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Endocrine Neoplasms in Familial Syndromes of Hyperparathyroidism

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Endocrine Neoplasms in Familial Syndromes of Hyperparathyroidism 236 Y Li and W F Simonds Hyperparathyroidism-associated 23:6 R229–R247 Review neoplasms Endocrine neoplasms in familial syndromes of hyperparathyroidism Correspondence Yulong Li and William F Simonds should be addressed to W F Simonds Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Email National Institutes of Health, Bethesda, Maryland, USA [email protected] Abstract Familial syndromes of hyperparathyroidism, including multiple endocrine Key Words neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2A (MEN2A), f multiple endocrine and the hyperparathyroidism-jaw tumor (HPT-JT), comprise 2–5% of primary neoplasia type 1 (MEN1) hyperparathyroidism cases. Familial syndromes of hyperparathyroidism are also f multiple endocrine neoplasia type 2A associated with a range of endocrine and nonendocrine tumors, including potential (MEN2A) malignancies. Complications of the associated neoplasms are the major causes of f hyperparathyroidism-jaw morbidities and mortalities in these familial syndromes, e.g., parathyroid carcinoma tumor (HPT-JT) in HPT-JT syndrome; thymic, bronchial, and enteropancreatic neuroendocrine tumors f malignant tumor in MEN1; and medullary thyroid cancer and pheochromocytoma in MEN2A. Because f neuroendocrine tumor of the different underlying mechanisms of neoplasia, these familial tumors may have different characteristics compared with their sporadic counterparts. Large-scale clinical trials are frequently lacking due to the rarity of these diseases. With technological advances and the development of new medications, the natural history, diagnosis, Endocrine-Related Cancer Endocrine-Related and management of these syndromes are also evolving. In this article, we summarize the recent knowledge on endocrine neoplasms in three familial hyperparathyroidism syndromes, with an emphasis on disease characteristics, molecular pathogenesis, recent developments in biochemical and radiological evaluation, and expert opinions on surgical and medical therapies. Because these familial hyperparathyroidism syndromes are associated with a wide variety of tumors in different organs, this review is focused on those endocrine neoplasms with malignant potential. Endocrine-Related Cancer (2016) 23, R229–R247 Introduction Primary hyperparathyroidism has an estimated pre­ spectrum of endocrine tumors and other malignancies. valence of 0.1% in the United States. Familial forms Some of these fami lial endocrine tumors behave very represent some 2–5% of primary hyperparathyroidism differently from their sporadic counterparts, showing and are caused by germline genetic mutations distinct clinical characteristics and disease courses. (Table 1). Among these, multiple endocrine neoplasia Many of these tumors also have a significant malignant type 1 (MEN1), multiple endocrine neoplasia type potential and require different treatment approaches. 2A (MEN2A), and the hyperparathyroidism­jaw Being familiar with their unique features and natural tumor syndrome (HPT­JT) are familial syndromes history may facilitate diagnosis and help to establish of hyperparathyroidism that are associated with a individua lized management to improve outcomes. http://erc.endocrinology-journals.org © 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-16-0059 Printed in Great Britain Downloaded from Bioscientifica.com at 09/23/2021 12:37:41PM via free access 10.1530/ERC-16-0059 Review Y Li and W F Simonds Hyperparathyroidism-associated 23:6 R230 neoplasms Table 1 Familial causes of hyperparathyroidism. Germline gene Molecular Disorder mutation pathology Endocrine neoplasms with malignant potential Familial syndromes leading to primary hyperparathyroidism and including endocrine tumors with malignant potential Multiple endocrine neoplasia type 1 syndrome MEN1 Loss of function Malignant duodenopancreatic neuroendocrine tumor; thymic and bronchial neuroendocrine tumors Multiple endocrine neoplasia type 2A RET Gain of function Medullary thyroid cancer; malignant syndrome pheochromocytoma Hyperparathyroidism-jaw tumor syndrome CDC73 Loss of function Parathyroid carcinoma Familial disorders leading to primary hyperparathyroidism only Familial hypocalciuric hypercalcemia CASR Loss of function Not applicable Neonatal severe primary hyperparathyroidism CASR Loss of function Not applicable Familial isolated hyperparathyroidism Unknown Unknown Not applicable (CDC73, MEN1, CASR mutation testing negative) We herein summarize and update the knowledge on developing parathyroid carcinoma, ranging from 15 endocrine neoplasms with malignant potential found in to 37.5% in different case series (Sharretts & Simonds familial syndromes