Telomerase reverse transcriptase (TERT) promoter mutations have been linked to adverse clinical parameters in thyroid cancer, but TERT-expressing tumours are not always mutated. Little is known regarding other TERT-related genetic aberrations. To delineate the role of TERT gene aberrancies in follicular thyroid tumours, 95 follicular carcinomas (FTCs), 43 follicular adenomas (FTAs) and 33 follicular tumours of uncertain malignant potential (FT-UMPs) were collected. The tumours were assayed for TERT expression, TERT promoter mutations, TERT promoter hypermethylation and TERT gene copy number (CN) alterations and the results were compared to clinical parameters. Cases with mutation, detectable mRNA expression, CN gain or hypermethylation were classified as TERT aberrant, and these aberrancies were regularly found in FTC and FT-UMP but uncommonly found in FTA. In total, 59% FTCs and 63% FT-UMPs exhibited one or more of these TERT gene aberrancies. Moreover, 24 out of 28 FTCs (86%) with TERT expression displayed an evident TERT gene aberration, and statistics showed an increased risk for relapse in FTCs with TERT expression, CN gain or hypermethylation. We conclude that TERT expression in follicular thyroid tumours is coupled to promoter mutations, CN gain and increased promoter methylation. The molecular similarities regarding TERT aberrations between the FTC and FT-UMP groups indicate that a significant subset of FT-UMP cases may display future recurrences. TERT aberrancies are thus promising as future additional markers for determining malignant potential of follicular thyroid tumours.
Johan O Paulsson, Ninni Mu, Ivan Shabo, Na Wang, Jan Zedenius, Catharina Larsson, and C Christofer Juhlin
C Juhlin, C Larsson, T Yakoleva, I Leibiger, B Leibiger, A Alimov, G Weber, A Höög, and A Villablanca
Inactivation of the hyperparathyroidism–jaw tumour syndrome (HPT– JT) gene, HRPT2, was recently established as a genetic mechanism in the development of parathyroid tumours. Its encoded protein parafibromin has tumour-suppressor properties that play an important role in tumour development in the parathyroids, jaws and kidneys. Inactivating HRPT2 mutations are common in HPT– JT and parathyroid carcinomas, and have been described in a few cases of parathyroid adenomas with cystic features. In this study, 46 cases of cystic parathyroid adenomas previously investigated for HRPT2 mutations were characterized with regard to MEN1 gene mutations, cyclin D1 expression and parafibromin expression. In normal tissues and cell lines, parafibromin was ubiquitously expressed. Furthermore, parafibromin was detected as a dominating nuclear and a weaker cytoplasmic signal in transfected cell lines. In the three parathyroid tumours with inactivating HRPT2 mutations parafibromin expression was not detectable, and in one of two cases with aberrantly sized parafibromin the protein was delocalized. Both high and low cyclin D1 levels were found among HRPT2-mutated and -unmutated tumours, suggesting that these events are not mutually exclusive in parathyroid tumour development. The presented data suggest that in the majority of benign parathyroid tumours the expression of parafibromin remains unaltered, while the loss of parafibromin expression is strongly indicative of gene inactivation through mutation of the HRPT2 gene.
Elizabeth Grubbs, Daniel Halperin, Steven G Waguespack, and Robert F Gagel
The multiple endocrine neoplasia (MEN) workshops had their beginnings at Queen’s University in Kingston, Ontario in June 1984. This initial meeting brought clinicians and scientists together to focus on mapping the gene for multiple endocrine neoplasia type 2 (MEN2). These efforts culminated in the identification of the RET protooncogene as the causative gene a decade later. Over the next 35 years there were a total of 16 international workshops focused on the several MEN syndromes. Importantly, these workshops were instrumental in efforts to define the molecular basis for multiple endocrine neoplasia type 1 (MEN1), MEN2, von Hippel-Lindau disease (VHL), Carney Complex, hereditary pheochromocytoma and hyperparathyroidism. In this same spirit some 150 scientists and clinicians met at MD Anderson Cancer Center, 27–29 March 2019, for the 16th International Workshop on Multiple Endocrine Neoplasia (MEN2019). Appropriate to its location in a cancer centre, the workshop focused on important issues in the causation and treatment of malignant aspects of the MEN syndromes: medullary thyroid carcinoma, pancreatic neuroendocrine tumours, malignant pheochromocytoma and parathyroid carcinoma. Workshops at the meeting focused on a better understanding of how the identified molecular defects in these genetic syndromes lead to transformation, how to apply targeted kinase inhibitors and immunotherapy to treat these tumours and important clinical management issues. This issue of Endocrine-Related Cancer describes these discussions and recommendations.
