{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T17:46:43Z","timestamp":1763747203279},"reference-count":58,"publisher":"The Endocrine Society","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,8,1]]},"abstract":"\n Context:<\/jats:title>\n Multiplicity of hormone-secreting tumors occurs in a substantial portion of hormone-excess states. Multiplicity increases the difficulty of management and drives the selection of special strategies.<\/jats:p>\n <\/jats:sec>\n \n Evidence Acquisition:<\/jats:title>\n This is a synthesis from publications about tumor development and expression, and also about types of clinical strategy for hormone-secreting tumors.<\/jats:p>\n <\/jats:sec>\n \n Evidence Synthesis:<\/jats:title>\n Comparisons were made between patient groups with solitary tumors vs those with multiple tumors. Major themes with clinical relevance emerged. Usually, tumor multiplicity develops from a genetic susceptibility in all cells of a tissue. This applies to hormone-secreting tumors that begin as either polyclonal (such as in the parathyroids of familial hypocalciuric hypercalcemia) or monoclonal tumors (such as in the parathyroids of multiple endocrine neoplasia type 1 [MEN1]). High penetrance of a hereditary tumor frequently results in bilaterality and in several other types of multiplicity. Managements are better for the hormone excess than for the associated cancers. Management strategies can be categorized broadly as ablation that is total, subtotal, or zero. Examples are discussed for each category, and 1 example of each category is named here: 1) total ablation of the entire tissue with effort to replace ablated functions (for example, in C-cell neoplasia of multiple endocrine neoplasia type 2); 2) subtotal ablation with increased likelihood of persistent disease or recurrent disease (for example, in the parathyroid tumors of MEN1); or 3) no ablation of tissue with or without the use of pharmacotherapy (for example, with blockers for secretion of stomach acid in gastrinomas of MEN1).<\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n Tumor multiplicity usually arises from defects in all cells of the precursor tissue. Even the optimized managements involve compromises. Still, an understanding of pathophysiology and of therapeutic options should guide optimized management.<\/jats:p>\n <\/jats:sec>","DOI":"10.1210\/jc.2013-1511","type":"journal-article","created":{"date-parts":[[2013,6,15]],"date-time":"2013-06-15T03:59:54Z","timestamp":1371268794000},"page":"3139-3148","source":"Crossref","is-referenced-by-count":8,"title":["Multiplicity of Hormone-Secreting Tumors: Common Themes About Cause, Expression, and Management"],"prefix":"10.1210","volume":"98","author":[{"given":"Stephen J.","family":"Marx","sequence":"first","affiliation":[{"name":"Genetics and Endocrinology Section, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","reference":[{"key":"2020071615263180100_B1","doi-asserted-by":"crossref","first-page":"820","DOI":"10.1073\/pnas.68.4.820","article-title":"Mutation and cancer: Statistical study of retinoblastoma","volume":"68","author":"Knudson","year":"1971","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071615263180100_B2","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1186\/1471-2407-6-131","article-title":"Somatic VHL gene alterations in MEN2-associated medullary thyroid carcinoma","volume":"6","author":"Kock","year":"2006","journal-title":"BMC Cancer"},{"key":"2020071615263180100_B3","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1126\/science.1235122","article-title":"Cancer genome landscapes","volume":"339","author":"Vogelstein","year":"2013","journal-title":"Science"},{"key":"2020071615263180100_B4","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1183\/09031936.00105911","article-title":"Clonality of multifocal nonsmall cell lung cancer: implications for staging and therapy","volume":"39","author":"Warth","year":"2012","journal-title":"Eur Respir J"},{"key":"2020071615263180100_B5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1530\/EJE-10-0775","article-title":"Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations","volume":"164","author":"Hebrant","year":"2011","journal-title":"Eur J Endocrinol"},{"key":"2020071615263180100_B6","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1210\/er.2003-0037","article-title":"Hereditary hormone excess: genes, molecular pathways, and syndromes","volume":"26","author":"Marx","year":"2005","journal-title":"Endocr Rev"},{"key":"2020071615263180100_B7","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1126\/science.1198785","article-title":"K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension","volume":"331","author":"Choi","year":"2011","journal-title":"Science"},{"key":"2020071615263180100_B8","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/nrendo.2012.230","article-title":"Role