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Ren MJ, Zhang ZL, Tian C, Liu GQ, Zhang CS, Yu HB, Xin Q. Importance of early detection in multiple endocrine neoplasia type 1: Clinical insights and future directions. World J Gastrointest Oncol 2025; 17:100013. [DOI: 10.4251/wjgo.v17.i4.100013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 01/11/2025] [Accepted: 02/18/2025] [Indexed: 03/25/2025] Open
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal-inherited syndrome involving multiple endocrine tumors. It is characterized by multiple mutations in the tumor suppressor gene MEN1, which is located on chromosome 11q13. As main etiology of MEN1 is genetic mutations, clinical symptoms may vary. In this editorial, we comment on the article by Yuan et al. This article describes a case of (MEN1) characterized by low incidence and diagnostic complexity. MEN1 commonly presents as parathyroid, pancreatic, and pituitary tumors. Diagnosis requires a combination of serologic tests, magnetic resonance imaging, computed tomography, endoscopic ultrasonography, immunologic and pathology. The diagnosis is unique depending on the site of disease. Surgical resection is the treatment of choice for MEN1. The prognosis depends on the site of origin, but early detection and intervention is the most effective.
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Affiliation(s)
- Mei-Jing Ren
- Department of Pathology, Tianjin Third Center Hospital, Tianjin 300170, China
| | - Zi-Li Zhang
- Department of Gastrointestinal Surgery, Tianjin Third Center Hospital, Tianjin 300170, China
| | - Can Tian
- Department of Pathology, Tianjin Third Center Hospital, Tianjin 300170, China
| | - Gui-Qiu Liu
- Department of Pathology, Tianjin Third Center Hospital, Tianjin 300170, China
| | - Chuan-Shan Zhang
- Department of Pathology, Tianjin Third Center Hospital, Tianjin 300170, China
| | - Hai-Bo Yu
- Department of Laboratory, The Second Hospital of Tianjin Medical University, Tianjin 300211, China
| | - Qi Xin
- Department of Pathology, Tianjin Third Center Hospital, Tianjin 300170, China
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Hawazie A, Druce M. Breast Cancer Risk and Management in the Endocrine Clinic: A Comprehensive Review. Clin Endocrinol (Oxf) 2025. [PMID: 39905814 DOI: 10.1111/cen.15209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 12/30/2024] [Accepted: 01/19/2025] [Indexed: 02/06/2025]
Abstract
OBJECTIVE This review seeks to provide endocrine clinicians with a comprehensive analysis of breast cancer risk, diagnostic modalities and management strategies in women with endocrine disorders, with particular emphasis on the influence of metabolic factors such as diabetes and obesity, and the role of Menopausal Hormone Therapy (MHT). DESIGN The review examines a spectrum of endocrine disorders commonly encountered in clinical practice, including Multiple Endocrine Neoplasia Types 1 (MEN1), 2 (MEN2) and 4 (MEN4), Von Hippel-Lindau syndrome (VHL), Pheochromocytoma and Paraganglioma (PPGL), Acromegaly, Hyperprolactinaemia, Polycystic Ovary Syndrome (PCOS), Congenital Adrenal Hyperplasia (CAH), Turner Syndrome, alongside metabolic conditions such as diabetes and obesity and the effects of MHT. The review critically appraises each disorder's association with breast cancer risk, screening implications and therapeutic management. PATIENTS This analysis focuses on women with the aforementioned endocrine and metabolic disorders, assessing their specific breast cancer risk profiles, informed by the latest clinical evidence and molecular insights. MEASUREMENTS The review comprehensively evaluates current evidence-based approaches to screening, diagnostic accuracy and treatment in this patient cohort. Emphasis is placed on the metabolic derangements, hormonal influences and genetic predispositions that modulate breast cancer risk, providing disorder-specific recommendations for individualised care. RESULTS The findings indicate a significantly elevated breast cancer risk in patients with MEN1, necessitating early initiation of MRI screening by age 40. In MEN2, emerging evidence suggests that combining RET inhibitors with endocrine therapy may yield clinical benefits, although further research is needed to validate this approach. The breast cancer risk associated with MEN4 and VHL syndromes, while documented, remains less well-characterised, requiring further investigation. Diabetes and obesity are confirmed as major modifiable risk factors, particularly in postmenopausal women, where hyperinsulinemia and metabolic dysfunction contribute to increased incidence and poorer outcomes, notably in triple-negative breast cancer (TNBC). The role of MHT, particularly combined oestrogen-progestogen therapy, is strongly associated with increased breast cancer risk, particularly for hormone receptor-positive malignancies, necessitating cautious use and personalised treatment planning. In contrast, oestrogen-only MHT appears to confer a reduced risk in women post-hysterectomy. For patients with PCOS, CAH and Turner Syndrome, while definitive evidence of elevated breast cancer risk is lacking, individualised screening strategies and careful hormone therapy management remain essential due to the complex interplay of hormonal and metabolic factors. CONCLUSIONS The review highlights the need for personalised breast cancer screening and management protocols in women with endocrine and metabolic disorders. For high-risk groups such as MEN1 patients, early initiation of MRI screening is warranted. In women with diabetes and obesity, targeted interventions addressing hyperinsulinemia and metabolic dysfunction are critical to mitigating their increased cancer risk. The association between MHT and breast cancer underscores the importance of individualised risk stratification in hormone therapy administration, particularly in women with predisposing genetic or endocrine conditions. Enhanced surveillance tailored to the unique risk profiles of endocrine disorder patients will facilitate early detection and improve clinical outcomes. However, further large-scale studies are necessary to refine these associations and develop robust, evidence-based guidelines.
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Affiliation(s)
- Arie Hawazie
- Centre for Endocrinology, Queen Mary University, London, UK
| | - Maralyn Druce
- Centre for Endocrinology, Queen Mary University, London, UK
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Halperin R, Tirosh A. Progress report on multiple endocrine neoplasia type 1. Fam Cancer 2025; 24:15. [PMID: 39826015 PMCID: PMC11742904 DOI: 10.1007/s10689-025-00440-4] [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: 07/16/2024] [Accepted: 01/03/2025] [Indexed: 01/20/2025]
Abstract
Multiple endocrine neoplasia type 1 (MEN1) syndrome is an autosomal dominant disorder caused by a germline pathogenic variant in the MEN1 tumor suppressor gene. Patients with MEN1 have a high risk for primary hyperparathyroidism (PHPT) with a penetrance of nearly 100%, pituitary adenomas (PitAd) in 40% of patients, and neuroendocrine neoplasms (NEN) of the pancreas (40% of patients), duodenum, lung, and thymus. Increased MEN1-related mortality is mainly related to duodenal-pancreatic and thymic NEN. Management of PHPT differs from that of patients with sporadic disease, as the surgical approach in MEN1-related PHPT includes near-total or total parathyroidectomy because of multigland hyperplasia in most patients and the consequent high risk of recurrence. NEN management also differs from patients with sporadic disease due to multiple synchronous and metasynchronous neoplasms. In addition, the lifelong risk of developing NEN requires special considerations to avoid excessive surgeries and to minimize damage to the patient's function and well-being. This progress report will outline current insights into surveillance and management of the major clinical manifestation of MEN1 syndrome in children and adults with MEN1 diagnosis. In addition, we will discuss MEN1-like clinical presentation with negative MEN1-genetic workup and future clinical and research directions.
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Affiliation(s)
- Reut Halperin
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Neuroendocrine Oncology Unit, Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, Ramat Gan, Israel
- The Chaim Sheba Medical Center, ENTIRE - Endocrine Neoplasia Translational Research Center, Tel Aviv University Faculty of Medicine, 2 Sheba Road, Tel HaShomer, Ramat Gan, Israel
| | - Amit Tirosh
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
- Neuroendocrine Oncology Unit, Division of Endocrinology, Diabetes and Metabolism, Sheba Medical Center, Ramat Gan, Israel.
- The Chaim Sheba Medical Center, ENTIRE - Endocrine Neoplasia Translational Research Center, Tel Aviv University Faculty of Medicine, 2 Sheba Road, Tel HaShomer, Ramat Gan, Israel.
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Berti V, Mungai F, Lucibello P, Brandi ML, Biagini C, Imperiale A. Up-to-Date Imaging for Parathyroid Tumor Localization in MEN1 Patients with Primary Hyperparathyroidism: When and Which Ones (A Narrative Pictorial Review). Diagnostics (Basel) 2024; 15:11. [PMID: 39795539 PMCID: PMC11719470 DOI: 10.3390/diagnostics15010011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/22/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
Patients diagnosed with multiple endocrine neoplasia type-1 (MEN1) often initially present with primary hyperparathyroidism (pHPT), and typically undergo surgical intervention. While laboratory tests are fundamental for diagnosis, imaging is crucial for localizing pathological parathyroids to aid in precise surgical planning. In this pictorial review, we will begin by comprehensively examining key imaging techniques and their established protocols, evaluating their effectiveness in detecting abnormal parathyroid glands. This analysis will emphasize both the advantages and potential limitations within the clinical context of MEN1 patients. Additionally, we will explore integrated imaging approaches that combine multiple modalities to enhance localization accuracy and optimize surgical planning-an essential component of holistic management in MEN1 cases. Various imaging techniques are employed for presurgical localization, including ultrasound (US), multiphase parathyroid computed tomography (CT) scanning (4D CT), magnetic resonance imaging (MRI), and nuclear medicine techniques like single photon emission computed tomography/CT (SPECT/CT) and positron emission tomography/CT (PET/CT). US is non-invasive, readily available, and provides high spatial resolution. However, it is operator-dependent and may have limitations in certain cases, such as intrathyroidal locations, the presence of bulky goiters, thyroid nodules, and previous thyroidectomy. Four-dimensional CT offers dynamic imaging, aiding in the identification of enlarged parathyroid glands, particularly in cases of ectopic or supernumerary glands. Despite concerns about radiation exposure, efforts are underway to optimize protocols and reduce doses, including the use of dual-energy CT. MR imaging offers excellent soft tissue contrast without radiation exposure, potentially providing superior differentiation between parathyroid glands and the surrounding structures. Radionuclide imaging, especially PET/CT using radiopharmaceuticals like [18F]FCH, shows promising results in localizing parathyroid tumors, particularly in patients with MEN1. [18F]FCH PET/CT demonstrates high sensitivity and may provide additional information compared to other imaging modalities, especially in cases of recurrent HPT.
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Affiliation(s)
- Valentina Berti
- Nuclear Medicine Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Francesco Mungai
- Radiology Unit, Careggi University Hospital, 50134 Florence, Italy;
| | - Paolo Lucibello
- Donatello Bone Clinic, Sesto Fiorentino, 50134 Florence, Italy; (P.L.); (C.B.)
| | - Maria Luisa Brandi
- Department of Endocrinology, University Vita-Salute San Raffaele, 20132 Milan, Italy;
| | - Carlo Biagini
- Donatello Bone Clinic, Sesto Fiorentino, 50134 Florence, Italy; (P.L.); (C.B.)
| | - Alessio Imperiale
- Department of Nuclear Medicine and Molecular Imaging, Institut de Cancérologie de Strasbourg Europe (ICANS), University Hospitals of Strasbourg, University of Strasbourg, 67200 Strasbourg, France
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van Leeuwaarde RS, Halfdanarson TR, Sudhakar SM, Meijers RWJ, Folpe AL, Brosens LAA. Sarcomas arising in MEN1 patients: demonstrating LOH of the MEN1 locus and loss of menin expression. Fam Cancer 2024; 24:10. [PMID: 39609309 DOI: 10.1007/s10689-024-00433-9] [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: 06/07/2024] [Accepted: 11/07/2024] [Indexed: 11/30/2024]
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a hereditary tumor syndrome characterized by endocrine tumors, typically from parathyroid, pancreatic, or anterior pituitary origin. In addition, benign cutaneous soft tissue tumors are prevalent in MEN1 patients. Although sarcomas have been reported in MEN1 patients it is unclear if these tumors should be considered as part of the MEN1 syndrome. Here, five patients with a MEN1 syndrome and a sarcoma are described. In all five sarcomas loss of heterozygosity of the MEN1 gene and loss of expression of menin are shown, suggesting that sarcomas may be a phenotypic expression of MEN1 syndrome.