C C Juhlin, A Villablanca, K Sandelin, F Haglund, J Nordenström, L Forsberg, R Bränström, T Obara, A Arnold, C Larsson, and A Höög
Parafibromin is a protein product derived from the hyperparathyroidism 2(HRPT2) tumor suppressor geneand its inactivation has been coupled to familial and sporadic forms of parathyroid malignancy. In this study, we have conducted immunohistochemistry on 33 parathyroid carcinomas (22 unequivocal and 11 equivocal) using four parafibromin antibodies directed to different parts of the protein. Furthermore, for a fraction of cases, the immunohistochemical results were compared with known HRPT2 mutational status. Our findings show that 68% (15 out of 22) of the unequivocal carcinomas exhibited reduced expression of parafibromin while the 25 sporadic adenomas used as controls were entirely positive for parafibromin expression. Additionally, three out of the six carcinomas with known HRPT2 mutations showed reduced expression of parafibromin. Using all four antibodies, comparable results were obtained on the cellular level in individual tumors suggesting that there exists no epitope of choice in parafibromin immunohistochemistry. The results agree with the demonstration of a ~60 kDa product preferentially in the nuclear fraction by western blot analysis. We conclude that parafibromin immunohistochemistry could be used as an additional marker for parathyroid tumor classification, where positive samples have low risk of malignancy, whereas samples with reduced expression could be either carcinomas or rare cases of adenomas likely carrying an HRPT2 mutation.
Carole Guerin, Pauline Romanet, David Taieb, Thierry Brue, André Lacroix, Frederic Sebag, Anne Barlier, and Frederic Castinetti
Over the last years, the knowledge of MEN2 and non-MEN2 familial forms of pheochromocytoma (PHEO) has increased. In MEN2, PHEO is the second most frequent disease: the penetrance and age at diagnosis depend on the mutation of RET. Given the prevalence of bilateral PHEO (50% by age 50), adrenal sparing surgery, aimed at sparing a part of the adrenal cortex to avoid adrenal insufficiency, should be systematically considered in patients with bilateral PHEO. Non-MEN2 familial forms of PHEO now include more than 20 genes: however, only small phenotypic series have been reported, suggesting that phenotypic features of isolated hereditary PHEO must be better explored, and follow-up series are needed to better understand the outcome of patients carrying mutations of these genes. The first part of this review will mainly focus on these points. In the second part, a focus will be given on MEN2 and non-MEN2 familial forms of hyperparathyroidism (HPTH). Again, the management of MEN2 HPTH should be aimed at curing the disease while preserving an optimal quality of life by a tailored parathyroidectomy. The phenotypes and outcome of MEN1-, MEN4- and HRPT2-related HPTH are briefly described, with a focus on the most recent literature data and is compared with familial hypocalciuric hypercalcemia.
F Lumachi, P Zucchetta, S Varotto, F Polistina, G Favia, and D D'Amico
In primary hyperparathyroidism (pHPT), parathyroidectomy is the treatment of choice, but anatomic variations of ectopic glands may cause surgical failure. Reliable preoperative noninvasive localization procedures would have a positive impact on the operative time and increase recovery rate. We retrospectively evaluated 186 patients with pHPT who were studied before successful parathyroidectomy by double tracer scintigraphy (99mTc-pertechnetate+201TI chloride or 99mTc-pertechnetate +99mTc-sestamibi, 160 patients), ultrasonography (148 patients) and computerized tomography (CT) scan (92 patients). During bilateral neck exploration, 159 (85.5%) single adenomas, 6 (3.2%) parathyroid carcinomas, and 3 (1.6%) double adenomas were found. Moreover, 18 (9.7%) patients had diffuse chief cells parathyroid hyperplasia. Removed parathyroid glands were in ectopic sites in 41 (22.0%) cases, mainly localized in the upper mediastinum or behind the esophagus. The overall sensitivity was 83.5 and 85.2% for 99mTc-pertechnetate+201TI chloride and 99mTc-pertechnetate+99mTc-sestamibi scintigraphy respectively, 80.4% for CT scan and 81.1% for ultrasonography. In patients with ectopic glands, sensitivity was 81.2, 79.5, 73.3 and 81.6% respectively. In 36 out of 41 patients with ectopic glands in whom the removed parathyroids were correctly localized, mean operative time was 95 min, and in 5 patients without preoperative localization it was 260 min. In conclusion, in pHPT, preoperative localization of an enlarged parathyroid is helpful, especially in ectopic adenomas and in anatomic variations in location, and it has been proved to reduce operative time and morbidity rate.