of KCNJ5 in familial and sporadic primary aldosteronism","volume":"9","author":"Mulatero","year":"2013","journal-title":"Nat Rev Endocrinol"},{"key":"2020071615263180100_B9","doi-asserted-by":"crossref","first-page":"4695","DOI":"10.3748\/wjg.15.4695","article-title":"Clonality and allelotype analyses of focal nodular hyperplasia compared with hepatocellular adenoma and carcinoma","volume":"15","author":"Cai","year":"2009","journal-title":"World J Gastroenterol"},{"key":"2020071615263180100_B10","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1097\/01.MP.0000081727.75778.0C","article-title":"C-Cell hyperplasia and medullary thyroid carcinoma: clinicopathological and genetic correlations in 66 consecutive patients","volume":"16","author":"Guyetant","year":"2003","journal-title":"Mod Pathol"},{"key":"2020071615263180100_B11","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1053\/j.gastro.2005.01.058","article-title":"Precursor lesions in patients with multiple endocrine neoplasia type 1-associated duodenal gastrinomas","volume":"128","author":"Anlauf","year":"2005","journal-title":"Gastroenterology"},{"key":"2020071615263180100_B12","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1210\/jc.2007-2279","article-title":"A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger Ellison syndrome: identification of risk factors","volume":"93","author":"Berna","year":"2008","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615263180100_B13","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1073\/pnas.98.3.1118","article-title":"A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors","volume":"98","author":"Crabtree","year":"2001","journal-title":"Proc Nat Acad Sci USA"},{"key":"2020071615263180100_B14","first-page":"2489","article-title":"A highly sensitive polymerase chain reaction method detects activating mutations of the GNAS gene in peripheral blood cells in McCune-Albright syndrome or isolated fibrous dysplasia","volume":"87","author":"Lietman","year":"2005","journal-title":"J Bone Joint Surg Am"},{"key":"2020071615263180100_B15","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1056\/NEJMoa1205119","article-title":"Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia","volume":"367","author":"Zhuang","year":"2012","journal-title":"N Engl J Med"},{"key":"2020071615263180100_B16","first-page":"4020","article-title":"Thyroid nodules in the follow-up of irradiated individuals: comparison of thyroid ultrasound with scanning and palpation","volume":"82","author":"Schneider","year":"1997","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615263180100_B17","first-page":"254","article-title":"Dose-response relationships for radiation-induced hyperparathyroidism","volume":"80","author":"Schneider","year":"1995","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615263180100_B18","doi-asserted-by":"crossref","first-page":"2784","DOI":"10.1210\/jc.2006-2833","article-title":"Germline NF1 mutation spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1","volume":"92","author":"Bausch","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071615263180100_B19","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/ng1048","article-title":"HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome","volume":"32","author":"Carpten","year":"2002","journal-title":"Nat Genet"},{"key":"2020071615263180100_B20","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1007\/s11605-012-1847-0","article-title":"Pancreatic lesions in von Hippel-Lindau disease? 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Endocrinol Metab"},{"key":"2020071615263180100_B42","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1111\/j.1365-2265.2007.03082.x","article-title":"Bilateral laparoscopic adrenalectomy for corticotrophin-dependent Cushing's syndrome: a review of the Mayo Clinic experience","volume":"68","author":"Chow","year":"2008","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071615263180100_B43","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/j.surg.2008.08.024","article-title":"Waiting for change: symptom resolution after adrenalectomy for Cushing's syndrome","volume":"144","author":"Sippel","year":"2008","journal-title":"Surgery"},{"key":"2020071615263180100_B44","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.3748\/wjg.v17.i10.1343","article-title":"Biochemically curative surgery for gastrinoma in multiple endocrine neoplasia type 1 patients","volume":"17","author":"Imamura","year":"2011","journal-title":"World J 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