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Affiliation(s)
- Rachel S van Leeuwaarde
- Department of Endocrine Oncology, University Medical Center Utrecht, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands.
| | | | - Shwetha M Sudhakar
- Department of Endocrine Oncology, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA
| | - Ruud W J Meijers
- Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Andrew L Folpe
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA
| | - Lodewijk A A Brosens
- Department of Pathology, UMC Utrecht, Utrecht University, Utrecht, The Netherlands
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Manoharan J, Albers MB, Rinke A, Adelmeyer J, Görlach J, Bartsch DK. Multiple Endocrine Neoplasia Type 1. DEUTSCHES ARZTEBLATT INTERNATIONAL 2024; 121:527-533. [PMID: 38863299 PMCID: PMC11542567 DOI: 10.3238/arztebl.m2024.0094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 04/25/2024] [Accepted: 04/25/2024] [Indexed: 06/13/2024]
Abstract
BACKGROUND Multiple endocrine neoplasia type 1 (MEN1) is a rare genetic disease of autosomal dominant inheritance, with an estimated prevalence of 3-20/100 000. Its main feature is neuroendocrine neoplasia in the parathyroid glands, the endocrine pancreas, the duodenum, and the pituitary gland. In this article, we review the diagnostic and therapeutic options for MEN1-associated tumors. METHODS We present an analysis and evaluation of retrospective case studies retrieved from PubMed, guidelines from Germany and abroad, and our own experience. RESULTS The disease is caused by mutations in the MEN1 gene. Mutation carriers should participate in a regular, specialized screening program from their twenties onward. The early diagnosis and individualized treatment of MEN1-associated tumors can prevent the development of life-threatening hormonal syndromes and prolong the expected life span of MEN1 patients from 55 to 70 years, as well as improving their quality of life. Surgical treatment is based on the location, size, growth dynamics, and functional activity of the tumors. The evidence for treatment strategies is derived from retrospective studies only (level III evidence) and the optimal treatment is often a matter of debate. This is a further reason for treatment in specialized centers. CONCLUSION MEN1 is a rare disease, and, consequently, the evidence base for its treatment is limited. Carriers of disease-causing mutations in the MEN1 gene should be cared for in specialized interdisciplinary centers, so that any appreciable tumor growth or hormonal activity can be detected early and organ-sparing treatment can be provided.
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Affiliation(s)
- Jerena Manoharan
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Max B. Albers
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Anja Rinke
- Department of Gastroenterology and Endocrinology, Philipps University Marburg, Marburg, Germany
| | - Jan Adelmeyer
- Department of Gastroenterology and Endocrinology, Philipps University Marburg, Marburg, Germany
| | - Jannis Görlach
- Department of Diagnostic and Interventional Radiology, Philipps University Marburg, Marburg, Germany
| | - Detlef K. Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
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Zhao YX, Wang O, Song A, Wang LJ, Gong FY, Duan L, Yang HB, Pan H, Zhu HJ. The risk of concurrent malignancies in patients with multiple endocrine neoplasia type 1: insights into clinical characteristics of those with multiple endocrine neoplasia type 1. J Endocrinol Invest 2024; 47:1931-1939. [PMID: 38161202 DOI: 10.1007/s40618-023-02288-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 12/17/2023] [Indexed: 01/03/2024]
Abstract
OBJECTIVE Summarize and analyze the characteristics of patients with Multiple Endocrine Neoplasia type 1 (MEN-1) who were diagnosed with malignant tumors that do not belong to MEN-1 components. METHODS Clinical data from patients with MEN-1 who visited Peking Union Medical College Hospital between April 2012 and April 2022 were collected. We compared the clinical characteristics of patients with malignant tumors outside of their MEN-1 components to those without additional tumors. MEN-1 gene testing was performed on most of these patients using Sanger sequencing, whole-exome sequencing, or MLPA. RESULTS A total of 221 MEN-1 patients were diagnosed, of which 23 (10.40%) were found to have malignant tumors that did not belong to MEN-1 components, including papillary thyroid carcinoma (PTC) (4.52%), breast cancer (1.81%), urologic neoplasms (1.35%), primary hepatic carcinoma (PCC) (0.09%), meningeal sarcoma (0.05%), glioblastoma (0.05%), cervical cancer (0.05%), and lung carcinoma (0.05%). MEN-1 gene mutations were identified in 11 patients, including missense mutations, frameshift mutations, and splice mutations. The prevalence of each endocrine neoplasm, particularly gastroenteropancreatic neuroendocrine tumor, was higher in MEN-1 patients with other malignant tumors compared to MEN-1 patients without malignant tumors. CONCLUSION Our retrospective study revealed a higher incidence of non-MEN-1 component malignant tumors in MEN-1 patients, especially breast cancer, PTC, and urologic neoplasms. These patients also exhibit more severe clinical phenotypes of MEN-1.
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Affiliation(s)
- Yu Xing Zhao
- Key Laboratory of, Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
- Chinese Research Center for Behavior Medicine in Growth and Development, Beijing, 100730, Beijing, China
| | - Ou Wang
- Key Laboratory of, Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
- Chinese Research Center for Behavior Medicine in Growth and Development, Beijing, 100730, Beijing, China
| | - An Song
- Key Laboratory of, Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
- Chinese Research Center for Behavior Medicine in Growth and Development, Beijing, 100730, Beijing, China
| | - Lin Jie Wang
- Key Laboratory of, Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
- Chinese Research Center for Behavior Medicine in Growth and Development, Beijing, 100730, Beijing, China
| | - Feng Ying Gong
- Key Laboratory of, Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
- Chinese Research Center for Behavior Medicine in Growth and Development, Beijing, 100730, Beijing, China
| | - Lian Duan
- Key Laboratory of, Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
- Chinese Research Center for Behavior Medicine in Growth and Development, Beijing, 100730, Beijing, China
| | - Hong Bo Yang
- Key Laboratory of, Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
- Chinese Research Center for Behavior Medicine in Growth and Development, Beijing, 100730, Beijing, China
| | - Hui Pan
- Key Laboratory of, Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China
- Chinese Research Center for Behavior Medicine in Growth and Development, Beijing, 100730, Beijing, China
| | - Hui Juan Zhu
- Key Laboratory of, Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
- Chinese Research Center for Behavior Medicine in Growth and Development, Beijing, 100730, Beijing, China.
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Gao J, Liu C, Zhou J, Pan Y, Zhang Y. The lesion detection rate of Ga-68 DOTATATE PET/MR in multiple endocrine neoplasia type 1. J Med Imaging Radiat Oncol 2024; 68:250-256. [PMID: 38563291 DOI: 10.1111/1754-9485.13641] [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: 08/15/2023] [Accepted: 03/07/2024] [Indexed: 04/04/2024]
Abstract
INTRODUCTION The purpose of the study was to determine the usefulness of Ga-68 DOTATATE PET/MR in the identification of tumours in individuals with multiple endocrine neoplasia type 1 (MEN1). METHODS In this retrospective investigation, five individuals who had tested positive for a hereditary MEN1 variant underwent Ga-68 DOTATATE PET/MR between May 2020 and January 2023. Several types of tumours associated with MEN1 were studied. MEN1-related tumours included pituitary, parathyroid, gastroenteropancreatic, and adrenal. The rates of lesion identification between MRI, Ga-68 DOTATATE PET, and Ga-68 DOTATATE PET/MRI were examined. The maximum and mean standard uptake values (SUVmax and SUVmean) were evaluated in carefully delineated volumes of interest (VOI) for the relevant tumours. RESULTS Of the 24 primary lesions, 14 were identified by Ga-68 DOTATATE PET, 18 by MRI, and 20 by Ga-68 DOTATATE PET/MRI. Two pituitary tumours were detected by all three techniques. All parathyroid tumours that were not detected by Ga-68 DOTATATE PET and MRI were found by Tc-99m MIBI SPECT/CT or/and EUS. Ga-68 DOTATATE PET/MR detected more gastroenteropancreatic lesions. All adrenal tumours not identified by Ga-68 DOTATATE PET were found by MRI or CT. The median SUVmax for lesions identified on Ga-68 DOTATATE PET/MRI was 18.4 (range, 3.8-85.2), and the median SUVmean was 12.0 (range, 2.3-49.8). CONCLUSION The combination of Ga-68 DOTATATE PET and MRI demonstrated a higher detection rate and may be more useful in the work-up of MEN1 providing a panoramic view of MEN1-related lesions. To increase the identification of MEN1-associated neuroendocrine lesions in the parathyroid gland, approaches other than Ga-68 DOTATATE PET/MRI should be used.
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Affiliation(s)
- Jing Gao
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chang Liu
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jinxin Zhou
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yu Pan
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yifan Zhang
- Department of Nuclear Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Jha S, Simonds WF. Molecular and Clinical Spectrum of Primary Hyperparathyroidism. Endocr Rev 2023; 44:779-818. [PMID: 36961765 PMCID: PMC10502601 DOI: 10.1210/endrev/bnad009] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 02/09/2023] [Accepted: 03/17/2023] [Indexed: 03/25/2023]
Abstract
Recent data suggest an increase in the overall incidence of parathyroid disorders, with primary hyperparathyroidism (PHPT) being the most prevalent parathyroid disorder. PHPT is associated with morbidities (fractures, kidney stones, chronic kidney disease) and increased risk of death. The symptoms of PHPT can be nonspecific, potentially delaying the diagnosis. Approximately 15% of patients with PHPT have an underlying heritable form of PHPT that may be associated with extraparathyroidal manifestations, requiring active surveillance for these manifestations as seen in multiple endocrine neoplasia type 1 and 2A. Genetic testing for heritable forms should be offered to patients with multiglandular disease, recurrent PHPT, young onset PHPT (age ≤40 years), and those with a family history of parathyroid tumors. However, the underlying genetic cause for the majority of patients with heritable forms of PHPT remains unknown. Distinction between sporadic and heritable forms of PHPT is useful in surgical planning for parathyroidectomy and has implications for the family. The genes currently known to be associated with heritable forms of PHPT account for approximately half of sporadic parathyroid tumors. But the genetic cause in approximately half of the sporadic parathyroid tumors remains unknown. Furthermore, there is no systemic therapy for parathyroid carcinoma, a rare but potentially fatal cause of PHPT. Improved understanding of the molecular characteristics of parathyroid tumors will allow us to identify biomarkers for diagnosis and novel targets for therapy.
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Affiliation(s)
- Smita Jha
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1752, USA
| | - William F Simonds
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1752, USA
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Massey S, Khan MA, Rab SO, Mustafa S, Khan A, Malik Z, Shaik R, Verma MK, Deo S, Husain SA. Evaluating the role of MEN1 gene expression and its clinical significance in breast cancer patients. PLoS One 2023; 18:e0288482. [PMID: 37437063 DOI: 10.1371/journal.pone.0288482] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 06/27/2023] [Indexed: 07/14/2023] Open
Abstract
BACKGROUND Breast cancer is a multifactorial disease which involves number of molecular factors that are critically involved in proliferation of breast cancer cells. MEN1 gene that is traditionally known for its germline mutations in neuroendocrine tumors is associated with high risk of developing breast cancer in females with MEN1 syndrome. However, the paradoxical role of MEN1 is reported in sporadic breast cancer cases. The previous studies indicate the functional significance of MEN1 in regulating breast cells proliferation but its relevance in development and progression of breast cancer is still not known. Our study targets to find the role of MEN1 gene aberration and its clinical significance in breast cancer. METHODS Breast tumor and adjacent normal tissue of 142 sporadic breast cancer patients were collected at the time of surgery. The expression analysis of MEN1 mRNA and protein was done through RT-PCR, immunohistochemistry and western blotting. Further to find the genetic and epigenetic alterations, automated sequencing and MS-PCR was performed respectively. Correlation between our findings and clinical parameters was determined using appropriate statistical tests. RESULTS MEN1 expression was found to be significantly increased in the breast tumor tissue with its predominant nuclear localization. The elevated expression of MEN1 mRNA (63.38% cases) and protein (60.56% cases) exhibited a significant association with ER status of the patients. Most of the cases had unmethylated (53.52%) MEN1 promoter region, which can be a key factor responsible for dysregulated expression of MEN1 in breast cancer cases. Our findings also revealed the significant association of MEN1 mRNA overexpression with Age and lymph node status of the patients. CONCLUSION Our results indicate upregulated expression of MEN1 in sporadic breast cancer patients and it could be critically associated with development and advancement of the disease.
