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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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Grover A, Jha S. Heritable hyperparathyroidism: Genetic insights and clinical implications. Best Pract Res Clin Endocrinol Metab 2025; 39:101984. [PMID: 40057424 PMCID: PMC11951071 DOI: 10.1016/j.beem.2025.101984] [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] [Indexed: 03/17/2025]
Abstract
Familial or heritable hyperparathyroidism (FHPT) is seen in approximately 10-15 % of patients with primary hyperparathyroidism (PHPT). Once the diagnosis of PHPT is established, consideration of heritable forms should be made in patients with positive family history, young onset, multi-glandular disease, and recurrent or persistent disease. FHPT encompasses both syndromic and non-syndromic forms. Syndromic forms include multiple endocrine neoplasia (MEN) types 1, 2, 3 and 4, hyperparathyroidism-jaw tumor syndrome, hereditary pheochromocytoma and paraganglioma, and the more recently reported, Birt-Hogg-Dubé (BHD) syndrome, and X-linked intellectual disability syndrome. Non-syndromic forms include familial hypocalciuric hypercalcemia (FHH)- types 1,2, and 3, neonatal severe hyperparathyroidism, GCM2-mediated hyperparathyroidism, transient neonatal hyperparathyroidism, and familial isolated hyperparathyroidism. In this review we aim to review the heritable forms of PHPT and highlight the important genetics insights and clinical implications.
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Affiliation(s)
- Ashna Grover
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
| | - Smita Jha
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9C432A, 10 Center Drive, Bethesda, MD 20892, USA.
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Das L, Dutta P. Association of primary hyperparathyroidism with pituitary adenoma and management issues. Best Pract Res Clin Endocrinol Metab 2025; 39:101978. [PMID: 39915142 DOI: 10.1016/j.beem.2025.101978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/17/2025]
Abstract
The co-occurrence of primary hyperparathyroidism (PHPT) and pituitary adenomas (PAs) is often indicative of underlying genetic syndromes such as Multiple Endocrine Neoplasia type 1 (MEN1) and, less commonly, MEN4. Although both conditions can occur sporadically, their simultaneous presence warrants evaluation for genetic mutations, with MEN1 mutations being the most frequent cause. The management of concurrent PHPT and PAs, especially in MEN1 patients, presents unique challenges. Management complexities arise from the syndromic nature, involving both surgical and medical interventions tailored to each condition. PHPT often manifests earlier and more aggressively in MEN1, requiring surgical intervention. However, recurrence rates remain high due to multiglandular involvement. Pituitary adenomas in MEN1 are primarily prolactinomas, and treatment with dopamine agonists results in significant tumour control in most cases. Overall, PAs associated with MEN1 are generally responsive to medical therapy, but careful long-term monitoring is essential. The utility of genetic screening cannot be overstated, as it aids in early detection, risk stratification, and management of both the index case and affected family members by cascade screening. A multidisciplinary approach is crucial for optimizing outcomes, with ongoing surveillance to manage recurrence and associated complications. In summary, the co-occurrence of PHPT and PAs, particularly in the context of MEN1, necessitates an integrated management strategy. Genetic testing is key in confirming diagnosis and guiding treatment, while surgical and medical interventions should be tailored to the extent and nature of glandular involvement. Close monitoring for recurrence and proactive family screening are essential components of long-term care.
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Affiliation(s)
- Liza Das
- Department of Telemedicine, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
| | - Pinaki Dutta
- Department of Endocrinology, PGIMER, Chandigarh, India.
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Worthy CC, Tora R, Uttarkar CN, Welch JM, Bliss L, Cochran C, Ninan A, Kumar S, Wank S, Auh S, Weinstein LS, Simonds WF, Agarwal SK, Blau JE, Jha S. Genotype-phenotype correlation in multiple endocrine neoplasia type 1. JCI Insight 2025; 10:e176993. [PMID: 39946193 PMCID: PMC11949022 DOI: 10.1172/jci.insight.176993] [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: 10/26/2023] [Accepted: 02/12/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUNDAmong patients with multiple endocrine neoplasia type 1 (MEN1), 80% develop duodenopancreatic neuroendocrine tumors (dpNETs), of whom 15%-25% die of metastasis. There is a need to identify biomarkers to predict aggressive disease. MEN1 genotype affords an attractive possibility as a biomarker, as it remains constant during life. Currently, patients are clinically diagnosed with MEN1 by the presence of ≥2 primary endocrine tumors (pituitary, parathyroid, and pancreas) or ≥1 primary endocrine tumor with a positive family history. From 10% to 30% of patients diagnosed clinically with MEN1 have no pathogenic germline MEN1 variants.METHODSThis was a retrospective study of 162 index patients or probands with genotype-positive and 47 with genotype-negative MEN1 enrolled from 1977 to 2022.RESULTSCompared with patients with genotype-negative disease, patients with genotype-positive disease were younger at diagnosis and had an increased frequency of recurrent parathyroid tumors, dpNETs, and angiofibromas or collagenomas. We propose a weighted scoring system to diagnose genotype-positive MEN1 based on clinical characteristics. No evidence of MEN1 mosaicism was seen in 30 tumors from 17 patients with genotype-negative MEN1. Patients with germline MEN1 variants in exons 2 and 3 had a reduced risk of distant metastases.CONCLUSIONThe clinical course of genotype-negative MEN1 is distinct from genotype-positive disease, raising uncertainty about the benefits of lifetime surveillance in patients with genotype-negative disease. MEN1 mosaicism is rare.TRIAL REGISTRATION ClinicalTrials.gov NCT04969926FUNDINGIntramural Research Program of National Institute of Diabetes and Digestive and Kidney Diseases, NIH (ZIA DK043006-46).
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Sungyoung Auh
- Biostatistics Program, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
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5
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LeSarge JC, Rjoob H, Clemens KK, Van Uum S, Schenkel LC, Khan TS. A Novel and Rare Pathogenic Gene Variant in 2 Patients With Multiple Endocrine Neoplasia Type 1 (MEN-1) Syndrome. JCEM CASE REPORTS 2025; 3:luaf003. [PMID: 39906900 PMCID: PMC11791340 DOI: 10.1210/jcemcr/luaf003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Indexed: 02/06/2025]
Abstract
Multiple endocrine neoplasia type 1 (MEN-1) is a syndrome characterized by development of tumors including parathyroid adenomas, duodenopancreatic neuroendocrine tumors, and pituitary adenomas. We describe 1 patient with a novel and another with a rare pathogenic MEN-1 variant. Case 1 was a 61-year-old woman with recurrent hypercalcemia who ultimately required a subtotal parathyroidectomy, with a thymectomy revealing a thymoma. She then developed a gastrinoma requiring pancreatectomy and also had a biochemically nonfunctioning sellar mass. Genetic testing found a novel MEN1:c.1192delC, p.(Gln398Argfs*47) pathogenic variant. Case 2 was a 38-year-old woman with a family history of MEN-1, who had recurrent hypercalcemia and nephrolithiasis requiring a subtotal parathyroidectomy. She had a macroprolactinoma, but no pancreatic lesions. Genetic testing found a rare MEN1:c.784-9G > A pathogenic variant. MEN-1 syndrome should be considered in patients presenting with 1 or more classical MEN-1-associated tumors based on clinical suspicion.
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Affiliation(s)
- Jordan C LeSarge
- Department of Medicine, Schulich School of Medicine & Dentistry, Western University and London Health Sciences Centre, London, ON, Canada N6A 5W9
| | - Hani Rjoob
- College of Medicine and Health Sciences, Palestine Polytechnic University, Hebron 198, Palestinian Territories
| | - Kristin K Clemens
- Department of Medicine, Schulich School of Medicine & Dentistry, Western University and London Health Sciences Centre, London, ON, Canada N6A 5W9
- Division of Endocrinology and Metabolism, St. Joseph's Healthcare, London, ON, Canada N6A 4V2
- Lawson Research Institute, London, ON, Canada N6A4V2
| | - Stan Van Uum
- Department of Medicine, Schulich School of Medicine & Dentistry, Western University and London Health Sciences Centre, London, ON, Canada N6A 5W9
- Division of Endocrinology and Metabolism, St. Joseph's Healthcare, London, ON, Canada N6A 4V2
| | - Laila C Schenkel
- Molecular Diagnostics Division, Molecular Genetics Laboratory, London Health Sciences Centre, London, ON, Canada N6A3K7
- Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada N6A3K7
| | - Tayyab S Khan
- Department of Medicine, Schulich School of Medicine & Dentistry, Western University and London Health Sciences Centre, London, ON, Canada N6A 5W9
- Division of Endocrinology and Metabolism, St. Joseph's Healthcare, London, ON, Canada N6A 4V2
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6
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Kuusela E, Kostiainen I, Ritvonen E, Ryhänen EM, Schalin-Jäntti C. Bone mineral density over ten years after primary parathyroidectomy in multiple endocrine neoplasia type 1. JBMR Plus 2024; 8:ziae129. [PMID: 39575107 PMCID: PMC11579653 DOI: 10.1093/jbmrpl/ziae129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 10/01/2024] [Accepted: 10/20/2024] [Indexed: 11/24/2024] Open
Abstract
Primary hyperparathyroidism (PHPT) associated with multiple endocrine neoplasia type 1 (MEN1) impairs bone mineral density and causes osteoporosis already in young patients. We aimed to investigate bone mineral density (BMD) in a contemporary cohort of patients with MEN1-related PHPT after long-term follow-up and compare these results with that of healthy controls. Thirty-five patients with genetically confirmed MEN1 were diagnosed with MEN1 at mean age 28.7 ± 13.6 years. Thirty-two (91.4%) underwent primary parathyroidectomy at mean age 33.3 ± 13.7 years; 12 had undergone at least 2 surgeries with on average 7.3 ± 5.9 years between the operations. BMD was assessed by DXA at the end of mean follow-up, 13.2 years after the primary parathyroidectomy and compared with that of 35 age- and gender-matched controls. More than 10 years after the first parathyroidectomy, mean BMD in patients with MEN1 is in the normal range. However, it is still significantly lower compared with healthy controls.
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Affiliation(s)
- Emma Kuusela
- Endocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki, ENDO-ERN (European Reference Network on Rare Endocrine Conditions), FIN-00290 Helsinki, Finland
| | - Iiro Kostiainen
- Endocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki, ENDO-ERN (European Reference Network on Rare Endocrine Conditions), FIN-00290 Helsinki, Finland
| | - Elina Ritvonen
- Endocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki, ENDO-ERN (European Reference Network on Rare Endocrine Conditions), FIN-00290 Helsinki, Finland
- Heart and Lung Center, Helsinki University Hospital and Helsinki University, FIN-00290 Helsinki, Finland
| | - Eeva M Ryhänen
- Endocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki, ENDO-ERN (European Reference Network on Rare Endocrine Conditions), FIN-00290 Helsinki, Finland
| | - Camilla Schalin-Jäntti
- Endocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki, ENDO-ERN (European Reference Network on Rare Endocrine Conditions), FIN-00290 Helsinki, Finland
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7
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Eremkina AK, Pylina SV, Elfimova AR, Gorbacheva AM, Humbert L, López Picazo M, Hajrieva AV, Solodovnikova EN, Kovalevich LD, Vetchinkina EA, Bondarenko EV, Tarbaeva NV, Mokrysheva NG. Analysis of Bone Phenotype Differences in MEN1-Related and Sporadic Primary Hyperparathyroidism Using 3D-DXA. J Clin Med 2024; 13:6382. [PMID: 39518523 PMCID: PMC11546830 DOI: 10.3390/jcm13216382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/04/2024] [Accepted: 10/17/2024] [Indexed: 11/16/2024] Open
Abstract
Background: The rarity and variability of MEN1-related primary hyperparathyroidism (mPHPT) has led to contradictory data regarding the bone phenotype in this patient population. Methods: A single-center retrospective study was conducted among young age- and sex-matched patients with mPHPT and sporadic hyperparathyroidism (sPHPT). The main parameters of calcium-phosphorus metabolism, bone remodeling markers, and bone mineral density (BMD) measurements were obtained during the active phase of hyperparathyroidism before parathyroidectomy (PTE) and 1 year after. Trabecular Bone Score (TBS) and 3D-DXA analysis of the proximal femur were used to evaluate the differences in bone architecture disruption between groups. Results: Patients with mPHPT had significant lower preoperative BMD compared to sPHPT at lumbar spine-LS (p = 0.002); femur neck-FN (p = 0.001); and total hip-TH (p = 0.002). 3D-DXA analysis showed the prevalence of cortical rather than trabecular bone damage in mPHPT compared to sPHPT: cortical thickness (p < 0.001); cortical surface BMD (p = 0.001); cortical volumetric BMD (p = 0.007); and trabecular volumetric BMD (p = 0.029). One year after, PTE DXA and 3D-DXA parameters were similar between groups, while 3D-visualisation showed more extensive regeneration in cortical sBMD and cortical thickness in mPHPT. Conclusions: mPHPT is associated with lower preoperative BMD values with predominant architecture disruption in the cortical bone. The absence of differences in DXA and 3D-DXA parameters 1 year after PTE between mPHPT/sPHPT combined with significantly lower BMD in mPHPT at the initial stage may indicate faster bone recovery after surgery in mPHPT than in sPHPT.
