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Andreas Machens and Henning Dralle

Objective

Decreasing tumor size in a population over time is widely interpreted as a measure of effectiveness of cancer screening programs. Nonetheless, thyroid cancer size is rarely analyzed as a function of time. This study aimed to explore secular trends of thyroid cancer diameter in Germany.

Design

Retrospective analysis of 1644 thyroid cancer patients from a large referral center for thyroid cancer (1995–2009).

Methods

Calculation of largest tumor diameters for each type of cancer as a function of time periods and birth cohorts.

Results

Over the past 25 years, subdivided into 5-year periods by year of thyroidectomy (1985–1989; 1990–1994; 1995–1999; 2000–2004; 2005–2009), tumor diameters diminished from 25 to 16 mm (P=0.025) for medullary thyroid cancer and from 28 to 18 mm (P=0.017) for papillary thyroid cancer. This reduction was greater for hereditary medullary thyroid cancer (from 27 to 11 mm; P=0.088) than sporadic medullary thyroid cancer (from 23 to 19 mm; P=0.11). No decline was observed for follicular thyroid cancer (means of 45 to 42 mm; P=0.52). From the first (1921–1940) to the most recent birth cohort (1981–2000), tumor size fell from 22 to 10 mm (P<0.001) for medullary thyroid cancer, from 24 to 22 mm (P<0.001) for papillary thyroid cancer, and from 49 to 38 mm (P=0.011) for follicular thyroid cancer. The reduction of medullary thyroid cancers affected exclusively patients with hereditary disease (from 20 to 7 mm; P<0.001).

Conclusion

The consistency and robustness of these data signify powerful secular trends toward smaller papillary, follicular, and medullary thyroid cancers. The causes and consequences of these trends warrant further investigation.

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Andreas Machens and Henning Dralle

Objective

Time trends of the extent of disease at first diagnosis and biochemical cure remain ill-defined for sporadic medullary thyroid cancer (MTC). This investigation aimed to delineate time trends and biochemical cure rates for sporadic MTC.

Design

This was an observational study of consecutive patients operated on for sporadic MTC between 1995 and 2015.

Methods

Time trends of clinical and histopathological variables indicative of the extent of disease and biochemical cure were calculated for 600 patients with sporadic MTC, 322 of whom had initial neck surgery and 278 of whom had neck reoperation at a tertiary surgical center in Germany.

Results

From 1995–2000 to 2011–2015, significant declines (all P<0.001) were noted in the percentage of node-positive tumors (from 73 to 49%), mediastinal lymph node metastasis (from 21 to 6%) and distant metastasis (from 23 to 6%). These changes were paralleled by significant increases (all P<0.001) in mean patient age (from 49.1 to 57.3years) and the percentage of MTC ≤10mm (from 19 to 39%) and biochemical cure (from 28 to 62%). When only patients with primary tumors >10mm were considered, the decreasing percentage of mediastinal lymph node metastasis and distant metastasis, and rising mean patient age and biochemical cure rates remained statistically significant.

Conclusions

Significant reductions in the extent of the disease and improved biochemical cure rates pointed toward increasing therapeutic control of sporadic MTC. The independent contribution of routine calcitonin screening to these time-dependent changes warrants more research.

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Andreas Machens, Christine Hofmann, Steffen Hauptmann and Henning Dralle

Objective: Studies of outcome in patients with medullary thyroid carcinoma require long follow-ups to accrue enough cancer-specific events. Owing to time-dependent changes in diagnosis and therapy, long observation periods render studies susceptible to ‘time bias’ which can yield spurious results. This study was designed to investigate cancer-specific event rates after initial neck resection in contemporaneous patients recruited within less than a decade.

Design: Institutional cohort study of 128 consecutive patients who underwent compartment-oriented neck surgery between 1994 and 2002 at a tertiary surgical center for hitherto untreated medullary thyroid carcinoma.

Methods: The Kaplan–Meier method was used in conjunction with the log-rank test for analysis of time-dependent outcomes.