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Affiliation(s)
- Sheersh Massey
- Human Genetics Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | - Mohammad Aasif Khan
- Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health San Science Center at Antonio (UTHSCSA), San Antonio, TX, United States of America
| | - Safia Obaidur Rab
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Saad Mustafa
- Human Genetics Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | - Asifa Khan
- Human Genetics Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | - Zoya Malik
- Human Genetics Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | - Rahimunnisa Shaik
- Human Genetics Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | - Mohit Kumar Verma
- Human Genetics Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | - Svs Deo
- Department of Surgical Oncology BRA-IRCH, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Syed Akhtar Husain
- Human Genetics Laboratory, Department of Biosciences, Jamia Millia Islamia, New Delhi, India
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Pierotti L, Pardi E, Dinoi E, Piaggi P, Borsari S, Della Valentina S, Sardella C, Michelucci A, Caligo MA, Bogazzi F, Marcocci C, Cetani F. Cutaneous lesions and other non-endocrine manifestations of Multiple Endocrine Neoplasia type 1 syndrome. Front Endocrinol (Lausanne) 2023; 14:1191040. [PMID: 37484956 PMCID: PMC10360178 DOI: 10.3389/fendo.2023.1191040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/13/2023] [Indexed: 07/25/2023] Open
Abstract
Background Multiple Endocrine Neoplasia type 1 is a rare genetic syndrome mainly caused by mutations of MEN1 gene and characterized by a combination of several endocrine and non-endocrine manifestations. The objective of this study was to describe cutaneous lesions and other non-endocrine manifestations of MEN1 in a cohort of patients with familial (F) and sporadic (S) MEN1, compare the prevalence of these manifestations between the two cohorts, and investigate the correlation with MEN1 mutation status. Methods We collected phenotypic and genotypic data of 185 patients with F-MEN1 and S-MEN1 followed from 1997 to 2022. The associations between F-MEN1 and S-MEN1 or MEN1 mutation-positive and mutation-negative patients and non-endocrine manifestations were determined using chi-square or Fisher's exact tests or multivariate exact logistic regression analyses. Results The prevalence of angiofibromas was significantly higher in F-MEN1 than in S-MEN1 in both the whole (p < 0.001) and index case (p = 0.003) cohorts. The prevalence of lipomas was also significantly higher in F-MEN1 than in S-MEN1 (p = 0.009) and in MEN1 mutation-positive than in MEN1 mutation-negative (p = 0.01) index cases. In the whole cohort, the prevalence of lipomas was significantly higher in MEN1 mutation-positive compared to MEN1 mutation-negative patients (OR = 2.7, p = 0.02) and in F-MEN1 than in S-MEN1 (p = 0.03), only after adjustment for age. No significant differences were observed for the other non-endocrine manifestations between the two cohorts. Hibernoma and collagenoma were each present in one patient (0.5%) and meningioma and neuroblastoma in 2.7% and 0.5%, respectively. Gastric leiomyoma was present in 1.1% of the patients and uterine leiomyoma in 14% of women. Thyroid cancer, breast cancer, lung cancer, basal cell carcinoma, melanoma, and colorectal cancer were present in 4.9%, 2.7%, 1.6%, 1.6%, 2.2%, and 0.5% of the whole series, respectively. Conclusions We found a significantly higher prevalence of angiofibromas and lipomas in F-MEN1 compared with S-MEN1 and in MEN1 mutation-positive compared to MEN1 mutation-negative patients. In patients with one major endocrine manifestation of MEN1 , the presence of cutaneous lesions might suggest the diagnosis of MEN1 and a possible indication for genetic screening.
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Affiliation(s)
- Laura Pierotti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Elena Pardi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Elisa Dinoi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Paolo Piaggi
- Department of Information Engineering, University of Pisa, Pisa, Italy
| | - Simona Borsari
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Chiara Sardella
- Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy
| | - Angela Michelucci
- Laboratory of Molecular Genetics, University Hospital of Pisa, Pisa, Italy
| | | | - Fausto Bogazzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Claudio Marcocci
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy
| | - Filomena Cetani
- Unit of Endocrinology, University Hospital of Pisa, Pisa, Italy
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12
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Ramamoorthy B, Nilubol N. Multiple Endocrine Neoplasia Type 1 Syndrome Pancreatic Neuroendocrine Tumor Genotype/Phenotype: Is There Any Advance on Predicting or Preventing? Surg Oncol Clin N Am 2023; 32:315-325. [PMID: 36925188 PMCID: PMC10348402 DOI: 10.1016/j.soc.2022.10.008] [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] [Indexed: 03/17/2023]
Abstract
Multiple endocrine neoplasia type 1 syndrome (MEN1) is a disease caused by mutations in the MEN1 tumor suppressor gene leading to hyperparathyroidism, pituitary adenomas, and entero-pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors (PNETs) are a major cause of mortality in patients with MEN1. Identification of consistent genotype-phenotype correlations has remained elusive, but MEN1 mutations in exons 2, 9, and 10 may be associated with metastatic PNETs; patients with these mutations may benefit from more intensive surveillance and aggressive treatment. In addition, epigenetic differences between MEN1-associated PNETs and sporadic PNETs are beginning to emerge, but further investigation is required to establish clear phenotypic associations.
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Affiliation(s)
- Bhavishya Ramamoorthy
- Surgical Oncology Program, Endocrine Surgery Section, National Cancer Institute, NIH, 10 Center Drive, Building 10 - Room 45952, Bethesda, MD 20892, USA
| | - Naris Nilubol
- Surgical Oncology Program, Endocrine Surgery Section, National Cancer Institute, NIH, 10 Center Drive, Building 10 - Room 45952, Bethesda, MD 20892, USA.
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13
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Lairmore TC, Abdulsattar J, De Benedetti A, Shi R, Huang S, Khalil MI, Witt SN. Loss of tumor suppressor menin expression in high grade cholangiocarcinomas. BMC Res Notes 2023; 16:15. [PMID: 36782257 PMCID: PMC9923918 DOI: 10.1186/s13104-023-06282-6] [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: 01/26/2023] [Accepted: 01/31/2023] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND MEN1, which codes for the protein menin, is a tumor suppressor in neuroendocrine tissue. In cholangiocarcinoma (CCA) cell lines the overexpression of menin decreased proliferation, angiogenesis, migration, and invasion in vitro and in xenografts, but its expression in CCA tumor tissue samples is not established. OBJECTIVE Determine whether the expression of menin correlates with disease progression in patient samples of CCA in a tissue microarray (TMA) by immunohistochemical (IHC) staining. RESULTS IHC analysis of 97 biopsies revealed that low-grade tumors (Grade I) exhibited intense, diffuse, finely granular nuclear menin immunoreactivity with a pronounced linear perinuclear pattern (mean IHC score = 2.00), whereas high-grade tumors (Grade III) mostly lacked such staining (mean IHC score = 0.35). Collectively, there was a significant inverse association between tumor grade and menin staining (P = 0.0005). We also found a significant association between fibrosis status and menin staining, in that, 81.2% (56/69) of patients without fibrosis had no menin staining, whereas 92.9% (26/28) patients with fibrosis exhibited menin staining (P < 0.0001). No association was found between fibrosis status and grade. Overall, menin expression is inversely associated with tumor grade and positively associated with fibrosis status.
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Affiliation(s)
- Terry C. Lairmore
- grid.411417.60000 0004 0443 6864Department of Surgery, Louisiana State University Health Sciences Center, Shreveport, LA 71103 USA ,grid.411417.60000 0004 0443 6864Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103 USA ,grid.411417.60000 0004 0443 6864Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71103 USA
| | - Jehan Abdulsattar
- grid.411417.60000 0004 0443 6864Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA 71103 USA
| | - Arrigo De Benedetti
- grid.411417.60000 0004 0443 6864Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103 USA ,grid.411417.60000 0004 0443 6864Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71103 USA
| | - Runhua Shi
- grid.411417.60000 0004 0443 6864Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103 USA
| | - Shile Huang
- grid.411417.60000 0004 0443 6864Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103 USA ,grid.411417.60000 0004 0443 6864Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71103 USA
| | - Md Imtiaz Khalil
- grid.411417.60000 0004 0443 6864Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71103 USA
| | - Stephan N. Witt
- grid.411417.60000 0004 0443 6864Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103 USA ,grid.411417.60000 0004 0443 6864Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71103 USA
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14
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Băicoianu-Nițescu LC, Gheorghe AM, Carsote M, Dumitrascu MC, Sandru F. Approach of Multiple Endocrine Neoplasia Type 1 (MEN1) Syndrome-Related Skin Tumors. Diagnostics (Basel) 2022; 12:2768. [PMID: 36428828 PMCID: PMC9689678 DOI: 10.3390/diagnostics12112768] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 10/27/2022] [Accepted: 11/07/2022] [Indexed: 11/16/2022] Open
Abstract
Non-endocrine findings in patients with MEN1 (multiple endocrine neoplasia) syndrome also include skin lesions, especially tumor-type lesions. This is a narrative review of the English-language medical literature including original studies concerning MEN1 and dermatological issues (apart from dermatologic features of each endocrine tumor/neuroendocrine neoplasia), identified through a PubMed-based search (based on clinical relevance, with no timeline restriction or concern regarding the level of statistical significance). We identified 27 original studies involving clinical presentation of patients with MEN1 and cutaneous tumors; eight other original studies that also included the genetic background; and four additional original studies were included. The largest cohorts were from studies in Italy (N = 145 individuals), Spain (N = 90), the United States (N = 48 and N = 32), and Japan (N = 28). The age of patients varied from 18 to 76 years, with the majority of individuals in their forties. The most common cutaneous tumors are angiofibromas (AF), collagenomas (CG), and lipomas (L). Other lesions are atypical nevi, basocellular carcinoma, squamous cell carcinoma, acrochordons, papillomatosis confluens et reticularis, gingival papules, and cutaneous T-cell lymphoma of the eyelid. Non-tumor aspects are confetti-like hypopigmentation, café-au-lait macules, and gingival papules. MEN1 gene, respective menin involvement has also been found in melanomas, but the association with MEN1 remains debatable. Typically, cutaneous tumors (AF, CG, and L) are benign and are surgically treated only for cosmetic reasons. Some of them are reported as first presentation. Even though skin lesions are not pathognomonic, recognizing them plays an important role in early identification of MEN1 patients. Whether a subgroup of MEN1 subjects is prone to developing these types of cutaneous lesions and how they influence MEN1 evolution is still an open issue.
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Affiliation(s)
| | - Ana-Maria Gheorghe
- Department of Endocrinology, C.I. Parhon National Institute of Endocrinology, 011863 Bucharest, Romania
| | - Mara Carsote
- Department of Endocrinology, C. Davila University of Medicine and Pharmacy & C.I. Parhon National Institute of Endocrinology, 011683 Bucharest, Romania
| | - Mihai Cristian Dumitrascu
- Department of Obstetrics and Gynaecology, C. Davila University of Medicine and Pharmacy & University Emergency Hospital, 050474 Bucharest, Romania
| | - Florica Sandru
- Department of Dermatology, Elias University Emergency Hospital, 011461 Bucharest, Romania
- Department of Dermatology, C. Davila University of Medicine and Pharmacy & Elias University Emergency Hospital, 011368 Bucharest, Romania
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15
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Pieterman CRC, Valk GD. Update on the clinical management of multiple endocrine neoplasia type 1. Clin Endocrinol (Oxf) 2022; 97:409-423. [PMID: 35319130 PMCID: PMC9540817 DOI: 10.1111/cen.14727] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 02/22/2022] [Accepted: 02/28/2022] [Indexed: 11/30/2022]
Abstract
This review provides an overview of novel insights in the clinical management of patients with Multiple Endocrine Neoplasia Type 1, focusing on the last decade since the last update of the MEN1 guidelines. With regard to Diagnosis: Mutation-negative patients with 2/3 main manifestations have a different clinical course compared to mutation-positive patients. As for primary hyperparathyroidism: subtotal parathyroidectomy is the initial procedure of choice. Current debate centres around the timing of initial parathyroidectomy as well as the controversial topic of unilateral clearance in young patients. For duodenopancreatic neuroendocrine tumours (NETs), the main challenge is accurate and individualized risk stratification to enable personalized surveillance and treatment. Thymus NETs remain one of the most aggressive MEN1-related tumours. Lung NETs are more frequent than previously thought, generally indolent, but rare aggressive cases do occur. Pituitary adenomas are most often prolactinomas and nonfunctioning microadenomas with an excellent prognosis and good response to therapy. Breast cancer is recognized as part of the MEN1 syndrome in women and periodical screening is advised. Clinically relevant manifestations are already seen at the paediatric age and initiating screening in the second decade is advisable. MEN1 has a significant impact on quality of life and US data show a significant financial burden. In conclusion, patient outcomes have improved, but much is still to be achieved. For care tailored to the needs of the individual patient and improving outcomes on an individual basis, studies are now needed to define predictors of tumour behaviour and effects of more individualized interventions.
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Affiliation(s)
| | - Gerlof D. Valk
- Department of Endocrine OncologyUniversity Medical Center UtrechtUtrechtThe Netherlands
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16
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Dirven I, Bravenboer B, Raeymaeckers S, Andreescu CE. Lymphadenopathy after COVID-19 vaccination in patients with endocrine cancer: two case reports. Endocrinol Diabetes Metab Case Rep 2022; 2022:22-0258. [PMID: 36112088 PMCID: PMC9513633 DOI: 10.1530/edm-22-0258] [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: 07/02/2022] [Accepted: 08/22/2022] [Indexed: 11/08/2022] Open
Abstract
Summary The Covid-19 vaccination has been rapidly implemented among patients with cancer. We present two cases of patients with endocrine tumours who developed lymphadenopathy following a Covid-19 vaccination. In the case of a patient with multiple endocrine neoplasia (MEN) 1 syndrome, an 18-fluorodeoxyglucose (18FDG)-PET/CT showed positive axillary lymph nodes. Further work-up with fine needle aspiration showed a reactive pattern following a Covid-19 vaccination in the ipsilateral arm shortly before the 18FDG-PET/CT. A second patient, in follow-up for thyroid cancer, developed clinical supraclavicular lymphadenopathy after a Covid-19 vaccination. Follow-up ultrasound proved the lesion to be transient. These cases demonstrate lymphadenopathy in response to a Covid-19 vaccination in two patients susceptible to endocrine tumours and metastatic disease. With growing evidence about the pattern and occurrence of lymphadenopathy after mRNA Covid-19 vaccination, recommendations for scheduling and interpretation of imaging among cancer patients should be implemented to reduce equivocal findings, overdiagnosis, and overtreatment, while maintaining a good standard of care in oncological follow-up. Learning points Reactive lymphadenopathy is very common after an mRNA vaccination against Covid-19 and should be part of the differential diagnosis in patients with endocrine tumours who recently received a Covid-19 mRNA vaccination and present with an ipsilateral lymphadenopathy. A good vaccine history is essential in assessing the risk for lymphadenopathy and if possible, screening imaging in patients with endocrine tumours should be postponed at least 6 weeks after the previous vaccination. For now, a multidisciplinary care approach is recommended to determine the necessary steps in the diagnostic evaluation of lymphadenopathy in the proximity of a Covid-19 vaccination.