Giulia Masi, Luisa Barzon, Maurizio Iacobone, Giovanni Viel, Andrea Porzionato, Veronica Macchi, Raffaele De Caro, Gennaro Favia, and Giorgio Palù
CDC73 (HRPT2) germline mutations are responsible for more than half of cases of hyperparathyroidism-jaw tumor syndrome (HPT-JT) and for a subset of familial isolated HPT (FIHP). We performed a clinical, genetic, and histopathologic study in three unrelated Italian kindreds with HPT-JT and FIHP. We identified three germline inactivating mutations of the CDC73 gene in the probands and affected patients of the three kindreds, but also in some asymptomatic subjects. HPT-JT and FIHP patients had similar laboratory, clinical, and demographic features and shared primary HPT and other neoplasms, the most common of which was uterine polyposis. Genetic analysis of tumor samples demonstrated a second somatic CDC73 mutation only in a parathyroid adenoma and no cases with the loss of the wild-type allele or methylation of the CDC73 promoter, even though immunohistochemical analysis demonstrated the loss of nuclear parafibromin expression in all tumors, including a uterine polyp. In conclusion, our results indicate that FIHP and HPT-JT associated with CDC73 mutations do not have distinct clinical, genetic, and histopathologic features, but may represent variants of the same genetic disease. This study also confirms that uterine involvement represents a clinical manifestation of the syndrome.
Kelly Brewer, Jessica Costa-Guda, and Andrew Arnold
Primary hyperparathyroidism (PHPT) is a common endocrine disorder characterized by dysregulation of parathyroid hormone release. The large majority of PHPT cases are attributable to sporadic, single-gland parathyroid adenoma, in which MEN1 and CCND1/cyclin D1 are the most well-established drivers of tumorigenesis. Sporadic parathyroid carcinoma, which appears to mostly arise through molecular pathways distinct from those causing benign parathyroid tumors, is rare and is most frequently driven by mutational inactivation of the CDC73 (HRPT2) tumor suppressor gene. Targeted investigation of suspected tumor driver genes, as well as unbiased whole-genome or exome sequencing of small cohorts, have revealed additional novel candidate tumor genes in sporadic parathyroid neoplasia, generally at modest or low mutational frequencies consistent with marked molecular genetic heterogeneity from tumor to tumor. The ability of these additional candidates to participate in the pathogenic process of driving parathyroid tumorigenesis in vivo largely remains to be demonstrated experimentally. This review will summarize the molecular genetic abnormalities identified to date in sporadic PHPT and discuss the strength of evidence for their proposed roles in parathyroid tumor formation.
Rachel S van Leeuwaarde, Joanne M de Laat, Carolina R C Pieterman, Koen Dreijerink, Menno R Vriens, and Gerlof D Valk
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.
S Takahashi, M Hakuta, K Aiba, Y Ito, N Horikoshi, M Miura, K Hatake, and E Ogata
Parathyroid hormone (PTH) and PTH-related protein/peptide (PTHrP) bind to the same PTH/PTHrP receptor and stimulate osteoblasts to secrete pro-inflammatory cytokines like interleukin (IL)-6. In patients with primary hyperparathyroidism, elevation of plasma levels of tumor necrosis factor (TNF)-alpha and IL-6 was also described. We, therefore, postulated that PTHrP secreted from cancer cells stimulates the secretion of cytokines and causes increases in their blood levels. Blood concentrations of several cytokines (TNF-alpha, IL-1beta, IL-5, IL-6, IL-8, IL-11 and IL-12) in cancer-bearing patients with or without elevation of blood PTHrP were measured by ELISA. The patients with high plasma PTHrP levels (n=29, intact PTHrP: 8.5 +/- 1.4 pmol/l, normal: <1.1) had higher serum type 1 collagen C-telopeptide (ICTP). Twenty of the patients were hypercalcemic. Plasma concentrations of TNF-alpha, IL-6 and IL-8 were significantly increased in patients with high PTHrP, in either the presence or absence of hypercalcemia. The concentrations of TNF-alpha and IL-6 were also significantly correlated with those of PTHrP. Our observations indicate that high plasma levels of PTHrP in cancer-bearing patients contribute not only to the development of hypercalcemia, but also to the development of the syndrome caused by an excess of pro-inflammatory cytokines.