Results: Follow-up was available for 120 patients (94%) including 63 rearranged during transfection (RET) carriers. There were six locoregional recurrences in the 110 patients with clear surgical margins at initial neck resection, and 12 cancer-specific deaths in the 120 patients with available follow-up. On Kaplan–Meier analysis, most clinicopathological variables were significantly associated with recurrence-free survival and cancer-specific survival. Within the median observation period of 64.5 months, patients with node-negative tumors did not develop locoregional recurrence or die from their malignancies. The low event rates precluded multivariate analyses with all clinicopathological variables. With our extensive surgical approach, median recurrence-free survival and cancer-specific survival at 5 years were 95.2 and 89.3% respectively.

Discussion: Compared with literature data, our 5-year locoregional recurrence rate of 4.8% appeared very favorable, and our 5-year cancer-specific mortality rate of 10.7% was among the lowest ever reported. The growing proportion of localized medullary thyroid carcinomas among contemporaneous patients can be expected to ultimately lower the event rates, complicating future studies of outcome.

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Karin Frank-Raue, Christine Haag, Egbert Schulze, Roger Keuser, Friedhelm Raue, Henning Dralle and Kerstin Lorenz

Objective

Hyperparathyroidism-jaw tumour (HPT-JT) syndrome is a rare autosomal dominant cause of benign and malignant parathyroid tumours, ossifying jaw tumours, various cystic and neoplastic renal abnormalities and benign and malignant uterine tumours. Disease-causing mutations have been localised in the tumour suppressor gene CDC73. There is limited information available on the mutations, and resulting phenotypes and long-term follow-up data are especially scarce.

Design

We analysed the clinical data from 16 patients (including three families) carrying mutations in the CDC73 gene. We describe five new mutations/gene variants, the corresponding phenotypes of these carriers and the long-term follow-up.

Methods

The 16 patients were evaluated at an endocrine outpatient clinic and at a surgical department. DNA samples were obtained for sequence analysis of the CDC73 gene.

Results

Clinical features of HPT-JT syndrome were detected in 13 of the 15 carriers with germline CDC73 mutations. The major features were benign (n=7; 47%) or cancerous (n=3; 20%) HPT-JT was present in eight cases (53%). Most patients had severe hypercalcaemia, and median serum calcium levels were 3.36 mmol/l. A patient with non-secretory parathyroid carcinoma was included. HPT was diagnosed at a median age of 28.5 years. Mutational analysis of the CDC73 gene identified eight sequence changes, three of them have been reported previously, whereas five are novel: c.1346delG, c.88_94delTTCTCCT, the non-coding variants, c.307+5G>T and c.424−5T>C and c.*12C>A of unknown significance.

Conclusions

This study significantly increases the information available on the mutations and phenotypes of HPT-JT syndrome.

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Andreas Machens, Kerstin Lorenz, Carsten Sekulla, Wolfgang Höppner, Karin Frank-Raue, Friedhelm Raue and Henning Dralle

Objective

Twenty years ago, the groundbreaking discovery that rearranged during transfection (RET) mutations underlie multiple endocrine neoplasia 2 (MEN2) and familial medullary thyroid cancer (FMTC) ushered in the era of personalized medicine. MEN2-associated signs, taking time to manifest, can be subtle. This study sought to clarify to what extent conventional estimates of 1:200 000–500 000 underestimate the incidence of RET mutations in the population.

Design

Included in this retrospective investigation were 333 RET carriers born between 1951 and 2000 and operated on at the largest German surgical referral center (286 carriers) or elsewhere (47 carriers).

Methods

To estimate the incidence of RET mutations, the number of RET carriers born in Germany in five decades (1951–1960, 1961–1970, 1971–1980, 1981–1990, and 1991–2000) was divided by the corresponding number of German live births.

Results

Owing to improved diagnosis and capture of FMTC and MEN2 patients, minimum incidence estimates increased over time: overall from 5.0 (1951–1960) to 9.9 (1991–2000) per million live births and year (P=0.008), and by American Thyroid Association/ATA class from 1.7 to 3.7 for ATA class C (P=0.008); from 1.8 to 2.7 for ATA class A (P=0.017); from 1.5 to 2.2 for ATA class B (P=0.20); and from 0 to 1.4 for ATA class D mutations per million live births and year (P=0.008). Based on 1991–2000 incidence estimates the prevalence in Germany is ∼1:80 000 inhabitants.

