI: 10.1186/s40348-022-00135-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 01/24/2022] [Indexed: 11/24/2022] Open
Abstract
Background The PTEN hamartoma tumor syndrome (PHTS) encompasses several different syndromes, which are linked to an autosomal-dominant mutation of the tumor suppressor PTEN gene on chromosome 10. Loss of PTEN activity leads to an increased phosphorylation of different cell proteins, which may have an influence on growth, migration, and apoptosis. Excessive activity of the PI3K/AKT/mTOR pathway due to PTEN deficiency may lead to the development of benign and malignant tumors and overgrowth. Diagnosis of PHTS in childhood can be even more challenging than in adulthood because of a lack of well-defined diagnostic criteria. So far, there are no official recommendations for cancer surveillance in affected children and adolescents. Main body All individuals with PHTS are at high risk for tumor development and thus might benefit from cancer surveillance strategies. In childhood, macrocephaly may be the only evident symptom, but developmental delay, behavioral problems, dermatological features (e.g., penile freckling), vascular anomalies, lipoma, or enlarged perivascular spaces in cerebral magnetic resonance imaging (cMRI) may help to establish the diagnosis. Regular psychomotor assessment and assistance in subjects with neurological impairment play an important role in the management of affected children. Already in early childhood, affected patients bear a high risk to develop thyroid pathologies. For that reason, monitoring of thyroid morphology and function should be established right after diagnosis. We present a detailed description of affected organ systems, tools for initiation of molecular diagnostic and screening recommendations for patients < 18 years of age. Conclusion Affected families frequently experience a long way until the correct diagnosis for their child’s peculiarity is made. Even after diagnosis, it is not easy to find a physician who is familiar with this rare group of diseases. Because of a still-limited database, it is not easy to establish evidence-based (cancer) surveillance recommendations. The presented screening recommendation should thus be revised regularly according to the current state of knowledge.
Collapse
Affiliation(s)
- Michaela Plamper
- Pediatric Endocrinology and Diabetology Division, Children's Hospital, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
| | - Bettina Gohlke
- Pediatric Endocrinology and Diabetology Division, Children's Hospital, University of Bonn, Venusberg-Campus 1, 53127, Bonn, Germany
| | - Joachim Woelfle
- Children's and Adolescents Hospital, University of Erlangen, Erlangen, Germany
| |
Collapse
|
|
34
|
Watanabe T, Soeda S, Endo Y, Okabe C, Sato T, Kamo N, Ueda M, Kojima M, Furukawa S, Nishigori H, Takahashi T, Fujimori K. Rare Hereditary Gynecological Cancer Syndromes. Int J Mol Sci 2022; 23:1563. [PMID: 35163487 PMCID: PMC8835983 DOI: 10.3390/ijms23031563] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/25/2022] [Accepted: 01/28/2022] [Indexed: 12/04/2022] Open
Abstract
Hereditary cancer syndromes, which are characterized by onset at an early age and an increased risk of developing certain tumors, are caused by germline pathogenic variants in tumor suppressor genes and are mostly inherited in an autosomal dominant manner. Therefore, hereditary cancer syndromes have been used as powerful models to identify and characterize susceptibility genes associated with cancer. Furthermore, clarification of the association between genotypes and phenotypes in one disease has provided insights into the etiology of other seemingly different diseases. Molecular genetic discoveries from the study of hereditary cancer syndrome have not only changed the methods of diagnosis and management, but have also shed light on the molecular regulatory pathways that are important in the development and treatment of sporadic tumors. The main cancer susceptibility syndromes that involve gynecologic cancers include hereditary breast and ovarian cancer syndrome as well as Lynch syndrome. However, in addition to these two hereditary cancer syndromes, there are several other hereditary syndromes associated with gynecologic cancers. In the present review, we provide an overview of the clinical features, and discuss the molecular genetics, of four rare hereditary gynecological cancer syndromes; Cowden syndrome, Peutz-Jeghers syndrome, DICER1 syndrome and rhabdoid tumor predisposition syndrome 2.
Collapse
Affiliation(s)
- Takafumi Watanabe
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima 960-1295, Japan; (S.S.); (Y.E.); (C.O.); (T.S.); (N.K.); (M.U.); (M.K.); (S.F.); (K.F.)
| | - Shu Soeda
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima 960-1295, Japan; (S.S.); (Y.E.); (C.O.); (T.S.); (N.K.); (M.U.); (M.K.); (S.F.); (K.F.)
| | - Yuta Endo
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima 960-1295, Japan; (S.S.); (Y.E.); (C.O.); (T.S.); (N.K.); (M.U.); (M.K.); (S.F.); (K.F.)
| | - Chikako Okabe
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima 960-1295, Japan; (S.S.); (Y.E.); (C.O.); (T.S.); (N.K.); (M.U.); (M.K.); (S.F.); (K.F.)
| | - Tetsu Sato
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima 960-1295, Japan; (S.S.); (Y.E.); (C.O.); (T.S.); (N.K.); (M.U.); (M.K.); (S.F.); (K.F.)