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Affiliation(s)
- Anna K. Eremkina
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Svetlana V. Pylina
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Alina R. Elfimova
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Anna M. Gorbacheva
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | | | | | - Angelina V. Hajrieva
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Ekaterina N. Solodovnikova
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Liliya D. Kovalevich
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Ekaterina A. Vetchinkina
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Ekaterina V. Bondarenko
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Natalia V. Tarbaeva
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
| | - Natalia G. Mokrysheva
- Endocrinology Research Centre, 115478 Moscow, Russia; (S.V.P.); (A.R.E.); (A.M.G.); (A.V.H.); (E.N.S.); (L.D.K.); (E.A.V.); (E.V.B.); (N.V.T.); (N.G.M.)
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Frye CC, Brown TC, Olson JA. Evaluation and Surgical Management of Multiple Endocrine Neoplasias. Surg Clin North Am 2024; 104:909-928. [PMID: 38944508 DOI: 10.1016/j.suc.2024.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/01/2024]
Abstract
Multiple endocrine neoplasia (MEN) syndromes are rare autosomal dominant diseases that are associated with a mixture of both endocrine and non-endocrine tumors. Traditionally, there are 2 types of MEN that have unique clinical associations: MEN 1 (parathyroid hyperplasia, pancreatic neuroendocrine tumors, and pituitary tumors) and MEN 2 (medullary thyroid carcinoma and pheochromocytoma), which is further classified into MEN 2A (adds parathyroid adenomas) and 2B (adds ganglioneuromas and marfanoid habitus). Many of the endocrine tumors are resected surgically, and the pre, intra, and postoperative management strategies used must take into account the high recurrence rates asscioated with MEN tumors.
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Affiliation(s)
- C Corbin Frye
- Department of Surgery, General Surgery Resident, Washington University School of Medicine, St. Louis, MO, USA.
| | - Taylor C Brown
- Department of Surgery, Section of Surgical Oncology, Assistant Professor, Washington University School of Medicine, St. Louis, MO, USA
| | - John A Olson
- Department of Surgery, Section of Surgical Oncology, Chair and Professor, Washington University School of Medicine, St. Louis, MO, USA
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9
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Bräutigam K, Nesti C, Riss P, Scheuba C, Niederle B, Grob T, Di Domenico A, Neuenschwander M, Mazal P, Köhn N, Trepp R, Perren A, Kaderli RM. Syndromic MEN1 parathyroid adenomas consist of both subclonal nodules and clonally independent tumors. Virchows Arch 2024; 484:789-798. [PMID: 38244045 PMCID: PMC11106174 DOI: 10.1007/s00428-023-03730-3] [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: 08/18/2023] [Revised: 12/11/2023] [Accepted: 12/26/2023] [Indexed: 01/22/2024]
Abstract
Primary hyperparathyroidism with parathyroid tumors is a typical manifestation of Multiple Endocrine Neoplasia Type 1 (MEN1) and is historically termed "primary hyperplasia". Whether these tumors represent a multi-glandular clonal disease or hyperplasia has not been robustly proven so far. Loss of Menin protein expression is associated with inactivation of both alleles and a good surrogate for a MEN1 gene mutation. The cyclin-dependent kinase inhibitor 1B (CDKN1B) gene is mutated in MEN4 and encodes for protein p27 whose expression is poorly studied in the syndromic MEN1 setting.Here, we analyzed histomorphology and protein expression of Menin and p27 in parathyroid adenomas of 25 patients of two independent, well-characterized MEN1 cohorts. The pattern of loss of heterozygosity (LOH) was assessed by fluorescence in situ hybridization (FISH) in one MEN1-associated parathyroid adenoma. Further, next-generation sequencing (NGS) was performed on eleven nodules of four MEN1 patients.Morphologically, the majority of MEN1 adenomas consisted of multiple distinct nodules, in which Menin expression was mostly lost and p27 protein expression reduced. FISH analysis revealed that most nodules exhibited MEN1 loss, with or without the loss of centromere 11. NGS demonstrated both subclonal evolution and the existence of clonally unrelated tumors.Syndromic MEN1 parathyroid adenomas therefore consist of multiple clones with subclones, which supports the current concept of the novel WHO classification of parathyroid tumors (2022). p27 expression was lost in a large fraction of MEN1 parathyroids and must therefore be used with caution in suggesting MEN4.
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Affiliation(s)
- Konstantin Bräutigam
- Institute of Tissue Medicine and Pathology, University of Bern, Murtenstr. 31, 3008, Bern, Switzerland.
| | - Cédric Nesti
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Philipp Riss
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Christian Scheuba
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Bruno Niederle
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, Vienna, Austria
| | - Tobias Grob
- Institute of Tissue Medicine and Pathology, University of Bern, Murtenstr. 31, 3008, Bern, Switzerland
| | - Annunziata Di Domenico
- Institute of Tissue Medicine and Pathology, University of Bern, Murtenstr. 31, 3008, Bern, Switzerland
| | - Maja Neuenschwander
- Institute of Tissue Medicine and Pathology, University of Bern, Murtenstr. 31, 3008, Bern, Switzerland
| | - Peter Mazal
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Nastassja Köhn
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
- Department of General Surgery, Cantonal Hospital of Aarau, Aarau, Switzerland
| | - Roman Trepp
- Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Aurel Perren
- Institute of Tissue Medicine and Pathology, University of Bern, Murtenstr. 31, 3008, Bern, Switzerland
| | - Reto M Kaderli
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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10
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Tan J, Zhang Y, Han X, Fan Y, Xu J, Chen G, Liu C, Xu S. Microwave ablation for recurrent primary hyperparathyroidism in four patients with multiple endocrine neoplasia type 1: a case series report. Int J Hyperthermia 2024; 41:2308056. [PMID: 38314667 DOI: 10.1080/02656736.2024.2308056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 01/15/2024] [Indexed: 02/06/2024] Open
Abstract
Multiple endocrine neoplasia type 1 (MEN1), a rare tumor syndrome, is inherited in an autosomal dominant pattern, mainly manifested as primary hyperparathyroidism (PHPT). Surgery is preferred for patients with MEN1 and PHPT. Thermal ablation has been widely applied for PHPT but rarely for postoperative recurrent PHPT in MEN1 patients. Based on a series of cases, we aimed to investigate the clinical efficacy and safety of ultrasound-guided percutaneous microwave ablation in the treatment of MEN1 patients with postoperative recurrence of PHPT.
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Affiliation(s)
- Jie Tan
- Endocrine and Diabetes Center, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuzhi Zhang
- Key Laboratory of Traditional Chinese Medicine (TCM) Syndrome and Treatment of Yingbing (Thyroid Disease) of State Administration of Traditional Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
| | - Xue Han
- Endocrine and Diabetes Center, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yaofu Fan
- Endocrine and Diabetes Center, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Juan Xu
- Endocrine and Diabetes Center, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Guofang Chen
- Endocrine and Diabetes Center, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Ultrasound, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Chao Liu
- Endocrine and Diabetes Center, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- Department of Ultrasound, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shuhang Xu
- Endocrine and Diabetes Center, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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Santucci N, Ksiazek E, Pattou F, Baud G, Mirallié E, Frey S, Trésallet C, Sébag F, Guérin C, Mathonnet M, Christou N, Donatini G, Brunaud L, Gaujoux S, Ménégaux F, Najah H, Binquet C, Goudet P, Lifante JC. Recurrence After Surgery for Primary Hyperparathyroidism in 517 Patients With Multiple Endocrine Neoplasia Type 1: An Association Francophone de Chirurgie Endocrinienne and Groupe d'étude des Tumeurs Endocrines study. Ann Surg 2024; 279:340-345. [PMID: 37389888 DOI: 10.1097/sla.0000000000005980] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/01/2023]
Abstract
OBJECTIVE To assess recurrence according to the type of surgery for primary hyperparathyroidism (pHPT) in multiple endocrine neoplasia type 1 ( MEN1 ) patients and to identify the risk factors for recurrence after the initial surgery. BACKGROUND In MEN1 patients, pHPT is multiglandular, and the optimal extent of initial parathyroid resection influences the risk of recurrence. METHODS MEN1 patients who underwent initial surgery for pHPT between 1990 and 2019 were included. Persistence and recurrence rates after less than subtotal parathyroidectomy (LTSP) and subtotal parathyroidectomy (STP) were analyzed. Patients with total parathyroidectomy with reimplantation were excluded. RESULTS Five hundred seventeen patients underwent their first surgery for pHPT: 178 had LTSP (34.4%) and 339 STP (65.6%). The recurrence rate was significantly higher after LTSP (68.5%) than STP (45%) ( P < 0.001). The median time to recurrence after pHPT surgery was significantly shorter after LTSP than after STP: 4.25 (1.2-7.1) versus 7.2 (3.9-10.1) years ( P < 0.001). A mutation in exon 10 was an independent risk factor of recurrence after STP (odds ratio = 2.19; 95% CI: 1.31; 3.69; P = 0.003). The 5 and 10-year recurrent pHPT probabilities were significantly higher in patients after LTSP with a mutation in exon 10 (37% and 79% vs 30% and 61%; P = 0.016). CONCLUSIONS Persistence, recurrence of pHPT, and reoperation rate are significantly lower after STP than LTSP in MEN1 patients. Genotype seems to be associated with the recurrence of pHPT. A mutation in exon 10 is an independent risk factor for recurrence after STP, and LTSP may not be recommended when exon 10 is mutated.
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Affiliation(s)
- Nicolas Santucci
- Department of Digestive and Endocrine Surgery, Dijon University Hospital
- INSERM, University de Bourgogne-Franche-Comté, UMR1231, EPICAD Team "Lipids, Nutrition, Cancer"
| | | | - François Pattou
- Department of General and Endocrine Surgery, University Hospital, Lille, INSERM U1190, Lille
| | - Gregory Baud
- Department of General and Endocrine Surgery, University Hospital, Lille, INSERM U1190, Lille
| | - Eric Mirallié
- Department of Oncological, Digestive and Endocrine Surgery (CCDE) Hôtel Dieu, CIC-IMAD, Nantes
| | - Samuel Frey
- Department of Oncological, Digestive and Endocrine Surgery (CCDE) Hôtel Dieu, CIC-IMAD, Nantes
| | - Christophe Trésallet
- Department of Digestive and Endocrine Surgery, Avicenne University Hospital, AP-HP Sorbonne Paris Nord University, Bobigny
| | - Frédéric Sébag
- Department of General Endocrine and Metabolic Surgery, Conception University Hospital, APHM, Aix Marseille University, Marseille
| | - Carole Guérin
- Department of General Endocrine and Metabolic Surgery, Conception University Hospital, APHM, Aix Marseille University, Marseille
| | - Muriel Mathonnet
- Department of Surgery, Dupuytren University Hospital of Limoges, Limoges
| | - Niki Christou
- Department of Surgery, Dupuytren University Hospital of Limoges, Limoges
| | - Gianluca Donatini
- Department of General and Endocrine Surgery, University Hospital of Poitiers, Poitiers
| | - Laurent Brunaud
- Department of Gastrointestinal, Metabolic, and Cancer Surgery (CVMC), University Hospital of Nancy (CHRU Nancy), INSERM NGERE U1256, University of Lorraine, Rue du Morvan
| | - Sébastien Gaujoux
- Department of Endocrine and Pancreatic Surgery, AP-HP, Pitié-Salpêtrière Hospital, Paris
| | - Fabrice Ménégaux
- Department of Endocrine and Pancreatic Surgery, AP-HP, Pitié-Salpêtrière Hospital, Paris
| | - Haythem Najah
- Department of Hepatobiliary Surgery, Bordeaux University Hospital, Bordeaux
| | - Christine Binquet
- INSERM, University de Bourgogne-Franche-Comté, UMR1231, EPICAD Team "Lipids, Nutrition, Cancer"
- INSERM, CIC1432, Clinical Epidemiology, Dijon
| | - Pierre Goudet
- Department of Digestive and Endocrine Surgery, Dijon University Hospital
| | - Jean-Christophe Lifante
- Department of Digestive and Endocrine Surgery, University Hospital of Lyon Sud and EA 7425 HESPER, Health Services and Performance Research, University Claude Bernard Lyon 1, Lyon, France
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Goudet P, Cadiot G, Barlier A, Baudin E, Borson-Chazot F, Brunaud L, Caiazzo R, Cardot-Bauters C, Castinetti F, Chanson P, Cuny T, Dansin E, Gaujoux S, Giraud S, Groussin L, Le Bras M, Lifante JC, Mathonnet M, de Mestier L, Mirallié E, Pattou F, Romanet P, Sebag F, Tresallet C, Vezzosi D, Walter T, Tabarin A. French guidelines from the GTE, AFCE and ENDOCAN-RENATEN (Groupe d'étude des Tumeurs Endocrines/Association Francophone de Chirurgie Endocrinienne/Reseau national de prise en charge des tumeurs endocrines) for the screening, diagnosis and management of Multiple Endocrine Neoplasia Type 1. ANNALES D'ENDOCRINOLOGIE 2024; 85:2-19. [PMID: 37739121 DOI: 10.1016/j.ando.2023.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/24/2023]
Affiliation(s)
- Pierre Goudet
- Department of Digestive and Endocrine Surgery, Dijon University Hospital, Dijon, France; INSERM, U1231, EPICAD Team UMR "Lipids, Nutrition, Cancer", Dijon, France; INSERM, CIC1432, Clinical epidemiology Dijon, Dijon, France.