Conclusions

The molecular minimum incidence estimate of ≈1:100 000 was two- to fivefold greater than conventional estimates of 1:200 000–500 000.

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Henning Dralle, Rüdiger Schwarzrock, Walter Lang, Werner Böcker, Horst Ziegler, Sören Schröder and Heinz Geerlings

Abstract. The importance of lightmicroscopical and immunohistochemical features of 38 recurrent differentiated thyroid carcinomas (27 papillary carcinomas (PC), 11 follicular carcinomas (FC)) for post-operative serum thyroglobulin (TG) concentrations was analysed in regard to pre-operative serum TG levels with tumour type, histological and cytological differentiation, volume fraction of TG synthesizing tumour cells (TG immunohistomorphometry), tumour volume and radioiodine uptake (RIU).

Serum TG concentrations increased with tumour size and the number of TG synthesizing tumour cells (r = 0.5). PC and FC did not differ in their volume proportions of TG synthesizing tumour cells, while TG serum levels in FC significantly exceeded those of PC of similar size. The low TG serum levels found in PC might be explained by a specific defect in thyroglobulin secretion. Carcinomas with partial or total cytologic metaplasia (e.g. oxyphilic carcinomas) had low volume proportions of TG synthesizing cells and low serum TG levels.

Thirteen of the 38 differentiated carcinomas (34.2%) showed both high TG serum levels and positive RIU, 17 (44.7%) disclosed only elevated TG serum levels and 6 (15.8%) a positive RIU. In two cases (5.3%) TG serum levels were not elevated and RIU's were negative. TG immunostaining was positive in all 38 cases.

In summary, TG serum levels depend on the following morphologic factors in differentiated thyroid carcinomas: 1) Number of TG synthesizing tumour cells, 2) Mode of TG secretion and 3) Cytological differentiation of the tumour cells. Serum TG levels did not predict total body iodine scan.

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Furio Pacini, Martin Schlumberger, Henning Dralle, Rossella Elisei, Johannes W A Smit and Wilmar Wiersinga

Group-author : the European Thyroid Cancer Taskforce

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Kerstin Krause, Stefan Karger, Oliver Gimm, Sien-Yi Sheu, Henning Dralle, Andrea Tannapfel, Kurt Werner Schmid, Corinne Dupuy and Dagmar Fuhrer

Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide in the human thyroid. The aim of the present study was (I) to investigate whether DEHAL1 expression is different in differentially functioning thyroid pathologies and (II) to evaluate DEHAL1 as a possible marker of thyroid cell differentiation.

Design and methods: Real-time PCR for DEHAL1 and its isoform DEHAL1B was performed in a series of 105 thyroid specimens, including toxic thyroid nodules (TTN), Graves’ disease (GD) thyroids, benign cold thyroid nodules (CTN), normal thyroid tissues and thyroid cancers (follicular thyroid carcinomas (FTC), papillary thyroid carcinomas (PTC), partially differentiated thyroid cancers (PDTC) and anaplastic thyroid carcinomas (ATC)). In addition, DEHAL1 protein expression was studied by immunohistochemistry in 163 benign and malignant thyroid pathologies and normal thyroids.

Results: (I) The highest DEHAL1 mRNA levels were found in GD thyroids, while downregulation of DEHAL1 and DEHAL1B mRNA occurred in PTC and ATC (P<0.001 and <0.05 respectively); (II) DEHAL1 protein was overexpressed in TTNs and GD thyroids with predominant apical staining in all samples; (III) a weaker and patchy staining pattern was found in CTNs and normal thyroids; (IV) in differentiated thyroid cancers (FTC and PTC), a diffuse cytoplasmic DEHAL1 expression was found; and (V) in PDTC and ATC, DEHAL1 expression was faint or absent.

Conclusion: Upregulation of DEHAL1 protein expression and sublocalisation of DEHAL1 at the apical cell pole in TTNs and GD thyroids is consistent with increased thyroid hormone turnover during thyrotoxicosis. Diffuse cytoplasmatic localisation or downregulation of DEHAL1 expression in thyroid cancers suggests alteration or loss of DEHAL1 function during thyroid cell dedifferentiation.