| | - Norihito Kamo
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima 960-1295, Japan; (S.S.); (Y.E.); (C.O.); (T.S.); (N.K.); (M.U.); (M.K.); (S.F.); (K.F.)
| | - Makiko Ueda
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima 960-1295, Japan; (S.S.); (Y.E.); (C.O.); (T.S.); (N.K.); (M.U.); (M.K.); (S.F.); (K.F.)
| | - Manabu Kojima
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima 960-1295, Japan; (S.S.); (Y.E.); (C.O.); (T.S.); (N.K.); (M.U.); (M.K.); (S.F.); (K.F.)
| | - Shigenori Furukawa
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima 960-1295, Japan; (S.S.); (Y.E.); (C.O.); (T.S.); (N.K.); (M.U.); (M.K.); (S.F.); (K.F.)
| | - Hidekazu Nishigori
- Fukushima Medical Center for Children and Women, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan; (H.N.); (T.T.)
| | - Toshifumi Takahashi
- Fukushima Medical Center for Children and Women, Fukushima Medical University, 1 Hikarigaoka, Fukushima 960-1295, Japan; (H.N.); (T.T.)
| | - Keiya Fujimori
- Department of Obstetrics and Gynecology, Fukushima Medical University, Fukushima 960-1295, Japan; (S.S.); (Y.E.); (C.O.); (T.S.); (N.K.); (M.U.); (M.K.); (S.F.); (K.F.)
| |
Collapse
|
|
35
|
Nees LK, Heublein S, Steinmacher S, Juhasz-Böss I, Brucker S, Tempfer CB, Wallwiener M. Endometrial hyperplasia as a risk factor of endometrial cancer. Arch Gynecol Obstet 2022; 306:407-421. [PMID: 35001185 PMCID: PMC9349105 DOI: 10.1007/s00404-021-06380-5] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 12/23/2021] [Indexed: 12/30/2022]
Abstract
Endometrial hyperplasia (EH) is the precursor lesion for endometrioid adenocarcinoma of the endometrium (EC), which represents the most common malignancy of the female reproductive tract in industrialized countries. The most important risk factor for the development of EH is chronic exposure to unopposed estrogen. Histopathologically, EH can be classified into EH without atypia (benign EH) and atypical EH/endometrial intraepithelial neoplasia (EIN). Clinical management ranges from surveillance or progestin therapy through to hysterectomy, depending on the risk of progression to or concomitant EC and the patient´s desire to preserve fertility. Multiple studies support the efficacy of progestins in treating both benign and atypical EH. This review summarizes the evidence base regarding risk factors and management of EH. Additionally, we performed a systematic literature search of the databases PubMed and Cochrane Controlled Trials register for studies analyzing the efficacy of progestin treatment in women with EH.
Collapse
Affiliation(s)
- Lisa K Nees
- Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany
| | - Sabine Heublein
- Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany
| | - Sahra Steinmacher
- Department of Obstetrics and Gynecology, Universität Tübingen, Tübingen, Germany
| | - Ingolf Juhasz-Böss
- Department of Obstetrics and Gynecology, Universität Freiburg, Freiburg, Germany
| | - Sara Brucker
- Department of Obstetrics and Gynecology, Universität Tübingen, Tübingen, Germany
| | - Clemens B Tempfer
- Comprehensive Cancer Center, Ruhr University Bochum (RUCCC), Bochum, Germany
| | - Markus Wallwiener
- Department of Obstetrics and Gynecology, University of Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany.
| |
Collapse
|
|
36
|
Mitra S, Paramaguru R, Das P, Katti SV. Preneoplastic Lesions and Polyps of the Gastrointestinal Tract. SURGICAL PATHOLOGY OF THE GASTROINTESTINAL SYSTEM 2022:593-698. [DOI: 10.1007/978-981-16-6395-6_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
37
|
Albrecht S, Miedzybrodzki B, Palma L, Nguyen VH, Dudley RW, Pietsch T, Goschzik T, Jabado N, Goudie C, Foulkes WD. Medulloblastoma and Cowden syndrome: Further evidence of an association. FREE NEUROPATHOLOGY 2022; 3:1. [PMID: 37284158 PMCID: PMC10209873 DOI: 10.17879/freeneuropathology-2022-3684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 01/02/2022] [Indexed: 06/08/2023]
Abstract
Cowden syndrome (CS) is an autosomal dominant hamartoma and tumor predisposition syndrome caused by heterozygous pathogenic germline variants in PTEN in most affected individuals. Major features include macrocrania, multiple facial tricholemmomas, acral and oral keratoses and papillomas, as well as mammary, non-medullary thyroid, renal, and endometrial carcinomas. Lhermitte-Duclos disease (LDD), or dysplastic gangliocytoma of the cerebellum, is the typical brain tumor associated with CS; the lifetime risk for LDD in CS patients has been estimated to be as high as 30%. In contrast, medulloblastoma is much rarer in CS, with only 4 reported cases in the literature. We report a 5th such patient. All 5 patients were diagnosed between 1 and 2 years of age and not all showed the pathognomonic clinical stigmata of CS at the time of their medulloblastoma diagnosis. Where detailed information was available, the medulloblastoma was of the SHH-subtype, in keeping with the observation that in sporadic medulloblastomas, PTEN-alterations are usually encountered in the SHH-subtype. Medulloblastomas can be associated with several tumor-predisposition syndromes and of the 4 medulloblastoma subtypes, SHH-medulloblastomas in children have the highest prevalence of predisposing germline variants (approx. 40%). CS should be added to the list of SHH-medulloblastoma-associated syndromes. Germline analysis of PTEN should be performed in infants with SHH-medulloblastomas, regardless of their clinical phenotype, especially if they do not carry pathogenic germline variants in PTEN or PTEN, the most commonly altered predisposing genes in this age-group. In addition, these cases show that CS has a biphasic brain tumor distribution, both in regards to the age of onset and the tumor type: a small number of CS patients develop a medulloblastoma in infancy while many more develop LDD in adulthood.