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Affiliation(s)
- Iris Dirven
- Department of Endocrinology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Bert Bravenboer
- Department of Endocrinology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Steven Raeymaeckers
- Department of Radiology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Corina E Andreescu
- Department of Endocrinology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
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17
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Talbot JN, Zhang-Yin J, Kerrou K, Aveline C, Vagne B, Bélissant O, Tassart M, Périé S, Bouchard P, Christin-Maitre S, Ménégaux F, Groussin L, Gaujoux S, Balogová S, Montravers F. Multiple endocrine neoplasia type 1 or 4: detection of hyperfunctioning parathyroid glands with 18F-fluorocholine PET/CT. Illustrative cases and pitfalls. THE QUARTERLY JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING : OFFICIAL PUBLICATION OF THE ITALIAN ASSOCIATION OF NUCLEAR MEDICINE (AIMN) [AND] THE INTERNATIONAL ASSOCIATION OF RADIOPHARMACOLOGY (IAR), [AND] SECTION OF THE SOCIETY OF... 2022; 66:130-140. [PMID: 35005879 DOI: 10.23736/s1824-4785.22.03440-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
18F-fluorocholine (FCH) PET/CT is now well established to detect the hyperfunctioning parathyroid glands (HFPTG) in a case of sporadic primary hyperparathyroidism (pHPT), but only limited evidence is available about the utility of FCH PET/CT to detect the HFPTG in patients with multiple endocrine neoplasia (MEN) type 1 or 4. The pHPT in this context frequently consists in a multiglandular disease with small hyperplastic glands rather than adenomas, which is challenging for imaging modalities. The data of patients with MEN1 or MEN4 after parathyroidectomy referred to FCH PET/CT for presurgical localization of HFPTG were retrospectively reviewed, including follow-up after parathyroidectomy, in search for diagnostic performance and for potential pitfalls. In the present cohort, 16 patients referred to FCH PET/CT as part of their initial pHPT work-up were subsequently operated, 44 abnormal parathyroid glands (PT) were resected, of which 32 (73%) had been detected on FCH PET/CT and 2 considered as equivocal foci. Nine patients referred to FCH PET/CT for recurrent pHPT who were subsequently operated, 14 abnormal PT were resected, all had been detected on FCH PET/CT. FCH PET/CT permitted a unilateral approach for PTx in 4 of them. In one patient with MEN4 and pHPT, the HFPTG could not be visualized on FCH PET/CT but was localized by ultrasonography. Several causes of false positive or false negative results, incidental finding and pitfalls are listed and discussed. FCH PET/CT has a positive benefit/risk ratio in the detection of HFPTG in case of MEN1 (the data in MEN4 being currently very limited) with the most effective detection rate of current imaging modalities for HFPTG, few pitfalls, and an adequate impact on patient management compared to sesta MIBI SPECT and ultrasonography.
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Affiliation(s)
- Jean-Noël Talbot
- Department of Nuclear Medicine, Hôpital Tenon AP-HP, Sorbonne University, Paris, France
| | - Jules Zhang-Yin
- Department of Nuclear Medicine, Hôpital Tenon AP-HP, Sorbonne University, Paris, France
| | - Khadoun Kerrou
- Department of Nuclear Medicine, Hôpital Tenon AP-HP, Sorbonne University, Paris, France
| | - Cyrielle Aveline
- Department of Nuclear Medicine, Hôpital Tenon AP-HP, Sorbonne University, Paris, France
| | - Benedicte Vagne
- Department of Nuclear Medicine, Hôpital Tenon AP-HP, Sorbonne University, Paris, France
| | - Ophélie Bélissant
- Department of Nuclear Medicine, Hôpital Tenon AP-HP, Sorbonne University, Paris, France
| | - Marc Tassart
- Department of Radiology, Hôpital Tenon AP-HP, Sorbonne University, Paris, France
| | - Sophie Périé
- Department of Head and Neck Surgery, Hôpital Tenon AP-HP, Sorbonne University, Paris, France
| | - Phillipe Bouchard
- Department of Endocrinology, Hôpital Saint-Antoine AP-HP, Sorbonne University, Paris, France
| | - Sophie Christin-Maitre
- Department of Endocrinology, Hôpital Saint-Antoine AP-HP, Sorbonne University, Paris, France
| | - Fabrice Ménégaux
- Department of Surgery, Pitié-Salpétrière University Hospital, Sorbonne University, Paris, France
| | - Lionel Groussin
- Department of Endocrinology, Hôpital Cochin AP-HP, University of Paris, Paris, France
| | - Sébastien Gaujoux
- Department of Pancreatic and Endocrine Surgery, Hôpital Cochin AP-HP, University of Paris, Paris, France
| | - Soňa Balogová
- Department of Nuclear Medicine, Hôpital Tenon AP-HP, Sorbonne University, Paris, France -
- Department of Nuclear Medicine, St. Elisabeth Oncology Institute, Comenius University, Bratislava, Slovakia
| | - Françoise Montravers
- Department of Nuclear Medicine, Hôpital Tenon AP-HP, Sorbonne University, Paris, France
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18
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Tiplica GS, Fritz K, Butacu AI, Ungureanu L, Sălăvăstru CM. Gutartige nichtmelanozytäre Hauttumoren bei Syndromen. Hautarzt 2022; 73:114-126. [DOI: 10.1007/s00105-022-04947-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2022] [Indexed: 12/24/2022]
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Waguespack SG. Beyond the "3 Ps": A critical appraisal of the non-endocrine manifestations of multiple endocrine neoplasia type 1. Front Endocrinol (Lausanne) 2022; 13:1029041. [PMID: 36325452 PMCID: PMC9618614 DOI: 10.3389/fendo.2022.1029041] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 09/26/2022] [Indexed: 11/13/2022] Open
Abstract
Multiple endocrine neoplasia type 1 (MEN1), an autosomal-dominantly inherited tumor syndrome, is classically defined by tumors arising from the "3 Ps": Parathyroids, Pituitary, and the endocrine Pancreas. From its earliest descriptions, MEN1 has been associated with other endocrine and non-endocrine neoplastic manifestations. High quality evidence supports a direct association between pathogenic MEN1 variants and neoplasms of the skin (angiofibromas and collagenomas), adipose tissue (lipomas and hibernomas), and smooth muscle (leiomyomas). Although CNS tumors, melanoma, and, most recently, breast cancer have been reported as MEN1 clinical manifestations, the published evidence to date is not yet sufficient to establish causality. Well-designed, multicenter prospective studies will help us to understand better the relationship of these tumors to MEN1, in addition to verifying the true prevalence and penetrance of the well-documented neoplastic associations. Nevertheless, patients affected by MEN1 should be aware of these non-endocrine manifestations, and providers should be encouraged always to think beyond the "3 Ps" when treating an MEN1 patient.
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20
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Chaves C, Nunes da Silva T, Dias Pereira B, Anselmo J, Claro I, Cavaco BM, Saramago A, Leite V. A case report of multiple endocrine neoplasia type 1 and autoimmune disease: Coincidence or correlation? Medicine (Baltimore) 2021; 100:e28145. [PMID: 34889280 PMCID: PMC8663848 DOI: 10.1097/md.0000000000028145] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 11/17/2021] [Indexed: 01/05/2023] Open
Abstract
RATIONALE Multiple Endocrine Neoplasia type 1 (MEN1) is a familial syndrome that results from the disruption of a tumor suppressor protein called MENIN. Its management is challenging, as MEN1 affects different endocrine tissues and predisposes to both benign and malignant tumors. MENIN-deficient cells have recently been recognized to play a role in triggering autoimmunity. Herein, we present a case of MEN1 with multiple endocrine and autoimmune disorders. PATIENT CONCERNS A 50 years old female with a 25 years history of complicated nephrolithiasis presented with primary hyperparathyroidism. DIAGNOSES Over several decades, she was diagnosed with recurrent primary hyperparathyroidism, autoimmune thyroiditis, multinodular goiter, pernicious anemia, metastatic gastric type 1 neuroendocrine tumor, macroprolactinemia, gonadotropin deficiency, mucosa-associated lymphoid tissue lymphoma of the thyroid gland, positive anti-calcium sensor receptor antibodies, and BRCA 1/2-negative invasive breast cancer. The autoimmune regulator gene was sequenced, but no pathogenic variants were found. Next-generation sequencing revealed both a pathogenic MEN1 mutation and a benign CDC73 gene variant. Familial genetic screening revealed a large kindred with multiple carriers of one or both genetic variants (MEN1 = 19; CDC73 = 7). INTERVENTIONS The patient underwent surgical excision of three parathyroid glands, total thyroidectomy and breast tumorectomy plus tamoxifen, and monthly injections of octreotide. The patient and family members with the MEN1 mutation are under a life-long surveillance program for MEN1 prototypic tumors. OUTCOMES The patient was stable and alive during a 24-years follow-up period. LESSONS With the present case, the authors highlight a new interplay between MENIN and the immune system, which may have implications for future targeted life-long surveillance and treatment of MEN1 patients.
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Affiliation(s)
- Carolina Chaves
- Serviço de Endocrinologia e Nutrição, Hospital Divino Espírito Santo de Ponta Delgada, Azores Islands, Portugal
| | - Tiago Nunes da Silva
- Serviço de Endocrinologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
| | - Bernardo Dias Pereira
- Serviço de Endocrinologia e Nutrição, Hospital Divino Espírito Santo de Ponta Delgada, Azores Islands, Portugal
| | - João Anselmo
- Serviço de Endocrinologia e Nutrição, Hospital Divino Espírito Santo de Ponta Delgada, Azores Islands, Portugal
| | - Isabel Claro
- Serviço de Gastroenterologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
| | - Branca M. Cavaco
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
| | - Ana Saramago
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
| | - Valeriano Leite
- Serviço de Endocrinologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
- Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon, Portugal
- Nova Medical School, Lisbon, Portugal
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Shirali AS, Pieterman CRC, Lewis MA, Hyde SM, Makawita S, Dasari A, Thosani N, Ikoma N, McCutcheon IE, Waguespack SG, Perrier ND. It's not a mystery, it's in the history: Multidisciplinary management of multiple endocrine neoplasia type 1. CA Cancer J Clin 2021; 71:369-380. [PMID: 34061974 DOI: 10.3322/caac.21673] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/12/2021] [Accepted: 03/30/2021] [Indexed: 12/11/2022] Open
Affiliation(s)
- Aditya S Shirali
- Department of Surgical Oncology, Section of Surgical Endocrinology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Carolina R C Pieterman
- Department of Surgical Oncology, Section of Surgical Endocrinology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Mark A Lewis
- Department of Medicine, Intermountain Healthcare, Murray, Utah
| | - Samuel M Hyde
- Department of Obstetrics and Gynecology-Cancer Genetics, Northwestern Memorial Hospital, Chicago, Illinois
| | - Shalini Makawita
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nirav Thosani
- Division of Gastroenterology, Hepatology, and Nutrition, McGovern Medical School, UTHealth, Houston, Texas
| | - Naruhiko Ikoma
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ian E McCutcheon
- Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Steven G Waguespack
- Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nancy D Perrier
- Department of Surgical Oncology, Section of Surgical Endocrinology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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22
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Peltola E, Hannula P, Huhtala H, Metso S, Sand J, Laukkarinen J, Tiikkainen M, Sirén J, Soinio M, Nuutila P, Moilanen L, Laaksonen DE, Ebeling T, Arola J, Schalin-Jäntti C, Jaatinen P. Long-term morbidity and mortality in patients diagnosed with an insulinoma. Eur J Endocrinol 2021; 185:577-586. [PMID: 34374651 PMCID: PMC8784472 DOI: 10.1530/eje-21-0230] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 08/06/2021] [Indexed: 11/08/2022]
Abstract
OBJECTIVE Insulinomas are rare functional pancreatic neuroendocrine tumours. As previous data on the long-term prognosis of insulinoma patients are scarce, we studied the morbidity and mortality in the Finnish insulinoma cohort. DESIGN Retrospective cohort study. METHODS Incidence of endocrine, cardiovascular, gastrointestinal and psychiatric disorders, and cancers was compared in all the patients diagnosed with an insulinoma in Finland during 1980-2010 (n = 79, including two patients with multiple endocrine neoplasia type 1 syndrome), vs 316 matched controls, using the Mantel-Haenszel method. Overall survival was analysed with Kaplan-Meier and Cox regression analyses. RESULTS The median length of follow-up was 10.7 years for the patients and 12.2 years for the controls. The long-term incidence of atrial fibrillation (rate ratio (RR): 2.07 (95% CI: 1.02-4.22)), intestinal obstruction (18.65 (2.09-166.86)), and possibly breast (4.46 (1.29-15.39) and kidney cancers (RR not applicable) was increased among insulinoma patients vs controls, P < 0.05 for all comparisons. Endocrine disorders and pancreatic diseases were more frequent in the patients during the first year after insulinoma diagnosis, but not later on. The survival of patients with a non-metastatic insulinoma (n = 70) was similar to that of controls, but for patients with distant metastases (n = 9), the survival was significantly impaired (median 3.4 years). CONCLUSIONS The long-term prognosis of patients with a non-metastatic insulinoma is similar to the general population, except for an increased incidence of atrial fibrillation, intestinal obstruction, and possibly breast and kidney cancers. These results need to be confirmed in future studies. Metastatic insulinomas entail a markedly decreased survival.