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Frank Schuppert, Markus Reiser, Niels-E Heldin, Sülke Ede, Georg FW Scheumann, Henning Dralle and Alexander von zur Mühlen

Schuppert F, Reiser M, Heldin N-E, Ede S, Scheumann GFW, Dralle H, von zur Mühlen A. Thyrotropin receptor and leukocyte adhesion molecules in autoimmune thyroid disease: a study of their gene expression by Northern blot analysis and in situ hybridization. Eur J Endocrinol 1994;131:480–8. ISSN 0804–4643

In order to characterize the role of leukocyte-activating antigens and other immunological parameters in autoimmune thyroid disease, mRNA levels of intercellular adhesion molecule 1 (ICAM-1), endothelial leukocyte adhesion molecule 1 (ELAM-1, E-selectin), invariant chain (Ii) and the thymic hormone thymosin β4 (Tβ4) were investigated in 18 human thyroid glands, including eight Graves' thyroids, two Hashimoto's thyroids, two endemic goiters and six healthy controls. Northern blot analysis showed that in autoimmune thyroid disease, expression of ICAM-1 and Tβ4 was correlated to transcript levels of Ii, whereas in the healthy controls, expression of Tβ4, ICAM-1 and ELAM-1 was low or nearly absent. ELAM-1 and TSH receptor (TSH-R) expression, the latter serving as a thyroid specific marker, was increased in some diseased glands but showed no relation to the immunological parameters mentioned above. Localization of the specific mRNAs by in situ hybridization demonstrated a cell-specific expression of TSH-R (thyrocytes), ELAM-1 (vascular endothelial cells) and Tβ4 (cells of hematopoietic origin). In contrast, transcripts of Ii and ICAM-1 were found in thyrocytes, leukocytes and endothelial cells. Our results implicate a coordinate expression of ICAM-1, Tβ4 and Ii in autoimmune thyroid disease, yielding distinct cellular expression patterns. Differential expression of ICAM-1. Ii and the TSH-R in thyroid epithelial cells indicates active regulatory events within the thyrocyte.

Frank Schuppert, Department of Clinical Endocrinology, Medizinische Hochschule Hannover, Konstanty-Gutschow-Strasse 8, D-30625 Hannover, Germany

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Martin Fassnacht, Wiebke Arlt, Irina Bancos, Henning Dralle, John Newell-Price, Anju Sahdev, Antoine Tabarin, Massimo Terzolo, Stylianos Tsagarakis and Olaf M Dekkers

By definition, an adrenal incidentaloma is an asymptomatic adrenal mass detected on imaging not performed for suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, but may also represent conditions requiring therapeutic intervention (e.g. adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastasis). The purpose of this guideline is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with adrenal incidentalomas based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions crucial for the management of adrenal incidentaloma patients, addressing these four with systematic literature searches: (A) How to assess risk of malignancy?; (B) How to define and manage low-level autonomous cortisol secretion, formerly called ‘subclinical’ Cushing’s syndrome?; (C) Who should have surgical treatment and how should it be performed?; (D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed?

Selected recommendations:

(i) At the time of initial detection of an adrenal mass establishing whether the mass is benign or malignant is an important aim to avoid cumbersome and expensive follow-up imaging in those with benign disease. (ii) To exclude cortisol excess, a 1mg overnight dexamethasone suppression test should be performed (applying a cut-off value of serum cortisol ≤50nmol/L (1.8µg/dL)). (iii) For patients without clinical signs of overt Cushing’s syndrome but serum cortisol levels post 1mg dexamethasone >138nmol/L (>5µg/dL), we propose the term ‘autonomous cortisol secretion’. (iv) All patients with ‘(possible) autonomous cortisol’ secretion should be screened for hypertension and type 2 diabetes mellitus, to ensure these are appropriately treated. (v) Surgical treatment should be considered in an individualized approach in patients with ‘autonomous cortisol secretion’ who also have comorbidities that are potentially related to cortisol excess. (vi) In principle, the appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health and patient preference. (vii) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. Furthermore, we offer recommendations for the follow-up of patients with adrenal incidentaloma who do not undergo adrenal surgery, for those with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses and for young and elderly patients with adrenal incidentalomas