Collapse
Affiliation(s)
| | - Barbara Miedzybrodzki
- Division of Dermatology, Department of Pediatrics, McGill University Health Centre, Montreal Children's Hospital, Montreal, QCCanada
| | - Laura Palma
- Department of Human Genetics, McGill University, Montreal, QCCanada
- Division of Medical Genetics, Department of Specialized Medicine, McGill University Health Centre, Montreal, QCCanada
| | - Van Hung Nguyen
- Department of Pathology, McGill University, Montreal, QCCanada
| | - Roy W.R. Dudley
- Division of Neurosurgery, Department of Pediatric Surgery, Montreal Children's Hospital, McGill University Health Centre, Montreal, QCCanada
| | - Torsten Pietsch
- Department of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, BonnGermany
| | - Tobias Goschzik
- Department of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, BonnGermany
| | - Nada Jabado
- Department of Human Genetics, McGill University, Montreal, QCCanada
- Department of Pediatrics, McGill University, Montreal, QCCanada
- The Research Institute of the McGill University Health Centre, Child Health and Human Development Program, Montreal, QCCanada
| | - Catherine Goudie
- The Research Institute of the McGill University Health Centre, Child Health and Human Development Program, Montreal, QCCanada
- Division of Hematology-Oncology, Montreal Children's Hospital, Department of Pediatrics, McGill University, Montreal, QCCanada
| | - William D. Foulkes
- Department of Human Genetics, McGill University, Montreal, QCCanada
- Cancer Axis, Lady Davis Institute, The Jewish General Hospital, Montreal, QCCanada
- Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QCCanada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QCCanada
| |
Collapse
|
|
38
|
Abstract
Purpose of review Gastric cancer is a leading cause of cancer death in the world. Between 1% and 3% of cases are associated with specific genetic cancer risk syndromes. The purpose of this article is to review the latest insights, as well as gaps in knowledge, regarding some of the most common hereditary gastric cancer syndromes: hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), Lynch syndrome, the adenomatous polyposis syndromes, and the hamartomatous polyposis syndromes. Recent findings Patients carrying pathogenic variants in CDH1, but not meeting clinical criteria for HDGC, are increasingly being identified thanks to multigene panel testing; their absence from previous analyses overestimated gastric cancer penetrance. GAPPS is a recently described hereditary gastric cancer syndrome associated with specific point mutations in the promoter 1B region of the APC gene. Summary Risk of gastric cancer is highest among carriers of pathogenic variants in CDH1, with cumulative incidences approximately 40% and 30% for men and women, respectively. Mutations associated with Lynch syndrome and adenomatous polyposis syndromes confer greatest risk for gastric cancer in East Asian populations. Risk of gastric cancer in GAPPS and hamartomatous polyposis syndromes is difficult to estimate due to their rarity, but mutation status likely determines risk. Future research is needed to more precisely define risk of gastric cancer in these syndromes, so strategies for screening and prophylactic gastrectomy can be optimized.