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Affiliation(s)
- Elina Peltola
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Division of Internal Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland
- Correspondence should be addressed to E Peltola;
| | - Päivi Hannula
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Endocrinology, Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Heini Huhtala
- Faculty of Social Sciences, Tampere University, Tampere, Finland
| | - Saara Metso
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Endocrinology, Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Juhani Sand
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland
| | - Johanna Laukkarinen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland
| | | | - Jukka Sirén
- Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
- Surgery, Abdominal Center, University of Helsinki, Helsinki, Finland
| | - Minna Soinio
- Department of Endocrinology, Division of Medicine, Turku University Hospital, Turku, Finland
| | - Pirjo Nuutila
- Department of Endocrinology, Division of Medicine, Turku University Hospital, Turku, Finland
- Turku PET Centre, University of Turku, Turku, Finland
| | - Leena Moilanen
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
| | | | - Tapani Ebeling
- Faculty of Medicine, University of Oulu, Oulu, Finland
- Endocrinology, Department of Medicine, Oulu University Hospital, Oulu, Finland
| | - Johanna Arola
- Pathology, HUSLAB, Helsinki University Hospital, Helsinki, Finland
- Pathology, University of Helsinki, Helsinki, Finland
| | - Camilla Schalin-Jäntti
- Endocrinology, Abdominal Center
- Endocrinology, Abdominal Center, University of Helsinki, Helsinki, Finland
| | - Pia Jaatinen
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Division of Internal Medicine, Seinäjoki Central Hospital, Seinäjoki, Finland
- Endocrinology, Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
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23
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Febrero B, Segura P, Ruiz-Manzanera JJ, Teruel E, Ros I, Ríos A, Hernández AM, Rodríguez JM. Uncommon tumors in multiple endocrine neoplasia (MEN) type 1: Do they have a relationship with the prognosis of these patients? J Endocrinol Invest 2021; 44:1327-1330. [PMID: 32909176 DOI: 10.1007/s40618-020-01414-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 08/31/2020] [Indexed: 10/23/2022]
Abstract
INTRODUCTION The prognosis of MEN 1 patients is not only determined by pancreatic disease; it is also related to other uncommon tumors. The objective of this study is to analyze the tumors associated with MEN 1 outside the classic triad and to investigate their relationship with mortality. MATERIALS AND METHODS One hundred and five MEN 1 patients were studied in a tertiary referral hospital (1980-2019). RESULTS With a follow-up of 11 ± 4 years, seven patients died (8%), four as a consequence MEN syndrome. Thirty-three percent had adrenal gland tumors. One patient died of adrenal cancer. Eight percent presented with a neuroendocrine thoracic neoplasm, and one patient died. Another patient died due to cutaneous T-cell lymphoma. A further patient died because of a gastrinoma with liver metastasis. CONCLUSIONS To conclude, 75% of MEN-related deaths were the result of an uncommon pathology, and we, therefore, recommend that these tumors should be taken into account in the screening and follow-up of these patients.
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Affiliation(s)
- B Febrero
- General Surgery Service, Endocrine Surgery Unit, Instituto Murciano de Investigación Biosanitaria (IMIB), Virgen de La Arrixaca University Hospital, Crta./Madrid-Cartagena, S/N, 30120, El Palmar, Murcia, Spain.
| | - P Segura
- Endocrinology Service, Virgen de la Arrixaca University Hospital, 30120, Murcia, Spain
| | - J J Ruiz-Manzanera
- General Surgery Service, Endocrine Surgery Unit, Instituto Murciano de Investigación Biosanitaria (IMIB), Virgen de La Arrixaca University Hospital, Crta./Madrid-Cartagena, S/N, 30120, El Palmar, Murcia, Spain
| | - E Teruel
- Maxillofacial Surgery Service, Virgen de la Arrixaca University Hospital, 30120, Murcia, Spain
| | - I Ros
- General Surgery Service, Endocrine Surgery Unit, Instituto Murciano de Investigación Biosanitaria (IMIB), Virgen de La Arrixaca University Hospital, Crta./Madrid-Cartagena, S/N, 30120, El Palmar, Murcia, Spain
| | - A Ríos
- General Surgery Service, Endocrine Surgery Unit, Instituto Murciano de Investigación Biosanitaria (IMIB), Virgen de La Arrixaca University Hospital, Crta./Madrid-Cartagena, S/N, 30120, El Palmar, Murcia, Spain
| | - A M Hernández
- Endocrinology Service, Virgen de la Arrixaca University Hospital, 30120, Murcia, Spain
| | - J M Rodríguez
- General Surgery Service, Endocrine Surgery Unit, Instituto Murciano de Investigación Biosanitaria (IMIB), Virgen de La Arrixaca University Hospital, Crta./Madrid-Cartagena, S/N, 30120, El Palmar, Murcia, Spain
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24
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Kfir SK, Halperin R, Percik R, Uri I, Halpern N, Shlomai G, Laish I, Tirosh A, Tirosh A. Distinct Prognostic Factors in Sporadic and Multiple Endocrine Neoplasia Type 1-Related Pancreatic Neuroendocrine Tumors. Horm Metab Res 2021; 53:319-325. [PMID: 33878789 DOI: 10.1055/a-1464-1276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Pancreatic neuroendocrine tumors (PNET) may develop sporadically or in the context of hereditary syndromes. In patients with multiple endocrine neoplasia type 1 (MEN1), PNET is the leading cause of death. Our aim was to compare the mortality risk in sporadic and MEN1-related PNETs and identify high-risk populations. A retrospective Surveillance, Epidemiology, and End Results database analysis of patients with PNET was used. Patients with MEN1 were defined by syn/metachronous pituitary adenoma. Clinical data were retrieved, and all-cause mortality (ACM) risk was compared in univariate and multivariable analyses. The cohort included 569 patients (46.6% males) with sporadic (n=542) and MEN1-related (n=27) PNETs. Age at diagnosis of MEN1-related PNET was significantly younger than with sporadic PNETs (mean age 49.2±16.7 vs. 61.6±12.7 years, respectively; p < 0.001). Survival analysis showed a trend for a better outcome in patients with MEN1-related vs. sporadic PNET (Log-rank, p=0.09) and in subgroup analysis for patients with advanced disease (p=0.08). Furthermore, among patients followed expectantly, those with MEN1-related PNET had lower ACM risk than their sporadic counterparts (p=0.08). Multivariable analysis demonstrated lower ACM risk in patients diagnosed with MEN1 (hazard ratio 0.35, 95% confidence interval 0.11-1.2, p=0.09), further supporting the trend detected in the univariate analysis. In conclusion, our study demonstrates the distinct clinical profile of patients with MEN1-related PNET compared to sporadic disease and emphasizes the expertise required to accurately manage patients with PNET in this rare context. The cautious decision-making required before embarking on surgical intervention is further emphasized in this robust analysis of a large cancer database.
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Affiliation(s)
- Sapir Kon Kfir
- Department of Internal Medicine D, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
| | - Reut Halperin
- Department of Internal Medicine D, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
- Division of Endocrinology and Metabolism, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
| | - Ruth Percik
- Division of Endocrinology and Metabolism, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
- Endo-oncology Clinic, Cancer Center, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Inbal Uri
- Division of Endocrinology and Metabolism, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
- Endo-oncology Clinic, Cancer Center, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Naama Halpern
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- GI Unit, Cancer Center, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
| | - Gadi Shlomai
- Department of Internal Medicine D, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
- Division of Endocrinology and Metabolism, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ido Laish
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Gastroenterology Institute, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
| | - Amir Tirosh
- Division of Endocrinology and Metabolism, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Amit Tirosh
- Division of Endocrinology and Metabolism, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Neuroendocrine Tumors Service, Sheba Medical Center at Tel Hashomer, Tel Hashomer, Israel
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25
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Geslot A, Vialon M, Caron P, Grunenwald S, Vezzosi D. New therapies for patients with multiple endocrine neoplasia type 1. ANNALES D'ENDOCRINOLOGIE 2021; 82:112-120. [PMID: 33839123 DOI: 10.1016/j.ando.2021.03.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Revised: 03/18/2021] [Accepted: 03/26/2021] [Indexed: 02/06/2023]
Abstract
In 1953, for the first time, Paul Wermer described a family presenting endocrine gland neoplasms over several generations. The transmission was autosomal dominant and the penetrance was high. Forty years later in 1997, the multiple endocrine neoplasia type 1 (MEN1) gene was sequenced, thus enabling diagnosis and early optimal treatment. Patients carrying the MEN1 gene present endocrine but also non-endocrine tumors. Parathyroid, pancreatic and pituitary impairment are the three main types of endocrine involvement. The present article details therapeutic management of hyperparathyroidism, neuroendocrine pancreatic tumors and pituitary adenomas in patients carrying the MEN1 gene. Significant therapeutic progress has in fact been made in the last few years. As concerns the parathyroid glands, screening of family members and regular monitoring of affected subjects now raise the question of early management of parathyroid lesions and optimal timing of parathyroid surgery. As concerns the duodenum-pancreas, proton-pump inhibitors are able to control gastrin-secreting syndrome, reducing mortality in MEN1 patients. Mortality in MEN1 patients is no longer mainly secondary to uncontrolled hormonal secretion but to metastatic (mainly pancreatic) disease progression. Tumor risk requires regular monitoring of morphological assessment, leading to iterative pancreatic surgery in a large number of patients. Finally, pituitary adenomas in MEN1 patients are traditionally described as aggressive, invasive and resistant to medical treatment. However, regular pituitary screening showed them to be in fact infra-centimetric and non-secreting in the majority of patients. Consequently, it is necessary to regularly monitor MEN1 patients, with regular clinical, biological and morphological work-up. Several studies showed that this regular monitoring impairs quality of life. Building a relationship of trust between patients and care provider is therefore essential. It enables the patient to be referred for psychological or psychiatric care in difficult times, providing long-term support and preventing any breakdown in continuity of care.
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Affiliation(s)
- Aurore Geslot
- Service d'endocrinologie, hôpital Larrey, 24, chemin de Pouvourville, 31029 Toulouse cedex 9, France
| | - Magaly Vialon
- Service d'endocrinologie, hôpital Larrey, 24, chemin de Pouvourville, 31029 Toulouse cedex 9, France
| | - Philippe Caron
- Service d'endocrinologie, hôpital Larrey, 24, chemin de Pouvourville, 31029 Toulouse cedex 9, France
| | - Solange Grunenwald
- Service d'endocrinologie, hôpital Larrey, 24, chemin de Pouvourville, 31029 Toulouse cedex 9, France
| | - Delphine Vezzosi
- Institut CardioMet, Toulouse, France; Service d'endocrinologie, hôpital Larrey, 24, chemin de Pouvourville, 31029 Toulouse cedex 9, France.
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26
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Al-Salameh A, Cadiot G, Calender A, Goudet P, Chanson P. Clinical aspects of multiple endocrine neoplasia type 1. Nat Rev Endocrinol 2021; 17:207-224. [PMID: 33564173 DOI: 10.1038/s41574-021-00468-3] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/07/2021] [Indexed: 01/31/2023]
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a rare syndrome characterized by the co-occurrence of primary hyperparathyroidism, duodenopancreatic neuroendocrine tumours (NETs) and/or pituitary adenomas. MEN1 can predispose patients to other endocrine and non-endocrine tumours, such as cutaneous tumours, central nervous system tumours and breast cancer. Endocrine tumours in patients with MEN1 differ from sporadic tumours in that they have a younger age at onset, present as multiple tumours in the same organ and have a different clinical course. Therefore, patients with overt MEN1 and those who carry a MEN1 mutation should be offered tailored biochemical and imaging screening to detect tumours and evaluate their progression over time. Fortunately, over the past 10 years, knowledge about the clinical phenotype of these tumours has markedly progressed, thanks to the implementation of national registries, particularly in France and the Netherlands. This Review provides an update on the clinical management of MEN1-related tumours. Epidemiology, the clinical picture, diagnostic work-up and the main lines of treatment for MEN1-related tumours are summarized. Controversial therapeutic aspects and issues that still need to be addressed are also discussed. Moreover, special attention is given to MEN1 manifestations in children and adolescents.