| | - Guillaume Cadiot
- Department of Hepato-Gastro-Enterology and Digestive Oncology, Robert Debré Hospital, Reims, France.
| | - Anne Barlier
- Aix Marseille Univ, APHM, INSERM, MMG, Laboratory of Molecular Biology Hospital La Conception, Marseille, France.
| | - Eric Baudin
- Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
| | - Françoise Borson-Chazot
- Federation of Endocrinology, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon1 University and INSERM U1290, Lyon, France.
| | - Laurent Brunaud
- Department of Gastrointestinal, Visceral, Metabolic, and Cancer Surgery (CVMC), University Hospital of Nancy (CHRU Nancy), University of Lorraine, 54511 Vandoeuvre-les-Nancy, France; INSERM U1256 NGERE, Lorraine University, 11, allée du Morvan, 54511 Vandoeuvre-les-Nancy, France.
| | - Robert Caiazzo
- General and Endocrine Surgery Department, University Hospital Center of Lille, Lille, France.
| | | | - Frédéric Castinetti
- Aix Marseille University, Marseille Medical Genetics, INSERM U1251 and Assistance Publique Hopitaux de Marseille, La Conception Hospital, Department of Endocrinology, Marseille, France.
| | - Philippe Chanson
- University Paris-Saclay, INSERM, Endocrine Physiology and Pathophysiology, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Service of Endocrinology and Reproductive Diseases, National Reference Center for Rare Pituitary Diseases, 94275 Le Kremlin-Bicêtre, France.
| | - Thomas Cuny
- APHM, Marseille Medical Genetics, INSERM U1251, Conception Hospital, Endocrinology Department, Aix Marseille University, Marseille, France.
| | - Eric Dansin
- Department of Medical Oncology, Oscar Lambret Center, 59000 Lille, France.
| | - Sébastien Gaujoux
- Department of Endocrine and Pancreatic Surgery, AP-HP, Pitié-Salpêtrière Hospital, Paris, France.
| | - Sophie Giraud
- Cancer Genetics Unit, Institut Bergonié, Bordeaux, France.
| | - Lionel Groussin
- Department of Endocrinology, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France; Institut Cochin, INSERM U1016, CNRS UMR8104, Université Paris Cité, 75014 Paris, France.
| | - Maëlle Le Bras
- Department of Endocrinology, Nantes University Hospital, Nantes, France.
| | - Jean-Christophe Lifante
- Department of Digestive and Endocrine Surgery, University Hospital of Lyon Sud, Lyon, France; EA 7425 HESPER, Health Services and Performance Research, University Claude Bernard Lyon 1, Lyon, France.
| | - Muriel Mathonnet
- Department of Surgery, Dupuytren University Hospital of Limoges, Limoges, France.
| | - Louis de Mestier
- Paris-Cité University, Department of Pancreatology and Digestive Oncology, Beaujon Hospital (AP-HP-Nord), Clichy, France.
| | - Eric Mirallié
- Department of Oncological, Digestive and Endocrine Surgery (CCDE) Hôtel Dieu, CIC-IMAD, Nantes, France.
| | - François Pattou
- Department of General and Endocrine Surgery, University Hospital. Lille, INSERM U1190, Lille, France.
| | - Pauline Romanet
- Aix Marseille University, APHM, INSERM, MMG, Laboratory of Molecular Biology, La Conception Hospital, Marseille, France.
| | - Frédéric Sebag
- Department of General Endocrine and Metabolic Surgery, Conception University Hospital, APHM, Aix Marseille University, Marseille, France.
| | - Christophe Tresallet
- Department of Digestive, Bariatric and Endocrine Surgery, Avicenne University Hospital, Sorbonne Paris Nord Universty, Assistance Pubique des Hôpitaux de Paris (APHP), Paris, France.
| | - Delphine Vezzosi
- Department of Endocrinology and Metabolic Diseases, CHU Larrey, 24 chemin de Pouvourville, TSA 30030, 31059 Toulouse Cedex, France.
| | - Thomas Walter
- Medical Oncology Department, Edouard-Herriot Hospital, Hospices Civils de Lyon, Lyon, France.
| | - Antoine Tabarin
- Endocrinology Department, INSERM Unit 1215, Bordeaux University Hospital, University of Bordeaux, Bordeaux, France.
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13
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Shariq OA, Abrantes VB, Lu LY, Tebben PJ, Foster TM, Dy BM, Lyden ML, Young WF, McKenzie TJ. Primary hyperparathyroidism in patients with multiple endocrine neoplasia type 1: Impact of genotype and surgical approach on long-term postoperative outcomes. Surgery 2024; 175:8-16. [PMID: 37891063 DOI: 10.1016/j.surg.2023.05.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 04/25/2023] [Accepted: 05/24/2023] [Indexed: 10/29/2023]
Abstract
BACKGROUND Protein-truncating germline pathogenic variants in the N- and C-terminal exons (2, 9, and 10) of the MEN1 gene may be associated with aggressive pancreatic neuroendocrine tumors. However, the impact of these variants on parathyroid disease is poorly understood. We sought to investigate the effects of genotype and surgical approach on clinical phenotype and postoperative outcomes in patients with multiple endocrine neoplasia type 1 (MEN1)-related primary hyperparathyroidism. METHODS We identified patients with MEN1 evaluated at our institution from 1985 to 2020 and stratified them by genotype, (truncating variants in exons 2, 9, or 10, or other variants), and index surgical approach, (less-than-subtotal parathyroidectomy [ RESULTS Of the 209 patients we identified, primary hyperparathyroidism was diagnosed in 194 (93%) and at a younger median age in those with truncating exon 2, 9, or 10 variants compared with other variants (27 years vs 31 years; P = .006). Median disease-free survival was significantly worse in patients who underwent CONCLUSION The MEN1 genotype may affect the age of onset of primary hyperparathyroidism and the time to recurrence after surgery.
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Affiliation(s)
| | | | - Lauren Y Lu
- Department of Surgery, Mayo Clinic, Rochester, MN
| | - Peter J Tebben
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN
| | | | - Benzon M Dy
- Department of Surgery, Mayo Clinic, Rochester, MN
| | | | - William F Young
- Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN
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14
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Libánský P, Čarková J, Kushnir I, Matějková Běhanová M, Procyklová K, Šedý J, Vaculová M, Včelák J, Zikán V, Adámek S. Recurrent Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 1 Syndrome. Physiol Res 2023; 72:S423-S427. [PMID: 38116778 PMCID: PMC10830164 DOI: 10.33549/physiolres.935223] [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: 07/29/2023] [Accepted: 09/12/2023] [Indexed: 01/05/2024] Open
Abstract
Primary hyperparathyroidism is a common endocrinopathy. Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare autosomal dominantly inherited endocrine tumor predisposition syndrome, with one of main manifestations being primary hyperparathyroidism. We retrospectively evaluated a set of 1011 patients who underwent surgery for primary hyperparathyroidism between the years 2018-2022, and found 78 (8 %) patients who underwent reoperations and 27 patients with MEN1 syndrome. In the group of patients with MEN1 syndrome, 7 (35 %) needed reoperations. Patients with multiple endocrine neoplasia syndrome have a higher risk of needing reoperation. Genetic testing can help identify MEN1 syndrome preoperatively and to better evaluate the approach to surgery.
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Affiliation(s)
- P Libánský
- 3rd Department of Surgery, 1st Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic.
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15
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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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16
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Faggiano A, Fazzalari B, Mikovic N, Russo F, Zamponi V, Mazzilli R, Guarnieri V, Piane M, Visco V, Petrucci S. Clinical Factors Predicting Multiple Endocrine Neoplasia Type 1 and Type 4 in Patients with Neuroendocrine Tumors. Genes (Basel) 2023; 14:1782. [PMID: 37761922 PMCID: PMC10531237 DOI: 10.3390/genes14091782] [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: 07/20/2023] [Revised: 09/03/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
The aim of this study is to evaluate the predictive role of specific clinical factors for the diagnosis of Multiple Endocrine Neoplasia type-1 (MEN1) and type-4 (MEN4) in patients with an initial diagnosis of gastrointestinal, bronchial, or thymic neuroendocrine tumor (NET). METHODS Patients referred to the NET Unit between June 2021 and December 2022 with a diagnosis of NET and at least one clinical criterion of suspicion for MEN1 and MEN4 underwent molecular analysis of the MEN1 and CDKN1B genes. Phenotypic criteria were: (1) age ≤ 40 years; (2) NET multifocality; (3) MEN1/4-associated manifestations other than NETs; and (4) endocrine syndrome related to NETs or pituitary/adrenal tumors. RESULTS A total of 22 patients were studied. In 18 patients (81.8%), the first-level genetic test was negative (Group A), while four patients (25%) were positive for MEN1 (Group B). No patient was positive for MEN4. In Group A, 10 cases had only one clinical criterion, and three patients met three criteria. In Group B, three patients had three criteria, and one met all criteria. CONCLUSION These preliminary data show that a diagnosis of NET in patients with a negative family history is suggestive of MEN1 in the presence of ≥three positive phenotypic criteria, including early age, multifocality, multiple MEN-associated manifestations, and endocrine syndromes. This indication may allow optimization of the diagnosis of MEN in patients with NET.
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Affiliation(s)
- Antongiulio Faggiano
- Endocrinology Unit, Sant’Andrea Hospital, ENETS Center of Excellence, 00189 Rome, Italy; (B.F.); (N.M.); (F.R.); (V.Z.); (R.M.)
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (M.P.); (V.V.); (S.P.)
| | - Beatrice Fazzalari
- Endocrinology Unit, Sant’Andrea Hospital, ENETS Center of Excellence, 00189 Rome, Italy; (B.F.); (N.M.); (F.R.); (V.Z.); (R.M.)
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (M.P.); (V.V.); (S.P.)
| | - Nevena Mikovic
- Endocrinology Unit, Sant’Andrea Hospital, ENETS Center of Excellence, 00189 Rome, Italy; (B.F.); (N.M.); (F.R.); (V.Z.); (R.M.)
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (M.P.); (V.V.); (S.P.)
| | - Flaminia Russo
- Endocrinology Unit, Sant’Andrea Hospital, ENETS Center of Excellence, 00189 Rome, Italy; (B.F.); (N.M.); (F.R.); (V.Z.); (R.M.)
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (M.P.); (V.V.); (S.P.)
| | - Virginia Zamponi
- Endocrinology Unit, Sant’Andrea Hospital, ENETS Center of Excellence, 00189 Rome, Italy; (B.F.); (N.M.); (F.R.); (V.Z.); (R.M.)
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (M.P.); (V.V.); (S.P.)
| | - Rossella Mazzilli
- Endocrinology Unit, Sant’Andrea Hospital, ENETS Center of Excellence, 00189 Rome, Italy; (B.F.); (N.M.); (F.R.); (V.Z.); (R.M.)
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (M.P.); (V.V.); (S.P.)
| | - Vito Guarnieri
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 Foggia, Italy;
| | - Maria Piane
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (M.P.); (V.V.); (S.P.)
- UOD Medical Genetics and Advanced Cell Diagnostics, Sant’Andrea Hospital, 00189 Rome, Italy
| | - Vincenzo Visco
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (M.P.); (V.V.); (S.P.)
- UOD Medical Genetics and Advanced Cell Diagnostics, Sant’Andrea Hospital, 00189 Rome, Italy
| | - Simona Petrucci
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00189 Rome, Italy; (M.P.); (V.V.); (S.P.)