Collapse
|
|
39
|
Smith JR, Liu E, Church AJ, Asch E, Cherella CE, Srivastava S, Kamihara J, Wassner AJ. Natural History of Thyroid Disease in Children with PTEN Hamartoma Tumor Syndrome. J Clin Endocrinol Metab 2021; 106:e1121-e1130. [PMID: 33347563 DOI: 10.1210/clinem/dgaa944] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Indexed: 01/12/2023]
Abstract
CONTEXT Thyroid ultrasound screening is recommended in children with PTEN hamartoma tumor syndrome (PHTS) due to increased risk of thyroid neoplasia, but the natural history of thyroid disease in children with PHTS is unclear. OBJECTIVE Determine the prevalence and natural history of thyroid disease in children with PHTS. METHODS Retrospective cohort study (1998-2019) in an academic pediatric hospital of individuals with genetically confirmed PHTS diagnosed before age 19 years. Clinical, thyroid ultrasound, and laboratory characteristics are described. Primary outcomes were the prevalence of thyroid nodules ≥10 mm diameter and time course and risk factors for nodule development assessed by Cox regression analysis. Secondary outcomes included thyroid nodule requiring biopsy, other ultrasound findings, and prevalence of autoimmune thyroid disease. RESULTS Among 64 subjects with PHTS, 50 underwent thyroid ultrasound. A thyroid nodule ≥10 mm was diagnosed in 22/50 (44%) subjects at median (range) age 13.3 (7.0-22.9) years. Nodules were diagnosed earlier in females than in males (10.8 [7.0-17.9] vs 14.2 [9.9-22.9] years, P = .009). In multivariate analysis, risk of thyroid nodules was significantly associated with female sex (hazard ratio 2.90, 95% CI 1.16-7.27, P = .02) and inversely associated with the presence of neurologic findings of PHTS (HR 0.27, 95% CI 0.10-0.69, P = .007). Abnormal-appearing lymph nodes with echogenic foci were observed by ultrasound in 20% of subjects, but these were not associated with malignancy. Autoimmune thyroid disease was present in 10/33 (30.3%) of subjects in whom it was assessed. CONCLUSION Thyroid disease is common in children with PHTS. This study supports current consensus recommendations for ultrasound screening.
Collapse
Affiliation(s)
| | - Enju Liu
- Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA
| | - Alanna J Church
- Department of Pathology, Boston Children's Hospital, Boston, MA, USA
| | - Elizabeth Asch
- Department of Radiology, Brigham and Women's Hospital, Boston, MA, USA
| | | | | | - Junne Kamihara
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Ari J Wassner
- Thyroid Center, Boston Children's Hospital, Boston, MA, USA
| |
Collapse
|
|
40
|
Cameselle-Teijeiro JM, Mete O, Asa SL, LiVolsi V. Inherited Follicular Epithelial-Derived Thyroid Carcinomas: From Molecular Biology to Histological Correlates. Endocr Pathol 2021; 32:77-101. [PMID: 33495912 PMCID: PMC7960606 DOI: 10.1007/s12022-020-09661-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/21/2020] [Indexed: 12/12/2022]
Abstract
Cancer derived from thyroid follicular epithelial cells is common; it represents the most common endocrine malignancy. The molecular features of sporadic tumors have been clarified in the past decade. However the incidence of familial disease has not been emphasized and is often overlooked in routine practice. A careful clinical documentation of family history or familial syndromes that can be associated with thyroid disease can help identify germline susceptibility-driven thyroid neoplasia. In this review, we summarize a large body of information about both syndromic and non-syndromic familial thyroid carcinomas. A significant number of patients with inherited non-medullary thyroid carcinomas manifest disease that appears to be sporadic disease even in some syndromic cases. The cytomorphology of the tumor(s), molecular immunohistochemistry, the findings in the non-tumorous thyroid parenchyma and other associated lesions may provide insight into the underlying syndromic disorder. However, the increasing evidence of familial predisposition to non-syndromic thyroid cancers is raising questions about the importance of genetics and epigenetics. What appears to be "sporadic" is becoming less often truly so and more often an opportunity to identify and understand novel genetic variants that underlie tumorigenesis. Pathologists must be aware of the unusual morphologic features that should prompt germline screening. Therefore, recognition of harbingers of specific germline susceptibility syndromes can assist in providing information to facilitate early detection to prevent aggressive disease.
Collapse
Affiliation(s)
- José Manuel Cameselle-Teijeiro
- Department of Pathology, Galician Healthcare Service (SERGAS), Clinical University Hospital, Travesía Choupana s/n, 15706, Santiago de Compostela, Spain.
- Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain.
- Medical Faculty, University of Santiago de Compostela, Santiago de Compostela, Spain.
| | - Ozgur Mete
- Department of Pathology and Endocrine Oncology Site, University Health Network, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Sylvia L Asa
- Department of Pathology, University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Virginia LiVolsi
- Department of Pathology and Laboratory Medicine, Perelmann School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA
| |
Collapse
|
|
41
|
Tabori U, Das A, Hawkins C. Germline predisposition to glial neoplasms in children and young adults: A narrative review. GLIOMA 2021. [DOI: 10.4103/glioma.glioma_12_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
|
|
42
|
Ramkumar RR, Murthy PB, Nguyen JK, McKenney J, Eng C, Campbell SC. PTEN Hamartoma Tumor Syndrome: A Case of Renal Cell Carcinoma in a Young Female. Urology 2020; 148:113-117. [PMID: 33227300 DOI: 10.1016/j.urology.2020.11.024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 11/08/2020] [Accepted: 11/11/2020] [Indexed: 01/29/2023]
Abstract
PTEN Hamartoma-Tumor-Syndrome (PHTS) describes a series of conditions characterized by germline-mutation of the PTEN tumor-suppressor gene. PHTS patients have an increased lifetime risk of multiple malignancies, including thyroid, breast, and endometrial cancers. PHTS patients also have 20-30 fold increased risk of renal cell carcinoma (RCC) compared to age-matched controls. As with many hereditary RCC syndromes, tumors present early and multifocally. We present a case of one of the youngest patients diagnosed with RCC in PHTS and review the urologic implications of this syndrome.