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Affiliation(s)
- Abdallah Al-Salameh
- Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, Le Kremlin-Bicêtre, France
- Service d'Endocrinologie, Maladies Métaboliques et Nutrition, CHU Amiens Picardie, Amiens, France
| | - Guillaume Cadiot
- Service d'Hépato-Gastro-Entérologie et de Cancérologie Digestive, Hôpital Robert Debré, Reims, France
| | - Alain Calender
- Unité Médicale des Cancers et Maladies Multifactorielles, Service de Génétique, Hospices Civils de Lyon, Lyon, France
| | - Pierre Goudet
- Service de Chirurgie Endocrinienne, Hôpital du Bocage, Dijon, France
| | - Philippe Chanson
- Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de l'Hypophyse, Le Kremlin-Bicêtre, France.
- Université Paris-Saclay, Inserm, Physiologie et Physiopathologie Endocriniennes, Le Kremlin-Bicêtre, France.
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27
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Brandi ML, Agarwal SK, Perrier ND, Lines KE, Valk GD, Thakker RV. Multiple Endocrine Neoplasia Type 1: Latest Insights. Endocr Rev 2021; 42:133-170. [PMID: 33249439 PMCID: PMC7958143 DOI: 10.1210/endrev/bnaa031] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Indexed: 02/06/2023]
Abstract
Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome that is inherited in an autosomal dominant pattern, is continuing to raise great interest for endocrinology, gastroenterology, surgery, radiology, genetics, and molecular biology specialists. There have been 2 major clinical practice guidance papers published in the past 2 decades, with the most recent published 8 years ago. Since then, several new insights on the basic biology and clinical features of MEN1 have appeared in the literature, and those data are discussed in this review. The genetic and molecular interactions of the MEN1-encoded protein menin with transcription factors and chromatin-modifying proteins in cell signaling pathways mediated by transforming growth factor β/bone morphogenetic protein, a few nuclear receptors, Wnt/β-catenin, and Hedgehog, and preclinical studies in mouse models have facilitated the understanding of the pathogenesis of MEN1-associated tumors and potential pharmacological interventions. The advancements in genetic diagnosis have offered a chance to recognize MEN1-related conditions in germline MEN1 mutation-negative patients. There is rapidly accumulating knowledge about clinical presentation in children, adolescents, and pregnancy that is translatable into the management of these very fragile patients. The discoveries about the genetic and molecular signatures of sporadic neuroendocrine tumors support the development of clinical trials with novel targeted therapies, along with advancements in diagnostic tools and surgical approaches. Finally, quality of life studies in patients affected by MEN1 and related conditions represent an effort necessary to develop a pharmacoeconomic interpretation of the problem. Because advances are being made both broadly and in focused areas, this timely review presents and discusses those studies collectively.
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Affiliation(s)
| | | | - Nancy D Perrier
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Gerlof D Valk
- University Medical Center Utrecht, CX Utrecht, the Netherlands
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28
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Niederle B, Selberherr A, Bartsch DK, Brandi ML, Doherty GM, Falconi M, Goudet P, Halfdanarson TR, Ito T, Jensen RT, Larghi A, Lee L, Öberg K, Pavel M, Perren A, Sadowski SM, Tonelli F, Triponez F, Valk GD, O'Toole D, Scott-Coombes D, Thakker RV, Thompson GB, Treglia G, Wiedenmann B. Multiple Endocrine Neoplasia Type 1 and the Pancreas: Diagnosis and Treatment of Functioning and Non-Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome - An International Consensus Statement. Neuroendocrinology 2021; 111:609-630. [PMID: 32971521 DOI: 10.1159/000511791] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 09/18/2020] [Indexed: 11/19/2022]
Abstract
The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. Duodenopancreatic neuroendocrine neoplasias (DP-NENs) are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to reevaluate recommendations for their diagnosis and treatment. Especially over the last 2 years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology, and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a "logbook" for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and international societies.
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Affiliation(s)
- Bruno Niederle
- Department of Surgery, Medical University of Vienna, Vienna, Austria,
| | | | - Detlef K Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Maria L Brandi
- Firmo Lab, Fondazione F.I.R.M.O. and University Florence, Florence, Italy
| | - Gerard M Doherty
- Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Massimo Falconi
- Pancreatic Surgery, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy
| | - Pierre Goudet
- Service de Chirurgie Viscérale et Endocrinienne, Centre Hospitalier Universitaire François Mitterand, Dijon, France
| | | | - Tetsuhide Ito
- Neuroendocrine Tumor Centre, Fukuoka Sanno Hospital and Department of Gastroenterology, Graduate School of Medical Sciences, International University of Health and Welfare, Sawara-ku, Fukuoka, Japan
| | - Robert T Jensen
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Alberto Larghi
- Digestive Endoscopy Unit, Fondazione Policlinico A. Gemelli IRCCS and Center for Endoscopic Research, Therapeutics and Training, Catholic University, Rome, Italy
| | - Lingaku Lee
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Kjell Öberg
- Endocrine Oncology, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden
| | - Marianne Pavel
- Endocrinology and Diabetology, Department of Medicine 1, University Clinic of Erlangen, Erlangen, Germany
| | - Aurel Perren
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Samira M Sadowski
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Francesco Tonelli
- Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
| | - Frédéric Triponez
- Thoracic and Endocrine Surgery, University Hospital of Geneva, Geneva, Switzerland
| | - Gerlof D Valk
- Department of Endocrine Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Dermot O'Toole
- Department of Clinical Medicine, St. James's Hospital and St Vincent's University Hospital and Trinity College, Dublin, Ireland
| | - David Scott-Coombes
- Department of Endocrine Surgery, University Hospital of Wales, Cardiff, United Kingdom
| | - Rajesh V Thakker
- Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, United Kingdom
| | - Geoffrey B Thompson
- Section of Endocrine Surgery, Department of Gastroenterologic and General Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Giorgio Treglia
- Imaging Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Bertram Wiedenmann
- Department of Gastroenterology and Hepatology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
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29
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Maria BC, Quadros AC, Alves N, Coutinho J. Incidental finding of MEN-1 syndrome during staging and follow-up of breast carcinoma. BMJ Case Rep 2020; 13:13/12/e238784. [PMID: 33370954 PMCID: PMC7754650 DOI: 10.1136/bcr-2020-238784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Type 1 multiple endocrine neoplasia (MEN-1) syndrome is an autosomal dominant disease, associated with germline mutations in the MEN-1 tumour suppressor gene (encoding the menin protein). Recent studies, through a better characterisation of the functions of the menin protein, have started to demonstrate how changes in this protein may be related to breast cancer. We present the case of a patient whose diagnosis of MEN-1 syndrome was made during treatment for a breast tumour-this diagnosis was obtained after finding multiple neoplastic lesions that fitted the MEN-1 syndrome spectrum, during the initial staging and subsequent follow-up of a breast tumour. In line with the growing evidence that links MEN-1 syndrome to breast cancer tumorigenesis, this case report highlights the following question: should we start screening this subset of patients earlier for breast cancer?
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Affiliation(s)
| | | | - Natália Alves
- Surgery, Centro Hospitalar Lisboa Norte EPE, Lisboa, Portugal
| | - João Coutinho
- Surgery, Centro Hospitalar Lisboa Norte EPE, Lisboa, Portugal
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30
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Axillary Hibernoma in woman with Lobular breast cancer and MEN1 syndrome: A case report. Int J Surg Case Rep 2020; 77:834-838. [PMID: 33395907 PMCID: PMC7721659 DOI: 10.1016/j.ijscr.2020.11.073] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 11/11/2020] [Accepted: 11/11/2020] [Indexed: 01/02/2023] Open
Abstract
There is no uniformly accepted indication to perform the correct management of hibernoma. Only the complete surgical resection of the known axillary lesion, could be diagnostic and, in most case, curative. A full multidisciplinary team is essential to focus on all aspects for the management of hibernoma and MEN-1 syndrome. Introduction The present study reports the case of an axillary hibernoma in a patient with lobular homolateral breast cancer and multiple endocrine neoplasia type1 (MEN-1). Hibernoma is a rare benign adipose tissue tumor, and usually manifests as a slowly growing and painless rubbery mass. These tumors can arise in various sites, but mammary hibernomas remain extraordinarily uncommon. Although hibernomas are metabolically active and therefore “glucose-avid” on fluorodeoxyglucose CT-positron emission tomography (FDG CT-PET), imaging alone is inadequate in providing a reliable diagnosis and definitive differential diagnosis from other malignancy. Only complete surgical excision is diagnostic and, in most cases, curative. Presentation of case A 42-years-old woman was followed for MEN-1 syndrome associating with hyperparathyroidism, insulinoma, non-secretory adrenal adenoma and thyroid lump. A FDG CT-PET found high glucid hypermetabolism in thickened elongated area on the front axillary line. Hibernoma was diagnosed after realization of prophylactic left mastectomy, homolateral sentinel lymph node biopsy and exeresis of the known axillary lesion. Discussion Clinical importance lies in distinguishing hibernoma from other benign and malignant breast neoplasms, as well as inflammatory conditions that come into the histologic or radiologic differential. Hibernoma is not currently classified as a non-endocrine tumor related to MEN1, but this association could be not fortuitous for the linkage between modification of Menin protein function and pathogenesis of hibernomas. Conclusion Our case deserves extraordinary attention because, not only it’s a case of MEN1 syndrome associated with hibernoma, but in the context of this lesion there are multiple micro-foci of infiltrating lobular carcinoma.
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Marini F, Giusti F, Tonelli F, Brandi ML. Multiple endocrine neoplasia type 1: a review of current diagnostic and treatment approaches. Expert Opin Orphan Drugs 2020. [DOI: 10.1080/21678707.2020.1811086] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Francesca Marini
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Francesca Giusti
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Francesco Tonelli
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
| | - Maria Luisa Brandi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
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La néoplasie endocrinienne multiple de type 1 : mise au point après le congrès de l’ENETS 2019. ANNALES D'ENDOCRINOLOGIE 2020; 80 Suppl 1:S19-S28. [PMID: 31606058 DOI: 10.1016/s0003-4266(19)30113-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Multiple Endocrine Neoplasia Type 1 (NEM1) is related to mutations of the menin gene. It is an autosomal dominant disease. Its prevalence is about 1/30 000 with a hugh penetrance. There is no genotype-phenotype correlation. This hereditary syndrome is characterized by the presence of tumors of the endocrine system (parathyroid, endocrine pancreas, pituitary and adrenal gland). Other disorders have also been described (bronchial and thymic carcinoid tumor, breast cancer, skin lesions). Management must take into account the specificities of these pathologies in NEM1 compared to sporadic forms (young age at diagnosis, multiple lesions within the same gland, multi-focal disease). © 2019 Published by Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Les Must de l'Endocrinologie 2019 réalisé avec le soutien institutionnel de Ipsen-Pharma.
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Espiard S, Vantyghem MC, Assié G, Cardot-Bauters C, Raverot G, Brucker-Davis F, Archambeaud-Mouveroux F, Lefebvre H, Nunes ML, Tabarin A, Lienhardt A, Chabre O, Houang M, Bottineau M, Stroër S, Groussin L, Guignat L, Cabanes L, Feydy A, Bonnet F, North MO, Dupin N, Grabar S, Duboc D, Bertherat J. Frequency and Incidence of Carney Complex Manifestations: A Prospective Multicenter Study With a Three-Year Follow-Up. J Clin Endocrinol Metab 2020; 105:5698168. [PMID: 31912137 DOI: 10.1210/clinem/dgaa002] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/03/2020] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Carney Complex (CNC) is a rare multiple endocrine and nonendocrine neoplasia syndrome. Manifestations and genotype-phenotype correlations have been described by retrospective studies, but no prospective study evaluating the occurrence of the different manifestations has been available so far. METHODS This multicenter national prospective study included patients with CNC, primary pigmented nodular adrenal disease (PPNAD), or a pathogenic PRKAR1A mutation; after a full initial workup, participants were followed for 3 years with annual standardized evaluation. RESULTS The cohort included 70 patients (50 female/20 male, mean age 35.4 ± 16.7 years, 81% carrying PRKAR1A mutation). The initial investigations allowed identification of several manifestations. At the end of the 3-year follow-up, the newly diagnosed manifestations of the disease were subclinical acromegaly in 6 patients, bilateral testicular calcifications in 1 patient, and cardiac myxomas in 2 patients. Recurrences of cardiac myxomas were diagnosed in 4 patients during the 3-year follow-up study period. Asymptomatic abnormalities of the corticotroph and somatotroph axis that did not meet criteria of PPNAD and acromegaly were observed in 11.4% and 30% of the patients, respectively. Patients carrying the PRKAR1A c.709-7del6 mutation had a mild phenotype. CONCLUSION This study underlines the importance of a systematic follow-up of the CNC manifestations, especially a biannual screening for cardiac myxoma. By contrast, regular screening for the other manifestations after a first extensive workup could be spread out, leading to a lighter and more acceptable follow-up schedule for patients. These are important results for recommendations for long-term management of CNC patients.