- UOD Medical Genetics and Advanced Cell Diagnostics, Sant’Andrea Hospital, 00189 Rome, Italy
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Perrier N, Lang BH, Farias LCB, Poch LL, Sywak M, Almquist M, Vriens MR, Yeh MW, Shariq O, Duh QY, Yeh R, Vu T, LiVolsi V, Sitges-Serra A. Surgical Aspects of Primary Hyperparathyroidism. J Bone Miner Res 2022; 37:2373-2390. [PMID: 36054175 DOI: 10.1002/jbmr.4689] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 08/18/2022] [Accepted: 08/24/2022] [Indexed: 11/12/2022]
Abstract
Parathyroidectomy (PTX) is the treatment of choice for symptomatic primary hyperparathyroidism (PHPT). It is also the treatment of choice in asymptomatic PHPT with evidence for target organ involvement. This review updates surgical aspects of PHPT and proposes the following definitions based on international expert consensus: selective PTX (and reasons for conversion to an extended procedure), bilateral neck exploration for non-localized or multigland disease, subtotal PTX, total PTX with immediate or delayed autotransplantation, and transcervical thymectomy and extended en bloc PTX for parathyroid carcinoma. The systematic literature reviews discussed covered (i) the use of intraoperative PTH (ioPTH) for localized single-gland disease and (ii) the management of low BMD after PTX. Updates based on prospective observational studies are presented concerning PTX for multigland disease and hereditary PHPT syndromes, histopathology, intraoperative adjuncts, localization techniques, perioperative management, "reoperative" surgery and volume/outcome data. Postoperative complications are few and uncommon (<3%) in centers performing over 40 PTXs per year. This review is the first global consensus about surgery in PHPT and reflects the current practice in leading endocrine surgery units worldwide. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Nancy Perrier
- Department of Surgical Oncology, Section of Surgical Endocrinology, University of Texas M D Anderson Cancer Center, Houston, TX, USA
| | - Brian H Lang
- Department of Surgery, Queen Mary Hospital, Pokfulam, Hong Kong
| | | | - Leyre Lorente Poch
- Endocrine Surgery Unit, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Mark Sywak
- Endocrine Surgery Unit, University of Sydney, Sydney, Australia
| | - Martin Almquist
- Department of Surgery, Skåne University Hospital, Lund University, Lund, Sweden
| | - Menno R Vriens
- Department of Surgical Oncology and Endocrine Surgery, University Medical Center, Utrecht, The Netherlands
| | - Michael W Yeh
- Department of Surgery, Section of Endocrine Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA, USA
| | - Omair Shariq
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Headington, UK
| | - Quan-Yang Duh
- Department of Surgery, University of California, San Francisco, CA, USA
| | - Randy Yeh
- Memorial Sloan Kettering Cancer Center, Molecular Imaging and Therapy Service, New York, NY, USA
| | - Thinh Vu
- Neuroradiology Department, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Virginia LiVolsi
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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18
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Bouriez D, Gronnier C, Haissaguerre M, Tabarin A, Najah H. Less Than Subtotal Parathyroidectomy for Multiple Endocrine Neoplasia Type 1 Primary Hyperparathyroidism: A Systematic Review and Meta-Analysis. World J Surg 2022; 46:2666-2675. [PMID: 35767091 DOI: 10.1007/s00268-022-06633-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/06/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Multiple endocrine neoplasia type 1 (MEN1)-associated primary hyperparathyroidism (pHPT) is classically associated with an asymmetric and asynchronous parathyroid involvement. Subtotal parathyroidectomy (STP), which is currently the recommended surgical treatment, carries a high risk of permanent hypoparathyroidism. The results of less than subtotal parathyroidectomy (LSTP) are conflicting, and its place in this setting is still a matter of debate. The aim of this study was to identify the place of LSTP in the surgical management of patients with MEN-associated pHPT. METHODS A systematic literature review was conducted in accordance with PRISMA and MOOSE guidelines, for studies comparing STP and LSTP for MEN1-associated pHPT. The results of the two techniques, regarding permanent hypoparathyroidism, persistent hyperparathyroidism and recurrent hyperparathyroidism were computed using pairwise random-effect meta-analysis. RESULTS Twenty-five studies comparing STP and LSTP qualified for inclusion in the quantitative synthesis. In total, 947 patients with MEN1-associated pHPT were allocated to STP (n = 569) or LSTP (n = 378). LSTP reduces the risk of permanent hypoparathyroidism [odds ratio (OR) 0.29, confidence interval (CI) 95% 0.17-0.49)], but exposes to higher rates of persistent hyperparathyroidism [OR 4.60, 95% CI 2.66-7.97]. Rates of recurrent hyperparathyroidism were not significantly different between the two groups [OR 1.26, CI 95% 0.83-1.91]. CONCLUSIONS LSTP should not be abandoned and should be considered as a suitable surgical option for selected patients with MEN1-associated pHPT. The increased risk of persistent hyperparathyroidism could improve with the emergence of more efficient preoperative localization imaging techniques and a more adequate patients selection.
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Affiliation(s)
- Damien Bouriez
- Digestive and Endocrine Surgery Department, Magellan Center, Bordeaux University Hospital, University of Bordeaux, Bordeaux, France
| | - Caroline Gronnier
- Digestive and Endocrine Surgery Department, Magellan Center, Bordeaux University Hospital, University of Bordeaux, Bordeaux, France
| | - Magalie Haissaguerre
- Endocrinology Department, INSERM Unit 1215, Bordeaux University Hospital, University of Bordeaux, Bordeaux, France
| | - Antoine Tabarin
- Endocrinology Department, INSERM Unit 1215, Bordeaux University Hospital, University of Bordeaux, Bordeaux, France
| | - Haythem Najah
- Digestive and Endocrine Surgery Department, Magellan Center, Bordeaux University Hospital, University of Bordeaux, Bordeaux, France.
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19
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Nosé V, Gill A, Teijeiro JMC, Perren A, Erickson L. Overview of the 2022 WHO Classification of Familial Endocrine Tumor Syndromes. Endocr Pathol 2022; 33:197-227. [PMID: 35285003 DOI: 10.1007/s12022-022-09705-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/22/2022] [Indexed: 12/16/2022]
Abstract
This review of the familial tumor syndromes involving the endocrine organs is focused on discussing the main updates on the upcoming fifth edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. This review emphasizes updates on histopathological and molecular genetics aspects of the most important syndromes involving the endocrine organs. We describe the newly defined Familial Cancer Syndromes as MAFA-related, MEN4, and MEN5 as well as the newly reported pathological findings in DICER1 syndrome. We also describe the updates done at the new WHO on the syndromic and non-syndromic familial thyroid diseases. We emphasize the problem of diagnostic criteria, mention the new genes that are possibly involved in this group, and at the same time, touching upon the role of some immunohistochemical studies that could support the diagnosis of some of these conditions. As pathologists play an important role in identifying tumors within a familial cancer syndrome, we highlight the most important clues for raising the suspicious of a syndrome. Finally, we highlight the challenges in defining these entities as well as determining their clinical outcome in comparison with sporadic tumors. Instead of the usual subject review, we present the highlights of the updates on familial cancer syndromes by answering select questions relevant to practicing pathologists.
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Affiliation(s)
- Vania Nosé
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
| | | | - José Manuel Cameselle Teijeiro
- Clinical University Hospital Santiago de Compostela and Medical Faculty, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Aurel Perren
- Institute of Pathology, University of Bern, Bern, Switzerland
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Landry JP, Pieterman CRC, Clemente-Gutierrez U, Grubbs EG, Fisher SB, Graham PH, Waguespack SG, Perrier ND. Evaluation of risk factors, long-term outcomes, and immediate and delayed autotransplantation to minimize postsurgical hypoparathyroidism in multiple endocrine neoplasia type 1 (MEN1): A retrospective cohort study. Surgery 2021; 171:1240-1246. [PMID: 34952716 DOI: 10.1016/j.surg.2021.10.046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 10/12/2021] [Accepted: 10/21/2021] [Indexed: 11/16/2022]
Abstract
BACKGROUND Postoperative hypoparathyroidism from inadequate parathyroid hormone is of concern after multigland resections in multiple endocrine neoplasia type 1-related primary hyperparathyroidism. We evaluated risk factors, long-term outcomes, and roles of autotransplantation and cryopreservation in postoperative hypoparathyroidism in multiple endocrine neoplasia type 1. METHODS Retrospective cohort study of patients with multiple endocrine neoplasia type 1 and parathyroidectomy who were evaluated at MD Anderson from 1990 to 2020. RESULTS We included 206 patients. Median follow-up after the last operation (index 65%, reoperation 35%) was 8 years. Index parathyroidectomy was subtotal in 47%, less than subtotal in 42%, and total in 12%; hypoparathyroidism was more frequent after total parathyroidectomy. Forty-seven patients (23%) had hypoparathyroidism ≥6 months; odds were significantly higher when cumulative ≥4 glands were resected (odds ratio 6 [2.96-12.24]) or when immediate postoperative parathyroid hormone was <15 pg/mL (odds ratio 13.10 [3.61-47.47]). After median 26 months postoperatively, 30% recovered parathyroid function spontaneously; this was less likely when ≥4 glands were resected (odds ratio 0.19 [0.05-0.72]). None of the 4 patients who were aparathyroid (parathyroid hormone undetectable or ≤3 pg/mL) at 6 months postoperatively recovered parathyroid function. Immediate autotransplantation success rate was 72%. Cryopreservation was performed in 96 operations with delayed autotransplantation in 10 patients (10% utilization), of whom 5 recovered parathyroid function (time to recovery 12-93 months). CONCLUSION Odds of prolonged hypoparathyroidism are higher when cumulative ≥4 glands are resected or postoperative parathyroid hormone is <15 pg/mL. Spontaneous recovery occurred but was less likely when ≥4 glands were resected or patients were aparathyroid at 6 months postoperatively. Cryopreservation should be sparingly used, but there is value in select high-risk patients such as reoperative parathyroidectomy/cervical surgery.
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Affiliation(s)
- Jace P Landry
- Department of Surgical Oncology, Section of Surgical Endocrinology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Carolina R C Pieterman
- Department of Surgical Oncology, Section of Surgical Endocrinology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Uriel Clemente-Gutierrez
- Department of Surgical Oncology, Section of Surgical Endocrinology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Elizabeth G Grubbs
- Department of Surgical Oncology, Section of Surgical Endocrinology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Sarah B Fisher
- Department of Surgical Oncology, Section of Surgical Endocrinology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Paul H Graham
- Department of Surgical Oncology, Section of Surgical Endocrinology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Steven G Waguespack
- Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Nancy D Perrier
- Department of Surgical Oncology, Section of Surgical Endocrinology, University of Texas MD Anderson Cancer Center, Houston, TX.
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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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Мокрышева НГ, Еремкина АК, Мирная СС, Крупинова ЮА, Воронкова ИА, Ким ИВ, Бельцевич ДГ, Кузнецов НС, Пигарова ЕА, Рожинская ЛЯ, Дегтярев МВ, Егшатян ЛВ, Румянцев ПО, Андреева ЕН, Анциферов МБ, Маркина НВ, Крюкова ИВ, Каронова ТЛ, Лукьянов СВ, Слепцов ИВ, Чагай НБ, Мельниченко ГА, Дедов ИИ. [The clinical practice guidelines for primary hyperparathyroidism, short version]. PROBLEMY ENDOKRINOLOGII 2021; 67:94-124. [PMID: 34533017 PMCID: PMC9753843 DOI: 10.14341/probl12801] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 08/19/2021] [Indexed: 12/14/2022]
Abstract
Primary hyperparathyroidism (PHPT) is an endocrine disorder of parathyroid glands characterized by excessive secretion of parathyroid hormone (PTH) with an upper normal or elevated blood calcium level. Classical PHPT refers to a symptomatic, multi-system disorder, wich can lead to a significant decrease in the quality of life, disability of patients, and even an increased risk of premature death. Hypercalcemia and the catabolic effect of PTH on various cells are considered as the main pathogenetic mechanisms of the PHPT associated complications. In the last two decades, there has been an increase in the incidence of PHPT, mainly due to the mild forms of the disease, primarily due to the routine calcium screening in North America, Western Europe and, Asia. High prevalence of the disease, as well as the variety of clinical manifestations, cause the attention of different specialists - physicians, rheumatologists, urologists, nephrologists, cardiologists and other doctors. This review cover the main issues of Russian guidelines for the management of PHPT, approved in 2020, including laboratory and instrumental methods, differential diagnosis, surgical and conservative approach, short-term and long-term follow-up. This guidelines also include the recommendations for special groups of patients with hereditary forms of PHPT, parathyroid carcinoma, PHPT during pregnancy.