Collapse
Affiliation(s)
- Rathika R Ramkumar
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH
| | - Prithvi B Murthy
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH
| | - Jane K Nguyen
- Department of Anatomic Pathology, Robert J. Tomsich Pathology and Laboratory and Medicine Institute, Cleveland Clinic, Cleveland, OH
| | - Jesse McKenney
- Department of Anatomic Pathology, Robert J. Tomsich Pathology and Laboratory and Medicine Institute, Cleveland Clinic, Cleveland, OH
| | - Charis Eng
- Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH; Center for Personalized Genetic Healthcare, Cleveland Clinic Community Care and Population Health, Cleveland, OH
| | - Steven C Campbell
- Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH.
| |
Collapse
|
|
43
|
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.
Collapse
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
| |
Collapse
|
|
44
|
Dhooge M, Baert-Desurmont S, Corsini C, Caron O, Andrieu N, Berthet P, Bonadona V, Cohen-Haguenauer O, De Pauw A, Delnatte C, Dussart S, Lasset C, Leroux D, Maugard C, Moretta-Serra J, Popovici C, Buecher B, Colas C, Noguès C. National recommendations of the French Genetics and Cancer Group - Unicancer on the modalities of multi-genes panel analyses in hereditary predispositions to tumors of the digestive tract. Eur J Med Genet 2020; 63:104080. [PMID: 33039684 DOI: 10.1016/j.ejmg.2020.104080] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 09/29/2020] [Accepted: 09/29/2020] [Indexed: 12/13/2022]
Abstract
In case of suspected hereditary predisposition to digestive cancers, next-generation sequencing can analyze simultaneously several genes associated with an increased risk of developing these tumors. Thus, "Gastro Intestinal" (GI) gene panels are commonly used in French molecular genetic laboratories. Lack of international recommendations led to disparities in the composition of these panels and in the management of patients. To harmonize practices, the Genetics and Cancer Group (GGC)-Unicancer set up a working group who carried out a review of the literature for 31 genes of interest in this context and established a list of genes for which the estimated risks associated with pathogenic variant seemed sufficiently reliable and high for clinical use. Pancreatic cancer susceptibility genes have been excluded. This expertise defined a panel of 14 genes of confirmed clinical interest and relevant for genetic counseling: APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, POLD1, POLE, PTEN, SMAD4 and STK11. The reasons for the exclusion of the others 23 genes have been discussed. The paucity of estimates of the associated tumor risks led to the exclusion of genes, in particular CTNNA1, MSH3 and NTHL1, despite their implication in the molecular pathways involved in the pathophysiology of GI cancers. A regular update of the literature is planned to up-grade this panel of genes in case of new data on candidate genes. Genetic and epidemiological studies and international collaborations are needed to better estimate the risks associated with the pathogenic variants of these genes either selected or not in the current panel.
Collapse
Affiliation(s)
- Marion Dhooge
- APHP.Centre (Cochin Hospital), Paris University, Paris, France.
| | - Stéphanie Baert-Desurmont
- Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics, Normandy Center for Genomic and Personalized Medicine, Rouen, France
| | - Carole Corsini
- Arnaud de Villeneuve University Hospital, Montpellier, France
| | - Olivier Caron
- Gustave-Roussy University Hospital, Villejuif, France
| | - Nadine Andrieu
- Institut Curie, PSL Research University, Department of Tumor Biology, Paris, France; Unité Inserm, Institut Curie, Paris, France
| | | | | | | | - Antoine De Pauw
- Institut Curie, PSL Research University, Department of Tumor Biology, Paris, France
| | | | | | | | - Dominique Leroux
- Grenoble University Hospital, Couple-Enfant Hospital, Grenoble, France
| | | | - Jessica Moretta-Serra
- Institut Paoli-Calmettes, Department of Clinical Cancer Genetics, Aix Marseille Univ, INSERM, IRD, SESSTIM, Marseille, France
| | - Cornel Popovici
- Institut Paoli-Calmettes, Department of Clinical Cancer Genetics, Aix Marseille Univ, INSERM, IRD, SESSTIM, Marseille, France
| | - Bruno Buecher
- Institut Curie, PSL Research University, Department of Tumor Biology, Paris, France
| | - Chrystelle Colas
- Institut Curie, PSL Research University, Department of Tumor Biology, Paris, France
| | - Catherine Noguès
- Institut Paoli-Calmettes, Department of Clinical Cancer Genetics, Aix Marseille Univ, INSERM, IRD, SESSTIM, Marseille, France
| | | |
Collapse
|
|
45
|
Kim RH, Wang X, Evans AJ, Campbell SC, Nguyen JK, Farncombe KM, Eng C. Early-onset renal cell carcinoma in PTEN harmatoma tumour syndrome. NPJ Genom Med 2020; 5:40. [PMID: 33083010 PMCID: PMC7525494 DOI: 10.1038/s41525-020-00148-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 08/14/2020] [Indexed: 02/05/2023] Open
Abstract
Individuals with PTEN hamartoma tumour syndrome (PHTS), including Cowden syndrome (CS), are susceptible to multiple benign hamartomas and an increased risk of cancer, particularly breast, endometrial, and thyroid. As a result, individuals undergo enhanced surveillance for early detection of these cancers. However, less commonly occurring cancers, such as colorectal and kidney, have insufficient guidelines for early detection. Currently, screening for kidney cancer via renal ultrasound begins at 40 years of age, because there were only rare cases of elevated risk in prospective series under 40. There have, however, been accumulating reports of kidney cancer in individuals with CS in their 30s, illustrating a need to lower the age of surveillance. We present additional evidence of renal cell carcinoma in two individuals with CS in their early twenties, and propose a reassessment of the abdominal surveillance in patients with PHTS. We propose biannual screening for kidney cancer beginning at 20 years of age.