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Affiliation(s)
- Stéphanie Espiard
- INSERM U1016, CNRS UMR8104, Institut Cochin, Université Paris Descartes, Paris
- Service d'Endocrinologie, Centre de référence des maladies rares de la surrénale, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
- Service d'endocrinologie, diabétologie, métabolisme et nutrition, CHR-U de Lille, Hôpital Huriez, Lille, France
| | - Marie-Christine Vantyghem
- Service d'endocrinologie, diabétologie, métabolisme et nutrition, CHR-U de Lille, Hôpital Huriez, Lille, France
| | - Guillaume Assié
- INSERM U1016, CNRS UMR8104, Institut Cochin, Université Paris Descartes, Paris
- Service d'Endocrinologie, Centre de référence des maladies rares de la surrénale, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
| | - Catherine Cardot-Bauters
- Service d'endocrinologie, diabétologie, métabolisme et nutrition, CHR-U de Lille, Hôpital Huriez, Lille, France
| | - Gerald Raverot
- Fédération d'endocrinologie, groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
| | - Françoise Brucker-Davis
- Service d'endocrinologie, diabétologie et médecine de la reproduction, CHU de Nice, Nice, France
| | | | - Hervé Lefebvre
- Service d'endocrinologie, diabète et maladie métabolique, CHU de Rouen, Rouen, France
| | - Marie-Laure Nunes
- Service d'endocrinologie, diabétologie et maladies métaboliques, Faculté de médecine Bordeaux-Victor-Ségalen, CHU de Bordeaux, Hôpital Haut-Lévêque, Pessac, France
| | - Antoine Tabarin
- Service d'endocrinologie, diabétologie et maladies métaboliques, Faculté de médecine Bordeaux-Victor-Ségalen, CHU de Bordeaux, Hôpital Haut-Lévêque, Pessac, France
| | | | - Olivier Chabre
- Service d'Endocrinologie, CHU Grenoble Alpes and Université Grenoble Alpes, Grenoble, France
| | - Muriel Houang
- Service d'endocrinologie pédiatrique, CHU Paris Est, Hôpital d'Enfants Armand-Trousseau, Paris, France
| | - Muriel Bottineau
- Université Paris Descartes, Sorbonne Paris Cité AP-HP, Unité de Biostatistique et Epidémiologie, Groupe Hospitalier Cochin Broca Hôtel-Dieu, Paris, France
| | - Sebastian Stroër
- Service de Radiologie B, AP-HP, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, Paris, France
| | - Lionel Groussin
- INSERM U1016, CNRS UMR8104, Institut Cochin, Université Paris Descartes, Paris
- Service d'Endocrinologie, Centre de référence des maladies rares de la surrénale, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
| | - Laurence Guignat
- Service d'Endocrinologie, Centre de référence des maladies rares de la surrénale, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
| | - Laure Cabanes
- Service de Cardiologie, Hôpital Cochin, APHP, Université Paris Descartes-Sorbonne Paris Cité, Paris, France
| | - Antoine Feydy
- Service de Radiologie B, AP-HP, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, Paris, France
| | - Fidéline Bonnet
- Service d'Hormonologie, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
| | - Marie Odile North
- Service d'Oncogénétique, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
| | - Nicolas Dupin
- Service de Dermatologie, Hôpital Cochin, Assistance publique - Hôpitaux de Paris, Paris, France
| | - Sophie Grabar
- Université Paris Descartes, Sorbonne Paris Cité AP-HP, Unité de Biostatistique et Epidémiologie, Groupe Hospitalier Cochin Broca Hôtel-Dieu, Paris, France
| | - Denis Duboc
- Service de Cardiologie, Hôpital Cochin, APHP, Université Paris Descartes-Sorbonne Paris Cité, Paris, France
| | - Jérôme Bertherat
- INSERM U1016, CNRS UMR8104, Institut Cochin, Université Paris Descartes, Paris
- Service d'Endocrinologie, Centre de référence des maladies rares de la surrénale, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris, France
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Mele C, Mencarelli M, Caputo M, Mai S, Pagano L, Aimaretti G, Scacchi M, Falchetti A, Marzullo P. Phenotypes Associated With MEN1 Syndrome: A Focus on Genotype-Phenotype Correlations. Front Endocrinol (Lausanne) 2020; 11:591501. [PMID: 33312161 PMCID: PMC7708377 DOI: 10.3389/fendo.2020.591501] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 10/16/2020] [Indexed: 12/21/2022] Open
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited tumor syndrome, associated with parathyroid, pituitary, and gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs). MEN1 is usually consequent to different germline and somatic mutations of the MEN1 tumor suppressor gene, although phenocopies have also been reported. This review analyzed main biomedical databases searching for reports on MEN1 gene mutations and focused on aggressive and aberrant clinical manifestations to investigate the potential genotype-phenotype correlation. Despite efforts made by several groups, this link remains elusive to date and evidence that aggressive or aberrant clinical phenotypes may be related to specific mutations has been provided by case reports and small groups of MEN1 patients or families. In such context, a higher risk of aggressive tumor phenotypes has been described in relation to frameshift and non-sense mutations, and predominantly associated with aggressive GEP NETs, particularly pancreatic NETs. In our experience a novel heterozygous missense mutation at c.836C>A in exon 6 was noticed in a MEN1 patient operated for macro-prolactinoma, who progressively developed recurrent parathyroid adenomas, expanding gastrinomas and, long after the first MEN1 manifestation, a neuroendocrine uterine carcinoma. In conclusion, proof of genotype-phenotype correlation is limited but current evidence hints at the need for long-term interdisciplinary surveillance in patients with aggressive phenotypes and genetically confirmed MEN1.
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Affiliation(s)
- Chiara Mele
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
- Istituto Auxologico Italiano, IRCCS, Division of General Medicine, S. Giuseppe Hospital, Piancavallo, Italy
| | - Monica Mencarelli
- Istituto Auxologico Italiano, IRCCS, Laboratory of Molecular Biology, S. Giuseppe Hospital, Piancavallo, Italy
| | - Marina Caputo
- Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
| | - Stefania Mai
- Istituto Auxologico Italiano, IRCCS, Laboratory of Metabolic Research, S. Giuseppe Hospital, Piancavallo, Italy
| | - Loredana Pagano
- Division of Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
| | - Gianluca Aimaretti
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
- Division of Endocrinology, University Hospital “Maggiore della Carità”, Novara, Italy
| | - Massimo Scacchi
- Istituto Auxologico Italiano, IRCCS, Division of General Medicine, S. Giuseppe Hospital, Piancavallo, Italy
| | - Alberto Falchetti
- Istituto Auxologico Italiano, IRCCS, Rehabilitation Unit, S. Giuseppe Hospital, Unit for Bone Metabolism Diseases, Verbania, Italy
- Diabetes & Lab of Endocrine and Metabolic Research, Dept. of Clinical Sciences & Community Health, University of Milan, Milan, Italy
| | - Paolo Marzullo
- Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
- Istituto Auxologico Italiano, IRCCS, Division of General Medicine, S. Giuseppe Hospital, Piancavallo, Italy
- *Correspondence: Paolo Marzullo,
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Larouche V, Akirov A, Thain E, Kim RH, Ezzat S. Co-occurrence of breast cancer and neuroendocrine tumours: New genetic insights beyond Multiple Endocrine Neoplasia syndromes. Endocrinol Diabetes Metab 2019; 2:e00092. [PMID: 31592449 PMCID: PMC6775469 DOI: 10.1002/edm2.92] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 08/16/2019] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Age-standardized incidence of female breast cancer is 145.1 per 100000/year and 5.86 per 100000/year for neuroendocrine tumours (NET) in Canada. Evidence is scarce about gene variants that may predispose patients to develop both neoplasms. The objective of this study was to identify germline gene variants associated with this combination of tumours. DESIGN AND PATIENTS A retrospective chart review (2007-2018) in a tertiary NET referral centre was completed. A series of 9 female patients with concurrent breast cancer and NET is presented. All patients underwent a 37 gene hereditary cancer next-generation sequencing panel. RESULTS Mean age was 61.4 years (35-85) at breast cancer diagnosis and 63.4 years (51-89) at NET diagnosis. Four patients had a pancreatic, three had a small bowel and two had a lung NET. Two patients were known cases of MEN1, and one patient was found to harbour a pathogenic variant in MEN1 and a variant of unknown significance (VUS) in ATM. A second patient was found to harbour a pathogenic variant in APC. A third patient was found to carry a pathogenic variant in PALB2 as well as a VUS in FANCM, MLH1 and STK11. Another patient was found to harbour a VUS in MSH2. One patient was found to carry a pathogenic variant in NTHL1. CONCLUSION The first cases of a PALB2, an APC and a NTHL1 pathogenic variants in patients with both breast cancer and NET were presented. NGS testing should be considered in specific patients with this combination of neoplasms, as certain germline variants beyond MEN1, have important implications for cancer surveillance.
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Affiliation(s)
- Vincent Larouche
- Division of Endocrinology and MetabolismDepartment of MedicineUniversity Health NetworkUniversity of TorontoTorontoOntarioCanada
- Division of Endocrinology and MetabolismJewish General HospitalMcGill UniversityMontrealQuebecCanada
| | - Amit Akirov
- Division of Endocrinology and MetabolismDepartment of MedicineUniversity Health NetworkUniversity of TorontoTorontoOntarioCanada
| | - Emily Thain
- Familial Cancer ClinicPrincess Margaret Cancer CentreUniversity Health NetworkTorontoOntarioCanada
| | - Raymond H. Kim
- Fred A Litwin Family Centre in Genetic MedicineUniversity Health NetworkTorontoOntarioCanada
- Division of Medical OncologyDepartment of MedicineUniversity of TorontoTorontoOntarioCanada
| | - Shereen Ezzat
- Division of Endocrinology and MetabolismDepartment of MedicineUniversity Health NetworkUniversity of TorontoTorontoOntarioCanada
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Harada K, Yasuda M, Hasegawa K, Yamazaki Y, Sasano H, Otsuka F. A novel case of myxoid variant of adrenocortical carcinoma in a patient with multiple endocrine neoplasia type 1. Endocr J 2019; 66:739-744. [PMID: 31118348 DOI: 10.1507/endocrj.ej19-0067] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Adrenocortical carcinoma (ACC) is a rare malignancy arising from adrenocortical parenchymal cells. Myxoid ACC is one of the newly identified, rare, but important histological variants of ACC, characterized by the presence of abundant extracellular Alcian Blue-positive myxoid material. Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant cancer predisposition syndrome, and the incidence of ACC in MEN1 patients has been reported to be between 1.4% and 6%. Here, we report the case of a 68-year-old Japanese woman harboring the past history of MEN1 associated with insulinoma, pituitary tumor, and hyperparathyroidism. She presented to our hospital with hypertension and hypokalemia. Imaging studies revealed a right adrenal tumor, and histological examination revealed myxoid ACC. Despite surgical resection of the tumor and mitotane therapy, the patient died 6 months after the surgery. To the best of our knowledge, this is the first reported case of the myxoid variant of ACC in a patient with MEN1. The patient's clinical course was characterized by the development of both multiple endocrine and non-endocrine neoplasm, hyperaldosteronism, and aggressive biological behavior. This case confirmed that myxoid morphology was also associated with aggressive behavior in ACC, but further studies are required to clarify the association between MEN1 and myxoid ACC.
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Affiliation(s)
- Ko Harada
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Miho Yasuda
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Kou Hasegawa
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Yuto Yamazaki
- Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Miyagi 980-8575, Japan
| | - Hironobu Sasano
- Department of Anatomic Pathology, Tohoku University Graduate School of Medicine, Miyagi 980-8575, Japan
| | - Fumio Otsuka
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
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Valk G. Update on phenotypes of MEN1 mutation carriers. ANNALES D'ENDOCRINOLOGIE 2019; 80:193-194. [DOI: 10.1016/j.ando.2019.04.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Kim SH, Park JH. ADRENAL INCIDENTALOMA, BREAST CANCER AND UNRECOGNIZED MULTIPLE ENDOCRINE NEOPLASIA TYPE 1. ACTA ENDOCRINOLOGICA-BUCHAREST 2019; 15:513-517. [PMID: 32377250 DOI: 10.4183/aeb.2019.513] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Background The incidence of adrenal incidentaloma has been increasing proportional to the use of radiologic examination. Multiple endocrine neoplasia1 (MEN1) syndrome may present with various tumors. The present study reports a case of adrenal incidentaloma with unrecognised MEN1 syndrome associated with breast cancer. Clinical case A 48-year-old woman presented with a 2.4cm left adrenal incidentaloma on abdominal computed tomography. Her history revealed primary amenorrhea, recurrent peptic ulcer and nephrolithiasis. Laboratory and radiologic examination revealed two pancreatic tail mass lesions with markedly elevated gastrin levels (1462 pg/mL), hypercalcemia with increased parathyroid hormone levels (72 pg/mL), a 1.5cm pituitary mass with hyperprolactinemia (234 ng/mL), a 1.0cm meningioma and a nonfunctional left adrenal mass. During this image work up, a 0.6cm nodule in the right breast was incidentally detected. Surgeries (laparoscopic distal pancreatectomy, parathyroidectomy and wide local excision of breast) and pathologic findings confirmed pancreatic neuroendocrine tumors, parathyroid gland hyperplasia, and breast cancer. Carbergoline treatment for 12 months decreased prolactin levels to 27 ng/mL. Genetic testing using peripheral blood revealed a pathogenic variant in MEN1 on chr11q13 (NM_000244.3:c.1365+1_1365+11 del, GTGAGGGACAG, heterozygous). Conclusion Considering the increasing incidence of adrenal incidentaloma and 20% prevalence of adrenal tumors in patients with MEN1, it is important to rule out MEN1 association in patients with adrenal incidentaloma. Additionally, breast cancer was detected during MEN1 work-up in this case. Female patients with MEN1 are at increased risk for breast cancer. Therefore, intensified breast cancer screening at a relatively young age should be considered in female MEN1 patients.