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Affiliation(s)
- Н. Г. Мокрышева
- Национальный медицинский исследовательский центр эндокринологии
| | - А. К. Еремкина
- Национальный медицинский исследовательский центр эндокринологии
| | | | - Ю. А. Крупинова
- Национальный медицинский исследовательский центр эндокринологии
| | - И. А. Воронкова
- Национальный медицинский исследовательский центр эндокринологии
| | - И. В. Ким
- Национальный медицинский исследовательский центр эндокринологии
| | - Д. Г. Бельцевич
- Национальный медицинский исследовательский центр эндокринологии
| | - Н. С. Кузнецов
- Национальный медицинский исследовательский центр эндокринологии
| | - Е. А. Пигарова
- Национальный медицинский исследовательский центр эндокринологии
| | - Л. Я. Рожинская
- Национальный медицинский исследовательский центр эндокринологии
| | - М. В. Дегтярев
- Национальный медицинский исследовательский центр эндокринологии
| | - Л. В. Егшатян
- Национальный медицинский исследовательский центр эндокринологии
| | | | - Е. Н. Андреева
- Национальный медицинский исследовательский центр эндокринологии
| | - М. Б. Анциферов
- Эндокринологический диспансер Департамента здравоохранения города Москвы
| | - Н. В. Маркина
- Эндокринологический диспансер Департамента здравоохранения города Москвы
| | - И. В. Крюкова
- Московский областной научно-исследовательский клинический институт им. М.Ф. Владимирского
| | - Т. Л. Каронова
- Национальный медицинский исследовательский центр им. В.А. Алмазова
| | | | | | - Н. Б. Чагай
- Ставропольский государственный медицинский университет
| | | | - И. И. Дедов
- Национальный медицинский исследовательский центр эндокринологии
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Marini F, Giusti F, Cioppi F, Maraghelli D, Cavalli T, Tonelli F, Brandi ML. Bone and Mineral Metabolism Phenotypes in MEN1-Related and Sporadic Primary Hyperparathyroidism, before and after Parathyroidectomy. Cells 2021; 10:cells10081895. [PMID: 34440663 PMCID: PMC8391385 DOI: 10.3390/cells10081895] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 07/12/2021] [Accepted: 07/26/2021] [Indexed: 11/29/2022] Open
Abstract
Primary hyperparathyroidism (PHPT) is the most common endocrinopathy in multiple endocrine neoplasia type 1 (MEN1). Persistent levels of increased parathyroid hormone (PTH) result in a higher incidence of osteopenia and osteoporosis compared to the general population. Surgical removal of hyper-functioning parathyroid tissue is the therapy of choice. This retrospective study evaluated the effect of parathyroidectomy (PTX) on bone metabolism and bone mass in two series of patients with MEN1 PHPT and sporadic PHPT (sPHPT) by comparing bone metabolism-related biochemical markers and bone mineral density (BMD) before and after surgery. Our data confirmed, in a higher number of cases than in previously published studies, the efficacy of PTX, not only to rapidly restore normal levels of PTH and calcium, but also to normalize biochemical parameters of bone resorption and bone formation, and to improve spine and femur bone mass, in both MEN1 PHPT and sPHPT. Evaluation of single-patient BMD changes after surgery indicates an individual variable bone mass improvement in a great majority of MEN1 PHPT patients. In MEN1 patients, PTX is strongly suggested in the presence of increased PTH and hypercalcemia to prevent/reduce the early-onset bone mass loss and grant, in young patients, the achievement of the bone mass peak; routine monitoring of bone metabolism and bone mass should start from adolescence. Therapy with anti-fracture drugs is indicated in MEN1 patients with BMD lower than the age-matched normal values.
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Affiliation(s)
- Francesca Marini
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 Florence, Italy; (F.M.); (F.G.); (D.M.)
- F.I.R.M.O. Italian Foundation for the Research on Bone Diseases, 50141 Florence, Italy;
| | - Francesca Giusti
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 Florence, Italy; (F.M.); (F.G.); (D.M.)
| | - Federica Cioppi
- SOD Bone and Mineral Metabolism Diseases, Azienda Ospedaliero Universitaria Careggi (AOUC), 50139 Florence, Italy;
| | - Davide Maraghelli
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 Florence, Italy; (F.M.); (F.G.); (D.M.)
| | - Tiziana Cavalli
- General, Mini-Invasive and Emergency Surgery Unit, Department of Surgery and Orthopaedics, ASST “Carlo Poma”, 46100 Mantua, Italy;
| | - Francesco Tonelli
- F.I.R.M.O. Italian Foundation for the Research on Bone Diseases, 50141 Florence, Italy;
| | - Maria Luisa Brandi
- F.I.R.M.O. Italian Foundation for the Research on Bone Diseases, 50141 Florence, Italy;
- Correspondence: ; Tel.: +39-055-2336663
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Cho YY, Chung YJ. A germline c.1546dupC MEN1 mutation in an MEN1 family: A case report. Medicine (Baltimore) 2021; 100:e26382. [PMID: 34160414 PMCID: PMC8238345 DOI: 10.1097/md.0000000000026382] [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: 04/08/2021] [Accepted: 06/02/2021] [Indexed: 01/04/2023] Open
Abstract
RATIONALE Multiple endocrine neoplasia type 1 (MEN1) is a rare tumor syndrome with an autosomal dominant inheritance, and genetic testing for MEN1 gene is important for both affected individuals and their relatives. We present a 2-person family affected by a germline c.1546dupC MEN1 mutation, and one of them had a full-spectrum of MEN-related endocrine tumors. PATIENT CONCERNS A female patient aged 32 years presented with jejunal ulcer perforation due to gastrinoma. DIAGNOSES We conducted genetic analysis and extensive biochemical/radiological evaluation for detecting other endocrine tumors. Multiple pancreatic neuroendocrine tumors (NETs), prolactinoma and primary hyperparathyroidism were diagnosed, and a frame-shift mutation, NM_130799.1:c.1546dupC (p.Arg516Profs∗15), was detected. One daughter of the proband, aged 12 years, had the same mutation for MEN1. INTERVENTION She underwent pancreatic surgery for pancreatic NETs and total parathyroidectomy for primary hyperparathyroidism. OUTCOMES After pancreatic surgery, long-term symptoms of epigastric soreness, acid belching, sweating, and palpitation in fasting were improved. Hypercalcemia was improved after parathyroidectomy and she was supplemented with oral calcium and vitamin D. Her daughter showed normal biochemical surveillance until 15 years of age. LESSONS We report 2 people in a family affected by MEN1 with the heterozygous germline c.1546dupC mutation, a variant that should be surveilled for early development of full-blown MEN1-associated endocrine tumors.
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Affiliation(s)
- Yoon Young Cho
- Division of Endocrinology and Metabolism, Department of Medicine, Soonchunhyang University Bucheon Hospital, Bucheon
| | - Yun Jae Chung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University, College of Medicine, Seoul, Korea
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Management of primary and renal hyperparathyroidism: guidelines from the German Association of Endocrine Surgeons (CAEK). Langenbecks Arch Surg 2021; 406:571-585. [PMID: 33880642 DOI: 10.1007/s00423-021-02173-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 04/06/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS The purpose of this review is to provide updated recommendations for the surgical management of primary (pHPT) and renal (rHPT) hyperparathyroidism, formulating a new guideline of the German Association of Endocrine Surgeons (CAEK). METHODS Evidence-based recommendations for the diagnosis and therapy of pHPT and rHPT were assessed by a multidisciplinary panel using PubMed for a comprehensive literature search together with a structured consensus dialogue (S2k guideline of the Association of the German Scientific Medical Societies, AWMF). RESULTS During the last 20 years, a variety of new preoperative localization procedures, such as sestamibi-SPECT, 4D-CT, and various PET/CT procedures, were established for pHPT. High-resolution imaging, together with intraoperative parathyroid hormone (IOPTH) measurement, enabled focused or minimally invasive surgery to become the most favored surgical technique. Patients with pHPT and nonlocalizing imaging have a higher risk of multiglandular disease. Surgical therapy provides very high cure rates, with a clear relation to the surgeon's experience in parathyroid procedures. Reoperative parathyroidectomy, children with pHPT or familial forms, and parathyroid carcinoma are addressed and require special surgical expertise. A multidisciplinary team of experienced nephrologists, transplant, and endocrine surgeons should assess the diagnosis and treatment of renal HPT. CONCLUSION Surgery is the only curative treatment for pHPT and should be considered for all patients with pHPT. For rHPT, a more selective approach is required, and parathyroidectomy is indicated only when conservative treatment options fail. In parathyroid carcinoma, the adequacy of local resection influences local disease control.
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Shyamasunder AH, Pai R, Ramamoorthy H, Sakhti D, Manipadam MT, Kapoor N, Paul TV, Jebasingh F, Thomas N, Abraham DT, Paul MJ, Chacko AG, Prabhu K, Rajaratnam S. Clinical Profile and Mutations Associated with Multiple Endocrine Neoplasia-Type1 (MEN1) and Their First-Degree Relatives at Risk of Developing MEN1: A Prospective Study. Horm Metab Res 2021; 53:245-256. [PMID: 33853118 DOI: 10.1055/a-1402-0183] [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: 02/06/2023]
Abstract
Multiple Endocrine Neoplasia type-1 (MEN1) is an autosomal dominant disorder with a combined occurrence of tumours of parathyroid glands, pancreatic islets, and anterior pituitary. About 90% of these patients carry mutations in the MEN1 gene, though the spectrum is not well defined in India. Forty clinically suspected cases of MEN1 were enrolled prospectively over six years; 32 patients (23 index-cases and nine affected relatives) with≥2 classical endocrine tumours of MEN1 were considered definite, and eight were categorised as 'MEN1-like'. Details of their clinical presentation, treatment and mutational analysis including MEN1 gene, 3' and 5' untranslated regions (UTR) of MEN1, CDKN1B, and CaSR genes were collated. Asymptomatic first-degree relatives were also screened. Among the 32 definite MEN1 patients, all had primary hyperparathyroidism, 22 (68.7%) had gastroentero-pancreatic neuroendocrine tumours, and 21 (66%) had pituitary adenoma. Of the 23 definite index-cases, 13 (56.5%) carried mutations in the MEN1 gene. Five of nine affected first-degree relatives (55.5%), and four of 10 asymptomatic relatives (40%) also had MEN1 mutations. Seven of 10 MEN1 mutation-negative definite index-cases harboured p.V109G polymorphism in the CDKN1B gene. All eight MEN1-like cases were negative for mutations and large deletions in MEN1, mutations in 3' and 5' UTR of MEN1, CaSR and CDKN1B genes. The study has helped to clearly document the pattern of mutations among Indian MEN1 patients. However, the absence of MEN1 mutation in ~44% of cases and the presence of p.V109G polymorphism in CDKN1B gene raise the question whether such polymorphisms could independently contribute to pathogenesis.
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Affiliation(s)
| | - Rekha Pai
- Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India
| | | | - Dhananjayan Sakhti
- Department of Pathology, Christian Medical College, Vellore, Tamil Nadu, India
| | | | - Nitin Kapoor
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
| | - Thomas Vizhalil Paul
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
| | - Felix Jebasingh
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
| | - Nihal Thomas
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
| | - Deepak Thomas Abraham
- Department of Endocrine Surgery, Christian Medical College, Vellore, Tamil Nadu, India
| | | | - Ari George Chacko
- Department of Neurosurgery, Christian Medical College, Vellore, Tamil Nadu, India
| | - Krishna Prabhu
- Department of Neurosurgery, Christian Medical College, Vellore, Tamil Nadu, India
| | - Simon Rajaratnam
- Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India
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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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Nastos C, Papaconstantinou D, Kofopoulos-Lymperis E, Peppa M, Pikoulis A, Lykoudis P, Palazzo F, Patapis P, Pikoulis E. Optimal extent of initial parathyroid resection in patients with multiple endocrine neoplasia syndrome type 1: A meta-analysis. Surgery 2020; 169:302-310. [PMID: 33008613 DOI: 10.1016/j.surg.2020.08.021] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 08/03/2020] [Accepted: 08/07/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Hyperparathyroidism is an almost universal feature of multiple endocrine neoplasia type 1 syndrome. We present a systematic review and meta-analysis of the postoperative outcomes of patients undergoing initial operative treatment of primary hyperparathyroidism complicating multiple endocrine neoplasia 1. METHODS A comprehensive literature search was performed with a priori defined exclusion criteria for studies comparing total parathyroidectomy, subtotal parathyroidectomy, and less than subtotal parathyroidectomy. RESULTS Twenty-one studies incorporating 1,131 patients (272 undergoing total parathyroidectomy, 510 subtotal parathyroidectomy, and 349 less than subtotal parathyroidectomy) were identified. Pooled results revealed increased risk for long-term hypoparathyroidism in total parathyroidectomy patients (relative risk 1.61; 95% confidence interval, 1.12-2.31; P = .009) versus those undergoing subtotal parathyroidectomy. In the less than subtotal parathyroidectomy or subtotal parathyroidectomy comparison group, a greater risk for recurrence of hyperparathyroidism (relative risk 1.37; 95% confidence interval, 1.05-1.79; P = .02), persistence of hyperparathyroidism (relative risk 2.26; 95% confidence interval, 1.49-3.41; P = .0001), and reoperation for hyperparathyroidism (relative risk 2.48; 95% confidence interval, 1.65-3.73; P < .0001) was noted for less than subtotal parathyroidectomy patients, albeit with lesser risk for long-term for hypoparathyroidism (relative risk 0.47; 95% confidence interval, 0.29-0.75; P = .002). CONCLUSION Subtotal parathyroidectomy compares favorably to total parathyroidectomy, exhibiting similar recurrence and persistence rates with a decreased propensity for long-term postoperative hypoparathyroidism. The benefit of the decreased risk of hypoparathyroidism in less than subtotal parathyroidectomy is negated by the increase in the risk for recurrence, persistence, and reoperation. Future studies evaluating the performance of less than subtotal parathyroidectomy in specific multiple endocrine neoplasia 1 phenotypes should be pursued in an effort to delineate a patient-tailored, operative approach that optimizes long-term outcomes.