Collapse
Affiliation(s)
- Raymond H Kim
- Fred A. Litwin Family Centre in Genetic Medicine, Familial Cancer Clinic, Princess Margaret Cancer Centre, University Health Network, Department of Medicine, University of Toronto, Toronto, ON Canada
| | - Xiangling Wang
- Center for Personalized Genetic Healthcare, Cleveland Clinic Community Care and Population Health, Cleveland, OH USA.,Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH USA.,Department of Nephrology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, OH USA
| | - Andrew J Evans
- Laboratory Medicine Program, Department of Pathology, University Health Network, Toronto, ON Canada
| | - Steven C Campbell
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, USA.,Department of Surgery, Cleveland Clinic Lerner College of Medicine, Cleveland, OH USA
| | - Jane K Nguyen
- Department of Anatomic Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH USA
| | - Kirsten M Farncombe
- Toronto General Hospital/Research Institute, University Health Network, Toronto, ON Canada
| | - Charis Eng
- Center for Personalized Genetic Healthcare, Cleveland Clinic Community Care and Population Health, Cleveland, OH USA.,Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland, OH USA.,Department of Genetics and Genome Sciences, and Germline High Risk Cancer Focus Group, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH USA
| |
Collapse
|
|
46
|
Jonker L, Lebbink C, Jongmans M, Nievelstein R, Merks J, Nieveen van Dijkum E, Links T, Hoogerbrugge N, van Trotsenburg A, van Santen H. Recommendations on Surveillance for Differentiated Thyroid Carcinoma in Children with PTEN Hamartoma Tumor Syndrome. Eur Thyroid J 2020; 9:234-242. [PMID: 33088791 PMCID: PMC7548843 DOI: 10.1159/000508872] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 05/12/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND PTEN hamartoma tumor syndrome (PHTS) represents a group of syndromes caused by a mutation in the PTEN gene. Children with a germline PTEN mutation have an increased risk of developing differentiated thyroid carcinoma (DTC). Several guidelines have focused on thyroid surveillance in these children, but studies substantiating these recommendations are lacking. OBJECTIVE The present study intends to provide the available evidence for a thyroid carcinoma surveillance program in children with PHTS. METHODS An extensive literature search was performed to identify all studies on DTC in pediatric PHTS patients. Two pediatric cases are presented to illustrate the pros and cons of thyroid carcinoma surveillance. Recommendations for other patient groups at risk for DTC were evaluated. Consensus within the study team on recommendations for children with PHTS was reached by balancing the incidence and behavior of DTC with the pros and cons of thyroid surveillance, and the different surveillance methods. RESULTS In 5 cohort studies the incidence of DTC in childhood ranged from 4 to 12%. In total 57 cases of DTC and/or benign nodular disease in pediatric PHTS patients were identified, of which 27 had proven DTC, with a median age of 12 years (range 4-17). Follicular thyroid carcinoma (FTC) was diagnosed in 52% of the pediatric DTC patients. No evidence was found for a different clinical behavior of DTC in PHTS patients compared to sporadic DTC. CONCLUSIONS Children with PHTS are at increased risk for developing DTC, with 4 years being the youngest age reported at presentation and FTC being overrepresented. DTC in pediatric PHTS patients does not seem to be more aggressive than sporadic DTC. RECOMMENDATIONS Surveillance for DTC in pediatric PHTS patients seems justified, as early diagnosis may decrease morbidity. Consensus within the study team was reached to recommend surveillance from the age of 10 years onwards, since at that age the incidence of DTC seems to reach 5%. Surveillance for DTC should consist of yearly neck palpation and triennial thyroid ultrasound. Surveillance in children with PHTS should be performed in a center of excellence for pediatric thyroid disease or PHTS.