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Affiliation(s)
- S H Kim
- Presbyterian Medical Center - Department of Internal Medicine, Jeonju, Republic of Korea
| | - J H Park
- Jeonbuk National University Medical School - Department of Internal Medicine, Jeonju, Republic of Korea
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Kamilaris CDC, Stratakis CA. Multiple Endocrine Neoplasia Type 1 (MEN1): An Update and the Significance of Early Genetic and Clinical Diagnosis. Front Endocrinol (Lausanne) 2019; 10:339. [PMID: 31263451 PMCID: PMC6584804 DOI: 10.3389/fendo.2019.00339] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 05/10/2019] [Indexed: 12/21/2022] Open
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a rare hereditary tumor syndrome inherited in an autosomal dominant manner and characterized by a predisposition to a multitude of endocrine neoplasms primarily of parathyroid, enteropancreatic, and anterior pituitary origin, as well as nonendocrine neoplasms. Other endocrine tumors in MEN1 include foregut carcinoid tumors, adrenocortical tumors, and rarely pheochromocytoma. Nonendocrine manifestations include meningiomas and ependymomas, lipomas, angiofibromas, collagenomas, and leiomyomas. MEN1 is caused by inactivating mutations of the tumor suppressor gene MEN1 which encodes the protein menin. This syndrome can affect all age groups, with 17% of patients developing MEN1-associated tumors before 21 years of age. Despite advances in the diagnosis and treatment of MEN1-associated tumors, patients with MEN1 continue to have decreased life expectancy primarily due to malignant neuroendocrine tumors. The most recent clinical practice guidelines for MEN1, published in 2012, highlight the need for early genetic and clinical diagnosis of MEN1 and recommend an intensive surveillance approach for both patients with this syndrome and asymptomatic carriers starting at the age of 5 years with the goal of timely detection and management of MEN1-associated neoplasms and ultimately decreased disease-specific morbidity and mortality. Unfortunately, there is no clear genotype-phenotype correlation and individual mutation-dependent surveillance is not possible currently.
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van Beek DJ, van Leeuwaarde RS, Pieterman CRC, Vriens MR, Valk GD. 'Quality in, quality out', a stepwise approach to EBM for rare diseases promoted by MEN1. Endocr Connect 2018; 7:/journals/ec/aop/ec-18-0359.xml. [PMID: 30352412 PMCID: PMC6215791 DOI: 10.1530/ec-18-0359] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 09/13/2018] [Indexed: 12/20/2022]
Abstract
Rare diseases pose specific challenges in the field of medical research to provide physicians with evidence based guidelines derived from studies with sufficient quality. An example of these rare diseases is multiple endocrine neoplasia type 1 (MEN1), which is an autosomal dominant endocrine tumor syndrome with an estimated occurrence rate of 2-3 per 100.000. For this complex disease, characterized by multiple endocrine tumors, it proves difficult to perform both adequate and feasible studies. The opinion of patients themselves is of utmost importance to identify the gaps in the evidence based medicine regarding clinical care. In the search for scientific answers to clinical research questions, the aim for best available evidence is obvious. Observational studies within patient cohorts, although prone to bias, seem the most feasible study design regarding the disease prevalence. Knowledge and adaptation to all types of bias is demanded in the strive for answers. Guided by our research on MEN1 patients, we elaborate on strategies to identify sufficient patients, to maximize and maintain patient enrollment and to standardize the data collection process. Preferably, data collection is performed prospectively, however, under certain conditions data storage in a longitudinal retrospective database with a disease-specific framework is suitable. Considering the global challenges on observational research on rare diseases, we propose a stepwise approach from clinical research questions to scientific answers.
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Affiliation(s)
- Dirk-Jan van Beek
- Department of Endocrine Surgical OncologyUniversity Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Carolina R C Pieterman
- Department of Endocrine OncologyUniversity Medical Center Utrecht, Utrecht, The Netherlands
| | - Menno R Vriens
- Department of Endocrine Surgical OncologyUniversity Medical Center Utrecht, Utrecht, The Netherlands
| | - Gerlof D Valk
- Department of Endocrine OncologyUniversity Medical Center Utrecht, Utrecht, The Netherlands
- Parelsnoer InstituteUtrecht, The Netherlands
| | - the DutchMEN Study Group
- Department of Endocrine Surgical OncologyUniversity Medical Center Utrecht, Utrecht, The Netherlands
- Department of Endocrine OncologyUniversity Medical Center Utrecht, Utrecht, The Netherlands
- Parelsnoer InstituteUtrecht, The Netherlands
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Herranz-Antolín S, Gil-García S, Álvarez-de Frutos V. Multiple endocrine neoplasia type 1 and breast cancer. An association to consider. ACTA ACUST UNITED AC 2018; 65:468-469. [PMID: 29910161 DOI: 10.1016/j.endinu.2018.05.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 04/30/2018] [Accepted: 05/06/2018] [Indexed: 11/17/2022]
Affiliation(s)
- Sandra Herranz-Antolín
- Sección de Endocrinología y Nutrición, Hospital Universitario de Guadalajara, Guadalajara, España.
| | - Saray Gil-García
- Centro de Salud de Azuqueca de Henares, Gerencia de Atención Integrada de Guadalajara, Azuqueca de Henares, Guadalajara, España
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It's raining MEN: Putting order to multiple endocrine neoplasms. ACTA ACUST UNITED AC 2018; 65:245-246. [PMID: 29706177 DOI: 10.1016/j.endinu.2018.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Accepted: 03/22/2018] [Indexed: 11/21/2022]
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Marx SJ. Recent Topics Around Multiple Endocrine Neoplasia Type 1. J Clin Endocrinol Metab 2018; 103:1296-1301. [PMID: 29897580 PMCID: PMC6276662 DOI: 10.1210/jc.2017-02340] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 02/02/2018] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Multiple endocrine neoplasia type 1 (MEN1) is complex with regard to clinical expressions, management, and molecular pathways. Advances are being made broadly and in focused aspects. Selected topics are presented for their developments since publication of the most recent MEN1 consensus guidelines 6 years ago. METHODS Topics were selected for clinical impact or broad interest or both. For each topic, information was obtained from original reports and reviews. RESULTS The selected topics are as follows: tumor behavior and breast cancer in MEN1; foregut neuroectoderm tumor screening, biomarkers periodically to detect tumor emergence of foregut neuroectoderm tumors, 68Ga dotatate positron emission tomography/computed tomography for pancreatic and duodenal neuroectodermal tumor imaging, and glucagon-like peptide-1 receptor scintigraphy for insulinoma; therapy, the size of pancreatic neuroendocrine tumor (NET) as one criterion for surgery, minimally invasive surgery of pancreatic NETs, and 177Lu dotatate therapy; MEN1 gene, the search for the MEN1/menin pathway and MEN1 or GCM2 mutation in familial isolated hyperparathyroidism, and MEN1 mutation-positive vs mutation-negative cases of MEN1 are different. CONCLUSIONS MEN1 topics are a rich and fast-moving area. Important highlights stand out, and major and rapid advances will continue into the near future.
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Affiliation(s)
- Stephen J Marx
- Eunice Kennedy Shriver National Institute of Child Health and Human
Development, National Institutes of Health, Bethesda, Maryland
- Correspondence and Reprint Requests: Stephen J. Marx, MD, 5402 Trent Street, Chevy Chase, Maryland 20815. E-mail:
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Manoharan J, Albers MB, Bartsch DK. The future: diagnostic and imaging advances in MEN1 therapeutic approaches and management strategies. Endocr Relat Cancer 2017; 24:T209-T225. [PMID: 28790162 DOI: 10.1530/erc-17-0231] [Citation(s) in RCA: 16] [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: 07/29/2017] [Accepted: 08/08/2017] [Indexed: 12/13/2022]
Abstract
Prospective randomized data are lacking, but current clinical expert guidelines recommend annual screening examinations, including laboratory assessments and various imaging modalities (e.g. CT, MRI, scintigraphy and EUS) for patients with multiple endocrine neoplasia type 1 (MEN1). Routine screening is proposed to detect and localize neuroendocrine manifestations as early as possible. The goal is timely intervention to improve quality of life and to increase life expectancy by preventing the development of life-threatening hormonal syndromes and/or metastatic disease. In recent years, some studies compared different and new imaging methods regarding their sensitivity and utility in MEN1 patients. This present article reviews the proposed diagnostic tools for MEN1 screening as well as potential future perspectives.
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Affiliation(s)
- Jerena Manoharan
- Department of VisceralThoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Max B Albers
- Department of VisceralThoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Detlef K Bartsch
- Department of VisceralThoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
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Agarwal SK. The future: genetics advances in MEN1 therapeutic approaches and management strategies. Endocr Relat Cancer 2017; 24:T119-T134. [PMID: 28899949 PMCID: PMC5679100 DOI: 10.1530/erc-17-0199] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 08/08/2017] [Indexed: 02/01/2023]
Abstract
The identification of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997 has shown that germline heterozygous mutations in the MEN1 gene located on chromosome 11q13 predisposes to the development of tumors in the MEN1 syndrome. Tumor development occurs upon loss of the remaining normal copy of the MEN1 gene in MEN1-target tissues. Therefore, MEN1 is a classic tumor suppressor gene in the context of MEN1. This tumor suppressor role of the protein encoded by the MEN1 gene, menin, holds true in mouse models with germline heterozygous Men1 loss, wherein MEN1-associated tumors develop in adult mice after spontaneous loss of the remaining non-targeted copy of the Men1 gene. The availability of genetic testing for mutations in the MEN1 gene has become an essential part of the diagnosis and management of MEN1. Genetic testing is also helping to exclude mutation-negative cases in MEN1 families from the burden of lifelong clinical screening. In the past 20 years, efforts of various groups world-wide have been directed at mutation analysis, molecular genetic studies, mouse models, gene expression studies, epigenetic regulation analysis, biochemical studies and anti-tumor effects of candidate therapies in mouse models. This review will focus on the findings and advances from these studies to identify MEN1 germline and somatic mutations, the genetics of MEN1-related states, several protein partners of menin, the three-dimensional structure of menin and menin-dependent target genes. The ongoing impact of all these studies on disease prediction, management and outcomes will continue in the years to come.
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Affiliation(s)
- Sunita K Agarwal
- Metabolic Diseases BranchNational Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
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van Leeuwaarde RS, de Laat JM, Pieterman CRC, Dreijerink K, Vriens MR, Valk GD. The future: medical advances in MEN1 therapeutic approaches and management strategies. Endocr Relat Cancer 2017; 24:T179-T193. [PMID: 28768698 DOI: 10.1530/erc-17-0225] [Citation(s) in RCA: 16] [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: 07/31/2017] [Accepted: 08/01/2017] [Indexed: 12/21/2022]
Abstract
Multiple endocrine neoplasia type 1 is a rare autosomal inherited disorder associated with a high risk for patients to simultaneously develop tumors of the parathyroid glands, duodenopancreatic neuroendocrine tumors and tumors of the anterior pituitary gland. Early identification of MEN1 in patients enables presymptomatic screening of manifestations, which makes timely interventions possible with the intention to prevent morbidity and mortality. Causes of death nowadays have shifted toward local or metastatic progression of malignant neuroendocrine tumors. In early cohorts, complications like peptic ulcers in gastrinoma, renal failure in hyperparathyroidism, hypoglycemia and acute hypercalcemia were the primary causes of early mortality. Improved medical treatments of these complications led to a significantly improved life expectancy. The MEN1 landscape is still evolving, considering the finding of breast cancer as a new MEN1-related manifestation and ongoing publications on follow-up and medical care for patients with MEN1. This review aims at summarizing the most recent insights into the follow-up and medical care for patients with MEN1 and identifying the gaps for future research.
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Affiliation(s)
| | - Joanne M de Laat
- Department of Endocrine OncologyUniversity Medical Center Utrecht, Utrecht, The Netherlands
| | - Carolina R C Pieterman
- Department of Endocrine OncologyUniversity Medical Center Utrecht, Utrecht, The Netherlands
| | - Koen Dreijerink
- Department of Endocrine OncologyUniversity Medical Center Utrecht, Utrecht, The Netherlands
| | - Menno R Vriens
- Department of Endocrine SurgeryUniversity Medical Center Utrecht, Utrecht, The Netherlands
| | - Gerlof D Valk
- Department of Endocrine OncologyUniversity Medical Center Utrecht, Utrecht, The Netherlands
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