of hyperparathyroidism, including 2010, Mehta et al. 2014). For comparison, parathyroid 1) HPT­JT­associated parathyroid carcinoma; 2) MEN1­ carcinoma only accounts for 0.005% of total cancer associated nonfunctioning pancreatic neuroendocrine cases in National Cancer Database Report (Hundahl tumors (pNETs), gastrinoma and insulinoma, and et al. 1999). Interestingly, somatic inactivating CDC73 thymic and bronchial NET (sometimes referred to mutations are strongly implicated in sporadic parathyroid as ‘carcinoid tumors’); and 3) MEN2A­associated carcinoma and have been found in up to 70% of such medullary thyroid cancer and pheochromocytoma. cancers (Shattuck et al. 2003, Do Cao et al. 2015). Because of space limitations, we favor the citation of HPT­JT is an extremely rare disease. The available recent review articles, wherein the curious reader can literature includes only case reports, case series, and easily find reference to the original studies. retrospective studies of small sample size. The prevalence of this disease in general population is unknown. Cases of Endocrine-Related Cancer Endocrine-Related HPT­JT have been reported in Australia, the US, Canada, Parathyroid cancer in the hyperparathyroidism- Europe, Japan, India, China, Thailand, and France (Howell jaw tumor syndrome et al. 2003, Bricaire et al. 2013, Kutcher et al. 2013, Kong HPT­JT is an autosomal­dominant familial cancer et al. 2014, Sriphrapradang et al. 2014, Khadilkar et al. 2015, syndrome caused by inactivating germline mutation Mathews et al. 2015, Shibata et al. 2015), suggesting that this of the cell division cycle 73 (CDC73) gene (formerly disease has neither ethnic preference. No gender preference called HRPT2), with incomplete penetrance and variable was found in a large patient cohort (Asare et al. 2015). expression (Carpten et al. 2002, Bradley et al. 2006). Because of its incomplete penetrance, patients with Clinical manifestations germline CDC73 mutation can present with a spectrum of phenotypes including seemingly sporadic parathyroid The vast majority of parathyroid carcinomas are cancer, familial isolated hyperparathyroidism (FIHP) functioning tumors that cause clinical symptoms or with or without parathyroid cancer, or full expression signs related to severe primary hyperparathyroidism of HPT­JT (Sharretts & Simonds 2010). Patients with and hypercalcemia, such as bone or joint pain, fatigue, HPT­JT may manifest hyperparathyroidism and other nephrolithiasis, muscle weakness, constipation, reduced medical conditions, including fibro­osseous tumors bone mass, and psychiatric abnormalities. Distinct of the maxilla or mandible (histologically classified as from primary hyperparathyroidism due to parathyroid cemento­ossifying fibromas), kidney tumors, and uterine adenoma, patients with parathyroid cancer (either sporadic lesions. Hypercalcemia and its complications (such as or in the context of HPT­JT or FIHP) usually present with nephrolithiasis) and bone disease are major causes of higher calcium levels and more severe symptoms (Shane mortality and morbidity in primary hyperparathyroidism. 2001, Wei & Harari 2012). Total serum calcium levels are Patients of HPT­JT also have an increased risk of usually more than 13 mg/dL and may be even higher than http://erc.endocrinology-journals.org © 2016 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/ERC-16-0059 Printed in Great Britain Downloaded from Bioscientifica.com at 09/23/2021 12:37:41PM via free access Review Y Li and W F Simonds Hyperparathyroidism-associated 23:6 R231 neoplasms 16 mg/dL, with parathyroid hormone levels at least three to of c­Myc, a proto­oncogene, and established regulator ten times of the upper normal limit and often in the range of cell growth (Lin et al. 2008), and enhances expression 200–1800 pg/mL (Wei & Harari 2012, Mehta et al. 2014, of c­Myc target genes (Jaenicke et al. 2016). Despite this Sriphrapradang et al. 2014). Nonfunctioning parathyroid knowledge of the cellular functions of parafibromin, carcinoma has been reported in a normocalcemic CDC73 our understanding of the necessary links between the mutation carrier (Guarnieri et al. 2006). Patients with loss of parafibromin function and the development of HPT­JT may also have or have had silent or clinically parathyroid cancer remains incomplete. evident cemento­ossifying fibromas of the maxilla or mandible or uterine abnormalities. Diagnosis Parathyroid carcinoma can cause compressive symptoms due to mass effect such as dysphagia, dyspnea, When a patient presents with severe symptomatology of dysphonia, or dysarthria (Shane 2001, Wei & Harari 2012). primary hyperparathyroidism and significantly elevated Parathyroid carcinomas are likely to be much bigger than serum calcium and parathyroid hormone levels, it should parathyroid adenomas,
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