Collapse
Affiliation(s)
- L.A. Jonker
- Department of Pediatric Endocrinology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
| | - C.A. Lebbink
- Department of Pediatric Endocrinology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - M.C.J. Jongmans
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
| | - R.A.J. Nievelstein
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Department of Pediatric Radiology and Nuclear Medicine, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
| | - J.H.M. Merks
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | - E.J.M. Nieveen van Dijkum
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - T.P. Links
- Department of Endocrinology, University Medical Center Groningen, Groningen, The Netherlands
| | - N. Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - A.S.P. van Trotsenburg
- Department of Pediatric Endocrinology, Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - H.M. van Santen
- Department of Pediatric Endocrinology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
- Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- *H.M. van Santen, Department of Pediatric Endocrinology, Wilhelmina Children's Hospital, University Medical Center Utrecht, PO Box 85090, NL–3508 AB Utrecht (The Netherlands),
| |
Collapse
|
|
47
|
N o 371 - Le morcellement durant la chirurgie gynécologique: Son utilisation, ses complications et les risques liés à la présence de tumeurs malignes insoupçonnées. JOURNAL OF OBSTETRICS AND GYNAECOLOGY CANADA 2020; 41:127-138. [PMID: 30580825 DOI: 10.1016/j.jogc.2018.11.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIF La présente directive clinique conseille les gynécologues quant au recours au morcellement tissulaire pendant une chirurgie gynécologique. RéSULTATS: Le morcellement effectué au cours d'une chirurgie gynécologique peut permettre l'ablation de masses utérines volumineuses, offrant ainsi aux femmes une solution chirurgicale à effraction minimale. Les conséquences oncologiques indésirables du morcellement tissulaire devraient être atténuées par l'amélioration de la sélection des patientes, la tenue d'examens préopératoires et l'adoption de techniques novatrices réduisant au minimum la dispersion tissulaire. ÉVIDENCE: La littérature publiée a été récupérée au moyen de recherches menées dans PubMed et Medline au printemps 2014 à l'aide d'une terminologie contrôlée (« leiomyosarcoma », « uterine neoplasm », « uterine myomectomy », « hysterectomy ») et de mots-clés (« leiomyoma », « endometrial cancer », « uterine sarcoma », « leiomyosarcoma », « morcellation »). Les résultats retenus provenaient de revues systématiques, d'essais cliniques randomisés, d'essais cliniques contrôlés et d'études observationnelles de langue anglaise ou française. Aucune restriction de date n'a été imposée. Les recherches ont été refaites régulièrement, et les résultats ont été incorporés à la directive clinique jusqu'en juillet 2017. Nous avons également tenu compte de la littérature grise (non publiée) trouvée sur les sites Web d'organismes d'évaluation des technologies de la santé et d'autres organismes liés aux technologies de la santé, dans des collections de directives cliniques et dans des registres d'essais cliniques, et obtenue auprès d'associations nationales et internationales de médecins spécialistes. VALEURS La qualité des données probantes a été évaluée en fonction des critères décrits dans le rapport du Groupe d'étude canadien sur les soins de santé préventifs. AVANTAGES, INCONVéNIENTS ET COûTS: Les gynécologues offrent aux femmes une chirurgie à effraction minimale pouvant comprendre le recours à un morcellateur électromécanique pour faciliter le retrait des tissus. Les femmes devraient être informées que l'utilisation d'un morcellateur en présence de tumeurs utérines (sarcomes, tumeurs endométriales), cervicales ou tubo-ovariennes jusque-là insoupçonnées est associée à un risque accru de dissémination. Le morcellement tissulaire devrait être précédé d'une évaluation complète, d'une sélection appropriée des patientes et de l'obtention du consentement éclairé de ces dernières, et devrait être effectué par des chirurgiens ayant une formation adéquate en matière de pratiques de morcellement tissulaire sûres. DéCLARATIONS SOMMAIRES: RECOMMANDATIONS.
Collapse
|
|
48
|
Murji A, Scott S, Singh SS, Bougie O, Leyland N, Laberge PY, Vilos GA. No. 371-Morcellation During Gynaecologic Surgery: Its Uses, Complications, and Risks of Unsuspected Malignancy. JOURNAL OF OBSTETRICS AND GYNAECOLOGY CANADA 2020; 41:116-126. [PMID: 30580824 DOI: 10.1016/j.jogc.2018.07.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE This guideline provides guidance to gynaecologists regarding the use of tissue morcellation in gynaecologic surgery. OUTCOMES Morcellation may be used in gynaecologic surgery to allow removal of large uterine specimens, thus providing women with a minimally invasive surgical option. Adverse oncologic outcomes of tissue morcellation should be mitigated through improved patient selection, preoperative investigations, and novel techniques that minimize tissue dispersion. EVIDENCE Published literature was retrieved through searches of PubMed and Medline in the spring of 2014 using appropriate controlled vocabulary (leiomyosarcoma, uterine neoplasm, uterine myomectomy, hysterectomy) and key words (leiomyoma, endometrial cancer, uterine sarcoma, leiomyosarcoma, and morcellation). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date limits, but results were limited to English or French language materials. Searches were updated on a regular basis and incorporated in the guideline to July 2017. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES The quality of evidence in this document was rated using the criteria described in the report of the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS Gynaecologists offer women minimally invasive surgery, and this may involve tissue morcellation and the use of a power morcellator for specimen retrieval. Women should be counselled that in the case of unexpected uterine (sarcoma, endometrial), cervical, and/or tubo-ovarian cancer, the use of a morcellator is associated with increased risk of tumour dissemination. Tissue morcellation should be performed only after complete investigation, appropriate patient selection, and informed consent and by surgeons with appropriate training in the safe practices of tissue morcellation. SUMMARY STATEMENTS RECOMMENDATIONS.