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Affiliation(s)
- Constantinos Nastos
- Third Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Chaidari, Greece
| | - Dimitrios Papaconstantinou
- Third Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Chaidari, Greece.
| | - Efstratios Kofopoulos-Lymperis
- Third Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Chaidari, Greece
| | - Melpomeni Peppa
- Endocrine Unit, Second Department of Internal Medicine Propaedeutic, Research Institute and Diabetes Center, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas Pikoulis
- Third Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Chaidari, Greece
| | - Panagis Lykoudis
- Third Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Chaidari, Greece
| | - Fausto Palazzo
- Department of Surgery and Cancer, Imperial College London, London, UK
| | - Paul Patapis
- Third Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Chaidari, Greece
| | - Emmanouil Pikoulis
- Third Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, Chaidari, Greece
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Khairi S, Osborne J, Jacobs MF, Clines GT, Miller BS, Hughes DT, Else T. Outcome of Clinical Genetic Testing in Patients with Features Suggestive for Hereditary Predisposition to PTH-Mediated Hypercalcemia. Discov Oncol 2020; 11:250-255. [PMID: 32761341 DOI: 10.1007/s12672-020-00394-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Accepted: 07/27/2020] [Indexed: 12/16/2022] Open
Abstract
Primary hyperparathyroidism (pHPT) is associated with familial syndromes such as multiple endocrine neoplasia type 1 (MEN1), 2A (MEN2A), MEN-like syndromes (CDKN1B), and CDC73-related disorder (hyperparathyroidism - jaw tumor syndrome (HPJT)). Familial hypocalciuric hypercalcemia (FHH) caused by CASR variants is an important differential diagnosis for pHPT. In order to evaluate the contribution of hereditary causes to pHPT in patients encountered in a specialized clinic, we conducted a retrospective study on patients with pHPT that underwent germline genetic testing. We evaluated 46 patients referred to a Cancer Genetics Clinic. Reasons for referral were young age (age < 40) for 29 patients (63%), multi-gland disease for 23 patients (50%), and a positive family history of pHPT for 11 patients (24%). All 46 patients underwent genetic evaluation. A total of 11 rare variants were found (CASR (4), CDC73 (2), MEN1 (2) CDKN1B (1), and RET (2)). One MEN1 variant was classified as pathogenic, and all others were variants of uncertain significance (VUS). All patients with CASR variants had clinical features of FHH and were counselled against parathyroidectomy. Both patients with CDC73 variants were counselled about recurrence of pHPT and parathyroid cancer. Neither of the RET variants were MEN2-associated. The CDKN1B variant was regarded as a true VUS and no action was taken. In this study, genetic testing impacted clinical care in 7 (15%) patients. We suggest that all patients < 40 years of age, with multi-gland disease, single gland disease refractory to treatment, and a positive family history for pHPT or associated tumors should be considered for genetic evaluation.
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Affiliation(s)
- Shafaq Khairi
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Jenae Osborne
- Department of Internal Medicine, Division of Genetic Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Michelle F Jacobs
- Department of Internal Medicine, Division of Genetic Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Gregory T Clines
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109, USA
| | - Barbra S Miller
- Department of Surgery, Division of Endocrine Surgery, University of Michigan, Ann Arbor, MI, USA
| | - David T Hughes
- Department of Surgery, Division of Endocrine Surgery, University of Michigan, Ann Arbor, MI, USA
| | - Tobias Else
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, 1150 West Medical Center Drive, Ann Arbor, MI, 48109, USA.
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Gorbacheva AM, Eremkina AK, Mokrysheva NG. [Hereditary syndromal and nonsyndromal forms of primary hyperparathyroidism]. ACTA ACUST UNITED AC 2020; 66:23-34. [PMID: 33351310 DOI: 10.14341/probl10357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 01/21/2020] [Accepted: 03/18/2020] [Indexed: 12/16/2022]
Abstract
Primary hyperparathyroidism is a common disorder of mineral homeostasis, characterized by overproduction of parathyroid hormone and upper normal or elevated calcium levels due to hyperplasia or a tumor of parathyroid gland. 90−95% of cases of primary hyperparathyroidism are sporadic, while hereditary genetic forms occur in 5–10% of all cases. Primary hyperparathyroidism as the component of hereditary syndromes can present in various clinical forms (asymptomatic, symptomatic), can be associated with other endocrine or non-endocrine diseases, and require special approaches to treatment. Given that primary hyperparathyroidism is one of the most common components of these syndromes, it can be used as an important diagnostic tool in identifying affected families. This review is devoted to modern ideas about the clinical course and genetic characteristics of hereditary variants of primary hyperparathyroidism and the diagnostic and treatment algorithms recommended today. The review considers primary hyperparathyroidism as a component of hereditary syndromes including multiple endocrine neoplasias types 1, 2A and 4 and syndrome of hyperparathyroidism with a jaw tumor. Also non-syndromic hereditary forms are descripted, such as familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia, and severe neonatal primary hyperparathyroidism.
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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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Lourenço DM, de Herder WW. Editorial: Early Genetic and Clinical Diagnosis in MEN1. Front Endocrinol (Lausanne) 2020; 11:218. [PMID: 32351454 PMCID: PMC7174644 DOI: 10.3389/fendo.2020.00218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 03/26/2020] [Indexed: 11/13/2022] Open
Affiliation(s)
- Delmar M. Lourenço
- Endocrine Genetics Unit (LIM-25), Endocrinology Division, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil
- Endocrine Oncology Division, Institute of Cancer of the State of São Paulo, São Paulo, Brazil
- *Correspondence: Delmar M. Lourenço Jr. ; ;
| | - Wouter W. de Herder
- Sector Endocrinology, Department of Internal Medicine, ENETS Centre of Excellence, Erasmus MC Cancer Institute, Erasmus MC - University Medical Center, Rotterdam, Netherlands
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Manoharan J, Albers MB, Bollmann C, Maurer E, Mintziras I, Wächter S, Bartsch DK. Single gland excision for MEN1-associated primary hyperparathyroidism. Clin Endocrinol (Oxf) 2020; 92:63-70. [PMID: 31626728 DOI: 10.1111/cen.14112] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 10/10/2019] [Accepted: 10/15/2019] [Indexed: 02/07/2023]
Abstract
IMPORTANCE Guidelines advocate subtotal parathyroidectomy (SPTX) or total parathyroidectomy with autotransplantation (TPTX) with bilateral cervical thymectomy for primary hyperparathyroidism (pHPT) associated with multiple endocrine neoplasia type 1 (MEN1). However, both procedures are associated with a significant risk of permanent hypoparathyroidism. OBJECTIVE The aim of the current study was to compare long-term results of either single gland excision (SGE, 1-2 glands), SPTX and TPTX for the treatment of MEN1-associated pHPT. DESIGN AND SETTING Data of genetically confirmed MEN1 patients who underwent surgery for pHPT between 1987 and 2017 were retrieved from a prospective database and were retrospectively analysed. RESULTS Eighty-nine MEN1 patients underwent either TPTX (n = 38, 42.7%), SPTX (n = 23, 25.8%) or SGE (n = 28, 31.5%). The rate of disease persistence after initial surgery was 2.6%, 0% and 14.2% in the TPTX, SPTX and SGE groups, respectively. After median follow-up of 112 (range 7-411) months, the rate of recurrent pHPT was significantly higher in the SGE group (n = 19, 21.3%) compared with the TPTX (n = 4, 4.4%, P = .001) and the SPTX (n = 9, 10.1%, P = .03) groups. Analysis of the recurrence-free time among the surgical groups revealed a significant difference (P = .036). The median time to recurrence was significantly shorter after SGE (101, range 3-301 months) than after SPTX (139, range 28-278 months, P = .018) and TPTX (204, range 75-396 months, P = .049). Twelve (32%) patients who underwent TPTX developed permanent hypoparathyroidism compared with only 4 (17%, P = .06) in the SPTX and 0 in the SGE group (P = .001). CONCLUSION Given the high rate of postoperative permanent hypoparathyroidism after TPTX and SPTX, SGE is a valid option for the treatment of MEN1-associated pHPT.
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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
| | - Carmen Bollmann
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Elisabeth Maurer
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Ioannis Mintziras
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Sabine Wächter
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
| | - Detlef K Bartsch
- Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Marburg, Germany
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Lamas C, Navarro E, Casterás A, Portillo P, Alcázar V, Calatayud M, Álvarez-Escolá C, Sastre J, Boix E, Forga L, Vicente A, Oriola J, Mesa J, Valdés N. MEN1-associated primary hyperparathyroidism in the Spanish Registry: clinical characterictics and surgical outcomes. Endocr Connect 2019; 8:1416-1424. [PMID: 31557724 PMCID: PMC6826168 DOI: 10.1530/ec-19-0321] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Accepted: 09/23/2019] [Indexed: 12/19/2022]
Abstract
Primary hyperparathyroidism is the most frequent manifestation of multiple endocrine neoplasia type 1 (MEN1) syndrome. Bone and renal complications are common. Surgery is the treatment of choice, but the best timing for surgery is controversial and predictors of persistence and recurrence are not well known. Our study describes the clinical characteristics and the surgical outcomes, after surgery and in the long term, of the patients with MEN1 and primary hyperparathyroidism included in the Spanish Registry of Multiple Endocrine Neoplasia, Pheochromocytomas and Paragangliomas (REGMEN). Eighty-nine patients (49 men and 40 women, 34.2 ± 13 years old) were included. Sixty-four out of the 89 underwent surgery: a total parathyroidectomy was done in 13 patients, a subtotal parathyroidectomy in 34 and a less than subtotal parathyroidectomy in 15. Remission rates were higher after a total or a subtotal parathyroidectomy than after a less than subtotal (3/4 and 20/22 vs 7/12, P < 0.05), without significant differences in permanent hypoparathyroidism (1/5, 9/23 and 0/11, N.S.). After a median follow-up of 111 months, 20 of the 41 operated patients with long-term follow-up had persistent or recurrent hyperparathyroidism. We did not find differences in disease-free survival rates between different techniques, patients with or without permanent hypoparathyroidism and patients with different mutated exons, but a second surgery was more frequent after a less than subtotal parathyroidectomy.
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Affiliation(s)
- Cristina Lamas
- Department of Endocrinology and Nutrition, Complejo Hospitalario Universitario de Albacete, Albacete, Spain
- Correspondence should be addressed to C Lamas:
| | - Elena Navarro
- Department of Endocrinology and Nutrition, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Anna Casterás
- Department of Endocrinology and Nutrition, Hospital Vall d’Hebron, Barcelona, Spain
| | - Paloma Portillo
- Department of Endocrinology and Nutrition, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain
| | - Victoria Alcázar
- Department of Endocrinology and Nutrition, Hospital Universitario Severo Ochoa, Leganés, Spain
| | - María Calatayud
- Department of Endocrinology and Nutrition, Hospital Univeristario Doce de Octubre, Madrid, Spain
| | | | - Julia Sastre
- Department of Endocrinology and Nutrition, Complejo Hospitalario de Toledo, Hospital Virgen de la Salud, Toledo, Spain
| | - Evangelina Boix
- Department of Endocrinology and Nutrition, Hospital General Universitario de Elche, Elche, Spain
| | - Lluis Forga
- Department of Endocrinology and Nutrition, Complejo Hospitalario de Navarra, Hospital de Navarra, Pamplona, Spain
| | - Almudena Vicente
- Department of Endocrinology and Nutrition, Complejo Hospitalario de Toledo, Hospital Virgen de la Salud, Toledo, Spain
| | - Josep Oriola
- Biochemistry and Molecular Genetics Department, Hospital Clínic i Universitari de Barcelona, Barcelona, Spain
| | - Jordi Mesa
- Department of Endocrinology and Nutrition, Hospital Vall d’Hebron, Barcelona, Spain
| | - Nuria Valdés
- Department of Endocrinology and Nutrition, Hospital Universitario Central de Asturias, Oviedo, Spain
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Surgical Management of Multiple Endocrine Neoplasia 1 and Multiple Endocrine Neoplasia 2. Surg Clin North Am 2019; 99:693-709. [DOI: 10.1016/j.suc.2019.04.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Marini F, Giusti F, Brandi ML. Multiple endocrine neoplasia type 1: extensive analysis of a large database of Florentine patients. Orphanet J Rare Dis 2018; 13:205. [PMID: 30428914 PMCID: PMC6237029 DOI: 10.1186/s13023-018-0938-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Accepted: 10/19/2018] [Indexed: 12/16/2022] Open
Abstract
Background Multiple endocrine neoplasia (MEN1) is a rare inherited multi-tumour syndrome, affecting specific neuroendocrine organs and non-endocrine tissues with a variable spectrum of over 20 possible different combinations, caused by inactivating heterozygote mutations of the MEN1 gene. Disease onset, penetrance, clinical presentation, course and prognosis are all extremely variable, even among individuals bearing the same causative mutation, which doesn’t allow prediction of the individual clinical phenotype (based on the specific result of the genetic test), thus compelling all patients and mutation carriers to undergo a common routine general screening program. Results We performed an extensive epidemiological, clinical and genetic analysis of the Florentine MEN1 patient database, which includes 145 MEN1 patients and 20 asymptomatic MEN1 carriers, constantly followed up at the Regional Referral Centre for Inherited Endocrine Tumours of the Tuscany Region, during the last three decades. We reported, here, the results of clinical, epidemiological and genetic descriptive statistics, as well as correlation analyses between tumours and mutation types and localisation. No direct genotype-phenotype correlation was described, but the importance of the genetic testing was confirmed for an early diagnosis and the identification of asymptomatic carriers. Conclusions As with all rare diseases, the possibility to collect and analyse data on a relatively large number of patients is important for increasing our knowledge of the epidemiologic aspects of the disease, and its natural course and prognosis of single manifestations of the syndrome, in order to set up the best diagnostic and therapeutic plans for patients. In this light, the creation and constant updating of large patient databases is fundamental. Results from database study can provide useful epidemiological, clinical and genetic information about MEN1 syndrome, which could help clinicians in the diagnostic and therapeutic management of single MEN1 patients.