Collapse
|
|
49
|
Tischkowitz M, Colas C, Pouwels S, Hoogerbrugge N. Cancer Surveillance Guideline for individuals with PTEN hamartoma tumour syndrome. Eur J Hum Genet 2020; 28:1387-1393. [PMID: 32533092 PMCID: PMC7608293 DOI: 10.1038/s41431-020-0651-7] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 04/16/2020] [Accepted: 04/28/2020] [Indexed: 01/22/2023] Open
Abstract
PTEN hamartoma tumour syndrome is a diverse multi-system disorder predisposing to the development of hamartomatous growths, increasing risk of breast, thyroid, renal cancer, and possibly increasing risk of endometrial cancer, colorectal cancer and melanoma. There is no international consensus on cancer surveillance in PHTS and all current guidelines are based on expert opinion. A comprehensive literature review was undertaken and guidelines were developed by clinicians with expertise from clinical genetics, gynaecology, endocrinology, dermatology, radiology, gastroenterology and general surgery, together with affected individuals and their representatives. Recommendations were put forward for surveillance for breast, thyroid and renal cancers. Limited recommendations were developed for other sites including endometrial, colon and skin. The proposed cancer surveillance recommendations for PHTS require a coordinated multidisciplinary approach and significant patient commitment. The evidence base for cancer surveillance in this guideline are limited, emphasising the need for prospective evaluation of the effectiveness of surveillance in the PHTS population.
Collapse
Affiliation(s)
- Marc Tischkowitz
- Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK.
| | - Chrystelle Colas
- Department of Genetics, Institut Curie, Paris Sciences et Lettres Research University, Paris, France
| | - Sjaak Pouwels
- Haaglanden Medical Center, The Hague, The Netherlands
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | | |
Collapse
|
|
50
|
Saginala K, Barsouk A, Aluru JS, Rawla P, Padala SA, Barsouk A. Epidemiology of Bladder Cancer. Med Sci (Basel) 2020; 8:E15. [PMID: 32183076 PMCID: PMC7151633 DOI: 10.3390/medsci8010015] [Citation(s) in RCA: 365] [Impact Index Per Article: 73.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 03/07/2020] [Accepted: 03/10/2020] [Indexed: 12/17/2022] Open
Abstract
Based on the latest GLOBOCAN data, bladder cancer accounts for 3% of global cancer diagnoses and is especially prevalent in the developed world. In the United States, bladder cancer is the sixth most incident neoplasm. A total of 90% of bladder cancer diagnoses are made in those 55 years of age and older, and the disease is four times more common in men than women. While the average 5-year survival in the US is 77%, the 5-year survival for those with metastatic disease is a measly 5%. The strongest risk factor for bladder cancer is tobacco smoking, which accounts for 50-65% of all cases. Occupational or environmental toxins likewise greatly contribute to disease burden (accounting for an estimated 20% of all cases), though the precise proportion can be obscured by the fact bladder cancer develops decades after exposure, even if the exposure only lasted several years. Schistosomiasis infection is the common cause of bladder cancer in regions of Africa and the Middle East and is considered the second most onerous tropical pathogen after malaria. With 81% of cases attributable to known risk factors (and only 7% to heritable mutations), bladder cancer is a prime candidate for prevention strategies. Smoking cessation, workplace safety practices, weight loss, exercise and schistosomiasis prevention (via water disinfection and mass drug administration) have all been shown to significantly decrease the risk of bladder cancer, which poses a growing burden around the world.
Collapse
Affiliation(s)
- Kalyan Saginala
- Plains Regional Medical Group Internal Medicine, Clovis, NM 88101, USA
| | - Adam Barsouk
- Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA
| | - John Sukumar Aluru
- Senior Research Associate, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02212, USA
| | - Prashanth Rawla
- Department of Medicine, Sovah Health, Martinsville, VA 24112, USA
| | - Sandeep Anand Padala
- Department of Medicine, Nephrology, Augusta University, Medical College of Georgia, Augusta, GA 30912, USA
| | - Alexander Barsouk
- Hematologist-Oncologist, Allegheny Health Network, Pittsburgh, PA 15212, USA
| |
Collapse
|