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Affiliation(s)
- Francesca Marini
- Department of Surgery and Translational Medicine, University of Florence, Largo Palagi 1, 50139, Florence, Italy
| | - Francesca Giusti
- Department of Surgery and Translational Medicine, University of Florence, Largo Palagi 1, 50139, Florence, Italy
| | - Maria Luisa Brandi
- Department of Surgery and Translational Medicine, University of Florence, Largo Palagi 1, 50139, Florence, Italy.
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Abstract
A genetic disorder should be suspected in patients with hypercalcemia, notably those who are young; have family members with hypercalcemia; or have had a tumor of the endocrine pancreas, thyroid, pituitary, adrenal gland, or jaw bone. All forms of hypercalcemia should be interpreted according to the serum level of parathyroid hormone (PTH). Genetic forms are thus classified as related or unrelated to a parathyroid gland disorder. When the PTH level is elevated or is not depressed despite the hypercalcemia, findings that suggest family history of hypercalcemia due to a genetic cause include syndromic manifestations in the patient or family members, parathyroid cancer (either suspected before surgery or confirmed during parathyroidectomy), multiple or recurrent parathyroid tumors, a family history of primary hyperparathyroidism, and the onset of primary hyperthyroidism before 50 years of age. In patients with moderate hypercalcemia, a normal PTH level, and relative hypocalciuria, the first hypothesis is a mutation in the calcium-sensing receptor gene, which is often difficult to distinguish from primary hyperparathyroidism, particularly when there is no known family history of hyperparathyroidism, as is often the case. A low PTH level suggests non-parathyroid hypercalcemia due to a genetic defect in patients with no evidence of other conditions associated with hypercalcemia and low PTH levels and in those whose calcitriol levels are elevated or normal (instead of depressed as expected when PTH is elevated). Patients with hypercalciuria but no evidence of conditions such as granulomatous diseases should be evaluated for increased vitamin D sensitivity due to a CYP 4A1 mutation. Other very rare causes include hypophosphatasia due to ALPL mutations, which is characterized by a low alkaline phosphatase level; and renal phosphate wasting due to an NPT2A mutation, in which serum phosphate levels are low. A thorough analysis of the clinical and laboratory data can point toward a genetic disorder in patients with hypercalcemia. The diagnosis is then confirmed by obtaining genetic tests tailored to the clinical and laboratory test abnormalities. The current development of diagnostic genetic testing is shedding new light on the phenotypes, thereby improving their management.
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Affiliation(s)
- Catherine Cormier
- Hôpital Cochin assistance publique, hôpitaux de Paris, 27, rue du faubourg Saint-Jacques, 75014 Paris, France.
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Impact of "Tailored" Parathyroidectomy for Treatment of Primary Hyperparathyroidism in Patients with Multiple Endocrine Neoplasia Type 1. World J Surg 2018; 42:1772-1778. [PMID: 29138914 DOI: 10.1007/s00268-017-4366-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
BACKGROUND Whether total parathyroidectomy (TPTX) or subtotal parathyroidectomy (SPTX) should be performed for primary hyperparathyroidism (PHPT) in patients with multiple endocrine neoplasia type 1 (MEN1) is controversial. At our institution, the parathyroidectomy strategy is based on the number of enlarged intraoperative parathyroid glands. We retrospectively analyzed our parathyroidectomy procedures. METHODS Data of PHPT treatment in patients with MEN1 who underwent parathyroidectomy from 1982 to 2012 at our department were retrospectively collected. The data were grouped according to the surgical procedure: TPTX, SPTX, and less than SPTX (LPTX). TPTX or SPTX was selected based on the preoperative examination findings and number of enlarged intraoperative parathyroid glands. The outcomes were the disease-free survival (DFS) rate and postoperative calcium replacement rate based on Kaplan-Meier analysis for each type of surgical procedure. RESULTS Forty-five patients were analyzed. The overall 5- and 10-year DFS was 91.7 and 55.8%, respectively. The 5- and 10-year DFS in each subgroup was 100.0 and 85.7% in the TPTX group, 89.4 and 57.3% in the SPTX group, and 91.6 and 57.3% in the LPTX group, respectively. The postoperative calcium replacement rate at 1 and 12 months was 91.7 and 58.3% in the TPTX group, 21.1 and 7.0% in the SPTX group, and 30.0 and 0.0% in the LPTX group, respectively. CONCLUSIONS Although LPTX was not satisfactory as a standard procedure, both SPTX and TPTX are effective treatment methods for PHPT in patients with MEN1. The parathyroidectomy strategy should be based on intraoperative evaluation of the parathyroid glands.
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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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Parnell KE, Oltmann SC. The surgical management of primary hyperparathyroidism: an updated review. INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2018. [DOI: 10.2217/ije-2017-0019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Patients with primary hyperparathyroidism often present clinically asymptomatic with various biochemical compositions of serum calcium, parathyroid hormone, vitamin D and urinary calcium. Understanding the subtle differences in clinical and biochemical presentations is key for timely diagnosis and referral to an experienced parathyroid surgeon. Surgery remains the only option for cure of primary hyperparathyroidism, which now favors a directed parathyroidectomy with intra-operative adjuncts. However it is important to understand and revise the surgical approach for patients with hereditary conditions or nonlocalizing studies. Revised guidelines from the Fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism in 2013 and the American Association of Endocrine Surgeons in 2016 are reviewed in this paper for an updated review of this condition.
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Affiliation(s)
- Kaela E Parnell
- Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, E6.104B, Dallas, TX 75390–9092, USA
| | - Sarah C Oltmann
- Department of Surgery, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, E6.104B, Dallas, TX 75390–9092, USA
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de Laat JM, van Leeuwaarde RS, Valk GD. The Importance of an Early and Accurate MEN1 Diagnosis. Front Endocrinol (Lausanne) 2018; 9:533. [PMID: 30254610 PMCID: PMC6141626 DOI: 10.3389/fendo.2018.00533] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 08/22/2018] [Indexed: 12/16/2022] Open
Abstract
Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant inherited condition, causing significant morbidity, and a reduction of life expectancy. A timely and accurate diagnosis of MEN1 is paramount to improve disease outcomes. This enables early identification of tumor manifestations allowing timely treatment for reducing morbidity and improving survival. Current management of MEN1 poses two challenges regarding the MEN1 diagnosis: diagnostic delay and the issue of phenocopies. A delay in diagnosis can be caused by a delay in identifying the index case, and by a delay in identifying affected family members of an index case. At present, lag time between diagnosis of MEN1 in index cases and genetic testing of family members was estimated to be 3.5 years. A subsequent delay in diagnosing affected family members was demonstrated to cause potential harm. Non-index cases have been found to develop clinically relevant tumor manifestations during the lag times. Centralized care, monitoring of patients outcomes on a national level and thereby improving awareness of physicians treating MEN1 patients, will contribute to improved care. The second challenge relates to "phenocopies." Phenocopies refers to the 5-25% of clinically diagnosed patients with MEN1in whom no mutation can be found. Up to now, the clinical diagnosis of MEN1 is defined as the simultaneous presence of at least two of the three characteristic tumors (pituitary, parathyroids, or pancreatic islets). These clinically diagnosed patients undergo intensive follow up. Recent insights, however, challenge the validity of this clinical criterion. The most common mutation-negative MEN1 phenotype is the combination of primary hyperparathyroidism and a pituitary adenoma. This phenotype might also be caused by mutations in the CDKN1B gene, causing the recently described MEN4 syndrome. Moreover, primary hyperparathyroidism and pituitary adenoma are relatively common in the general population. Limiting follow-up in patients with a sporadic co-occurrence of pHPT and PIT could reduce exposure to radiation from imaging, healthcare costs and anxiety.
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Tonelli F, Marini F, Giusti F, Brandi ML. Total and Subtotal Parathyroidectomy in Young Patients With Multiple Endocrine Neoplasia Type 1-Related Primary Hyperparathyroidism: Potential Post-surgical Benefits and Complications. Front Endocrinol (Lausanne) 2018; 9:558. [PMID: 30319541 PMCID: PMC6165877 DOI: 10.3389/fendo.2018.00558] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 09/03/2018] [Indexed: 11/13/2022] Open
Abstract
Background: The choice of surgical treatment for patients with Multiple Endocrine Neoplasia type 1 (MEN1)-related primary hyperparathyroidism (PHPT) remains controversial and it has not been specifically addressed in young patients. Methods: This is a retrospective case series study. The study includes the surgical data and the follow-up of 38 patients younger than 30 years of age, all diagnosed with MEN1, collected and followed-up between 1991 and 2017 at the Regional Referral Center for Inherited Endocrine Tumors of the Tuscany Region, and operated by parathyroidectomy. Genetic and/or clinical MEN1 diagnosis was made before surgery in all patients. Subtotal (9/38 patients) or total parathyroidectomy with auto-transplantation (28/38 patients) were performed in all patients but one, in whom a single mediastinal adenoma was excised from the aorto-pulmonary window. All patients but one, who was operated in 2017, had a post-operatory follow-up of at least 12 months. Results: Total parathyroidectomy (TPTX), with auto-transplantation, was the most frequently adopted operation both as primary (20/38 patients) and secondary (8/38 patients) surgery, followed by subtotal parathyroidectomy (SPTX; 9/38 patients) and limited parathyroidectomy (1/38 patient). At follow-up, lasting a mean of 11.8 ± 6.6 years (range 0-23 years), no persistent PHPT was observed. PHPT recurred in 4/28 TPTX (14%) and in 2/9 SPTX (22%). Permanent hypoparathyroidism showed no statistically significant difference between the procedures (2/9 in SPTX and 5/28 in TPTX). Conclusions: Data from this retrospective study showed the efficacy of TPTX for the treatment of MEN1-PHPT, also in adolescent and young patients, showing, in our series, no risk of PHPT permanence and a longer disease-free period and, subsequently, the possibility to postpone re-intervention with respect to both limited PTX and SPTX. The risk of permanent hypoparathyroidism in TPTX was comparable to STPX, and could be mitigated over the years.
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Genotype-phenotype pancreatic neuroendocrine tumor relationship in multiple endocrine neoplasia type 1 patients: A 23-year experience at a single institution. Surgery 2018; 163:212-217. [DOI: 10.1016/j.surg.2017.04.044] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 03/29/2017] [Accepted: 04/19/2017] [Indexed: 11/21/2022]
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El Lakis M, Nockel P, Guan B, Agarwal S, Welch J, Simonds WF, Marx S, Li Y, Nilubol N, Patel D, Yang L, Merkel R, Kebebew E. Familial isolated primary hyperparathyroidism associated with germline GCM2 mutations is more aggressive and has a lesser rate of biochemical cure. Surgery 2017; 163:31-34. [PMID: 29108698 DOI: 10.1016/j.surg.2017.04.027] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 03/14/2017] [Accepted: 04/05/2017] [Indexed: 10/18/2022]
Abstract
BACKGROUND Hereditary primary hyperparathyroidism may be syndromic or nonsyndromic (familial isolated hyperparathyroidism). Recently, germline activating mutations in the GCM2 gene were identified in a subset of familial isolated hyperparathyroidism. This study examined the clinical and biochemical characteristics and the treatment outcomes of GCM2 mutation-positive familial isolated hyperparathyroidism as compared to sporadic primary hyperparathyroidism. METHODS We performed a retrospective analysis of clinical features, parathyroid pathology, and operative outcomes in 18 patients with GCM2 germline mutations and 457 patients with sporadic primary hyperparathyroidism. RESULTS Age at diagnosis, sex distribution, race/ethnicity, and preoperative serum calcium concentrations were similar between the 2 groups. The preoperative serum levels of intact parathyroid hormone was greater in patients with GCM2-associated primary hyperparathyroidism (239 ± 394 vs 136 ± 113, P = .005) as were rates of multigland disease and parathyroid carcinoma in the GCM2 group (78% vs 14.3%, P < .001 and 5% vs 0%, P = .04, respectively), but the biochemical cure rate was less in the GCM2 group (86% vs 99%, P < .001). CONCLUSION GCM2-associated primary hyperparathyroidism patients have greater preoperative parathyroid hormone levels, a greater rate of multigland disease, a lesser rate of biochemical cure, and a substantial risk of parathyroid carcinoma. Knowledge of these clinical characteristics could optimize the surgical management of GCM2-associated familial isolated hyperparathyroidism.
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Affiliation(s)
- Mustapha El Lakis
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Pavel Nockel
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Bin Guan
- Metabolic Disease Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Sunita Agarwal
- Metabolic Disease Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - James Welch
- Metabolic Disease Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - William F Simonds
- Metabolic Disease Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Stephen Marx
- Metabolic Disease Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Yulong Li
- Metabolic Disease Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Naris Nilubol
- Metabolic Disease Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Dhaval Patel
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Lily Yang
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Roxanne Merkel
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Electron Kebebew
- Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Surgery, The George Washington University, School of Medicine and Health Sciences, Washington, DC.
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Kluijfhout WP, Beninato T, Drake FT, Vriens MR, Gosnell J, Shen WT, Suh I, Liu C, Duh QY. Unilateral Clearance for Primary Hyperparathyroidism in Selected Patients with Multiple Endocrine Neoplasia Type 1. World J Surg 2017; 40:2964-2969. [PMID: 27402205 PMCID: PMC5104782 DOI: 10.1007/s00268-016-3624-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Background Primary hyperparathyroidism is the most common manifestation of multiple endocrine neoplasia type 1 (MEN1). Guidelines advocate subtotal parathyroidectomy (STP) or total parathyroidectomy with autotransplantation due to high prevalence of multiglandular disease; however, both are associated with a significant risk of permanent hypoparathyroidism. More accurate imaging and use of intraoperative PTH levels may allow a less extensive initial parathyroidectomy (unilateral clearance, removing both parathyroids with cervical thymectomy) in selected MEN1 patients with primary hyperparathyroidism. Methods We performed a retrospective cohort study at a high-volume tertiary medical center including patients with MEN1 and primary hyperparathyroidism, who underwent STP or unilateral clearance as their initial surgery from 1995 to 2015. Unilateral clearance was offered to patients who had concordant sestamibi and ultrasound showing a single enlarged parathyroid gland. For both the groups, we compared rates of persistent/recurrent disease and permanent hypoparathyroidism. Results Eight patients had unilateral clearance and 16 had STP. Subtotal parathyroidectomy patients were younger (37 vs 52 years). One patient in each group had persistent disease. One (13 %) unilateral clearance and five (31 %) STP patients had recurrent hyperparathyroidism after a mean follow-up of 47 and 68 months (p = 0.62). No unilateral clearance patients and two of 16 SPT patients had permanent hypoparathyroidism (p = 0.54). Conclusions Some MEN1 patients with primary hyperparathyroidism who have concordant localizing studies may be selected for unilateral clearance as an alternative to STP. For appropriately selected MEN1 patients, unilateral clearance can achieve similar results as STP and has no risk of permanent hypoparathyroidism, and may facilitate possible future reoperations.
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Affiliation(s)
- Wouter P Kluijfhout
- Department of Surgery, University of California, Mt Zion, 1600 Divisadero Street, San Francisco, CA, 94115, USA. .,Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
| | - Toni Beninato
- Department of Surgery, University of California, Mt Zion, 1600 Divisadero Street, San Francisco, CA, 94115, USA
| | - Frederick Thurston Drake
- Department of Surgery, University of California, Mt Zion, 1600 Divisadero Street, San Francisco, CA, 94115, USA
| | - Menno R Vriens
- Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jessica Gosnell
- Department of Surgery, University of California, Mt Zion, 1600 Divisadero Street, San Francisco, CA, 94115, USA
| | - Wen T Shen
- Department of Surgery, University of California, Mt Zion, 1600 Divisadero Street, San Francisco, CA, 94115, USA
| | - Insoo Suh
- Department of Surgery, University of California, Mt Zion, 1600 Divisadero Street, San Francisco, CA, 94115, USA
| | - Chienying Liu
- Division of Endocrinology, University of California, San Francisco, CA, USA
| | - Quan-Yang Duh
- Department of Surgery, University of California, Mt Zion, 1600 Divisadero Street, San Francisco, CA, 94115, USA
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Pieterman CRC, de Laat JM, Twisk JWR, van Leeuwaarde RS, de Herder WW, Dreijerink KMA, Hermus ARMM, Dekkers OM, van der Horst-Schrivers ANA, Drent ML, Bisschop PH, Havekes B, Borel Rinkes IHM, Vriens MR, Valk GD. Long-Term Natural Course of Small Nonfunctional Pancreatic Neuroendocrine Tumors in MEN1-Results From the Dutch MEN1 Study Group. J Clin Endocrinol Metab 2017; 102:3795-3805. [PMID: 28938468 DOI: 10.1210/jc.2017-00372] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2017] [Accepted: 08/01/2017] [Indexed: 11/19/2022]
Abstract
BACKGROUND Pancreatic neuroendocrine tumors (pNETs) are highly prevalent in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic disease is an important cause of MEN1-related mortality. Especially small nonfunctional (NF) pNETs pose a challenge to the treating physician and more information is needed regarding their natural course. We assessed long-term natural history of small NF-pNETs and its modifiers in the Dutch MEN1 population. PATIENTS AND METHODS Retrospective longitudinal observational cohort study of patients with small (<2 cm) NF-pNETs from the Dutch national MEN1 database, which includes >90% of the Dutch MEN1 population. Modifiers of long-term natural course were analyzed using linear mixed-models analysis. RESULTS Growth rate of the 115 included small NF-pNETs from 99 patients was slow (0.4 mm/y; 95% confidence interval, 0.15 to 0.59). Seventy percent of the tumors was stable and a subgroup of 30% of the tumors was growing (1.6 mm/y; 95% confidence interval, 1.1 to 2.0). No differences in clinical characteristics were identified between growing and stable tumors. Within the subgroup of growing tumors, germline missense mutations were significantly associated with accelerated growth compared with nonsense and frameshift mutations. CONCLUSION The majority of small NF-pNETs are stable at long-term follow-up, irrespective of the underlying MEN1 genotype. A subgroup of tumors is slowly growing but cannot be identified on clinical grounds. In this subgroup, tumors with missense mutations exhibited faster growth. Additional events appear necessary for pNETs to progress. Future studies should be aimed at identifying these molecular driving events, which could be used as potential biomarkers.
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Affiliation(s)
- Carolina R C Pieterman
- Department of Endocrine Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
| | - Joanne M de Laat
- Department of Endocrine Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
| | - Jos W R Twisk
- Department of Clinical Epidemiology and Biostatistics, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
- Department of Health Sciences, VU University, 1007 MB Amsterdam, The Netherlands
| | - Rachel S van Leeuwaarde
- Department of Endocrine Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
| | - Wouter W de Herder
- Department of Internal Medicine, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands
| | - Koen M A Dreijerink
- Department of Endocrine Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
| | - Ad R M M Hermus
- Department of Endocrinology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
| | - Olaf M Dekkers
- Departments of Endocrinology and Metabolism and Clinical Epidemiology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
| | | | - Madeleine L Drent
- Department of Internal Medicine, Section of Endocrinology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Peter H Bisschop
- Department of Endocrinology and Metabolism, Academic Medical Center, 1100 DD Amsterdam, The Netherlands
| | - Bastiaan Havekes
- Department of Internal Medicine, Division of Endocrinology, Maastricht University Medical Center, 6202 AZ Maastricht, The Netherlands
| | - Inne H M Borel Rinkes
- Department of Endocrine Surgical Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
| | - Menno R Vriens
- Department of Endocrine Surgical Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
| | - Gerlof D Valk
- Department of Endocrine Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands
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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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Li Y, Simonds WF. Recent advances in the management of endocrine malignancies associated with hereditary hyperparathyroidism syndromes. INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2017. [DOI: 10.2217/ije-2016-0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Hereditary hyperparathyroidism syndromes, such as multiple endocrine neoplasm type 1, type 2A and the hyperparathyroidism-jaw tumor syndrome, are associated with an increased incidence of malignancies involving the neuroendocrine tissue of the pancreas and thymus, parathyroid and thyroid glands. The natural history of these endocrine tumors can differ from nonhereditary malignancies. The surgical approach, the only potentially curative treatment option for these endocrine malignancies, has evolved considerably in recent years. Newer targeted therapies, such as small molecule kinase inhibitors, somatostatin analogs and peptide receptor radionuclide therapy, are being developed. We provide here a comprehensive review of the current standards of treatment and emerging novel therapies for the endocrine malignancies commonly associated with hereditary hyperparathyroidism syndromes.
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Affiliation(s)
- Yulong Li
- Metabolic Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, MD 20892, USA
| | - William F Simonds
- Metabolic Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, MD 20892, USA
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Guerin C, Paladino NC, Lowery A, Castinetti F, Taieb D, Sebag F. Persistent and recurrent hyperparathyroidism. Updates Surg 2017; 69:161-169. [PMID: 28434176 DOI: 10.1007/s13304-017-0447-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 04/08/2017] [Indexed: 12/26/2022]
Abstract
Despite remarkable progress in imaging modalities and surgical management, persistence or recurrence of primary hyperparathyroidism (PHPT) still occurs in 2.5-5% of cases of PHPT. The aim of this review is to expose the management of persistent and recurrent hyperparathyroidism. A literature search was performed on MEDLINE using the search terms "recurrent" or "persistent" and "hyperparathyroidism" within the past 10 years. We also searched the reference lists of articles identified by this search strategy and selected those we judged relevant. Before considering reoperation, the surgeon must confirm the diagnosis of PHPT. Then, the patient must be evaluated with new imaging modalities. A single adenoma is found in 68% of cases, multiglandular disease in 28%, and parathyroid carcinoma in 3%. Others causes (<1%) include parathyromatosis and graft recurrence. The surgeon must balance the benefits against the risks of a reoperation (permanent hypocalcemia and recurrent laryngeal nerve palsy). If surgery is necessary, a focused approach can be considered in cases of significant imaging foci, but in the case of multiglandular disease, a bilateral neck exploration could be necessary. Patients with multiple endocrine neoplasia syndromes are at high risk of recurrence and should be managed regarding their hereditary pathology. The cure rate of persistent-PHPT or recurrent-PHPT in expert centers is estimated from 93 to 97%. After confirming the diagnosis of PHPT, patients with persistent-PHPT and recurrent-PHPT should be managed in an expert center with all dedicated competencies.
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Affiliation(s)
- Carole Guerin
- Department of Endocrine Surgery, La Conception Hospital, Assistance Publique Hopitaux de Marseille, 147 BD Baille, 13005, Marseille, France. .,Aix-Marseille University, Medical School, 27, bd Jean Moulin, 13385, Marseille Cedex 05, France.
| | - Nunzia Cinzia Paladino
- Department of Endocrine Surgery, La Conception Hospital, Assistance Publique Hopitaux de Marseille, 147 BD Baille, 13005, Marseille, France
| | - Aoife Lowery
- Department of Surgery, University Hospital Limerick and Graduate Entry Medical School University of Limerick, Limerick, Ireland
| | - Fréderic Castinetti
- Aix-Marseille University, Medical School, 27, bd Jean Moulin, 13385, Marseille Cedex 05, France.,Department of Endocrinology, La Conception Hospital, Assistance Publique Hopitaux de Marseille, 147 BD Baille, 13005, Marseille, France
| | - David Taieb
- Aix-Marseille University, Medical School, 27, bd Jean Moulin, 13385, Marseille Cedex 05, France.,Department of Nuclear Medicine, La Timone Hospital, Assistance Publique Hopitaux de Marseille, 264 Rue Saint-Pierre, 13385, Marseille, France
| | - Fréderic Sebag
- Department of Endocrine Surgery, La Conception Hospital, Assistance Publique Hopitaux de Marseille, 147 BD Baille, 13005, Marseille, France.,Aix-Marseille University, Medical School, 27, bd Jean Moulin, 13385, Marseille Cedex 05, France
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Abstract
Primary hyperparathyroidism (PHPT) is the most common cause of chronic hypercalcemia. With the advent of routine calcium screening, the classic presentation of renal and osseous symptoms has been largely replaced with mild, asymptomatic disease. In hypercalcemia caused by PHPT, serum parathyroid hormone levels are either high, or inappropriately normal. A single-gland adenoma is responsible for 80% of PHPT cases. Less frequent causes include 4-gland hyperplasia and parathyroid carcinoma. Diminished bone mineral density and nephrolithiasis are the major current clinical sequelae. Parathyroidectomy is the only definitive treatment for PHPT, and in experienced hands, cure rates approach 98%.
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Affiliation(s)
- Kyle A Zanocco
- Section of Endocrine Surgery, UCLA David Geffen School of Medicine, 10833 Le Conte Avenue, 72-182 CHS, Los Angeles, CA 90095, USA
| | - Michael W Yeh
- Section of Endocrine Surgery, UCLA David Geffen School of Medicine, 10833 Le Conte Avenue, 72-250 CHS, Los Angeles, CA 90095, USA.
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