The treatment for metastasised medullary thyroid cancer is still a topic of discussion. One of the main challenges remains to find effective adjuvant and palliative options for patients with metastatic disease. The diagnostic and treatment strategies for this tumour are discussed and possible new developments commented. Approaches that target rearranged during transfection (RET) are preferable to those that target RET downstream proteins as, theoretically, blocking RET downstream targets will block only one of the many pathways activated by RET. Combining several agents would seem to be more promising, in particular agents that target RET with those that independently target RET signalling pathways or the more general mechanism of tumour progression.
Thera P Links, Hans H G Verbeek, Robert M W Hofstra and John Th M Plukker
Stan Benjamens, Robin P F Dullaart, Wim J Sluiter, Michiel Rienstra, Isabelle C van Gelder and Thera P Links
Amiodarone is used for the maintenance of sinus rhythm in patients with arrhythmias, but thyroid dysfunction (amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH)) is a common adverse effect. As the onset of AIT and AIH may be unpredictable, the value of long-term regular monitoring of amiodarone treated patients for thyroid dysfunction is still uncertain.
We retrospectively documented the frequency at which overt thyroid dysfunction was preceded by subclinical thyroid dysfunction.
We included 303 patients treated with amiodarone between 1984 and 2007. AIT was defined as a lowered TSH level with an elevated free thyroxine (FT4) and AIH was defined as an elevated TSH level with a decreased or subnormal FT4. Subclinical AIT was defined as a lowered TSH level with a normal FT4 and subclinical AIH as an elevated TSH level with a normal FT4.
200 men and 103 women, aged 62 ± 12.0 years, suffering from atrial (260) or ventricular (43) arrhythmias, were evaluated. During a median follow-up of 2.8 (1.0–25) years, 44 patients developed AIT and 33 AIH. In 42 (55%) patients who developed AIT/AIH, earlier thyroid function tests showed no subclinical AIT or subclinical AIH. In 35 (45%) patients, AIT/AIH was preceded by subclinical AIT or subclinical AIH (16/44 for AIT and 19/33 for AIH).
In a considerable proportion of patients who developed AIT/AIH, earlier thyroid function tests showed no subclinical AIT/AIH. Less than half of the patients with a subclinical event subsequently developed overt AIT/AIH. This study provides data to reconsider the yield of regular testing of thyroid function to predict overt thyroid dysfunction in amiodarone treated patients.
Karin van der Tuin, Marina Ventayol, Willem Corver, Midia Khalifa, Dina Ruano, E P Corssmit, Frederik J Hes, Thera P Links, Jan Smit, Theo S. Plantinga, E Kapiteijn, Ton Van Wezel and Hans Morreau
OBJECTIVE: Gene alterations leading to activation of the MAPK pathway are of interest for targeted therapy in patients with advanced radioactive iodine-refractory (RAI-R) thyroid carcinoma. Due to technical reasons gene fusion analysis in RNA isolated from formalin-fixed tumor tissues has till now been limited. The objective of the present study was to identify targetable gene rearrangements in RNA isolated from formalin-fixed RAI-R thyroid carcinomas.
DESIGN: Retrospective study in 132 patients with RAI-R thyroid carcinoma (59 papillary-, 24 follicular-, 35 Hürthle cell-, and 14 anaplastic thyroid carcinoma).
METHODS: Total nucleic acid (undivided DNA and RNA) was isolated from formalin-fixed tissue. Extensive gene fusion analysis was performed in all samples that tested negative for pathogenic BRAF, NRAS, HRAS and KRAS variants.
RESULTS: Seven targetable gene fusions were identified in the remaining 60 samples without known DNA variants. This includes frequently reported gene fusions such as CCDC6/RET [PTC1], PRKAR1A/RET [PTC2] and ETV6/NTRK3 (n=2), and gene fusions that are less common in thyroid cancer (TPM3/NTRK1, EML4/ALK and EML4/NTRK3). Of note, most gene fusions were detected in papillary thyroid carcinoma and MAPK-associated alterations in Hürthle cell carcinomas are rare (2/35).
CONCLUSION: Targetable gene fusions were found in 12% of RAI-R thyroid carcinoma without DNA variants, and can be effectively identified in formalin-fixed tissue. These gene fusionsmight provide a preclinical rationale to include specific kinase inhibitors in the treatment regimen for these patients. The latter intends to restore iodine transport and/or take advantage of the direct effect on tumor cell vitality once progressive disease is seen.
Ha T T Phan, Pieter L Jager, Jacqueline E van der Wal, Wim J Sluiter, John T M Plukker, Rudi A J O Dierckx, Bruce H R Wolffenbuttel and Thera P Links
This retrospective study describes the role of serum thyroglobulin (Tg) in relation to tumor characteristics in the prediction of persistent/recurrent disease in patients with differentiated thyroid cancer (DTC) with negative Tg at the time of ablation.
Between 1989 and 2006, 94 out of 346 (27%) patients with DTC had undetectable Tg at the time of 131I ablation and were included in this evaluation. The group of 94 patients consisted of 15 males and 79 females in the age range of 16–89 years with a median follow-up of 8 years (range 1–17). All medical records and follow-up parameters of the 94 patients were evaluated for the occurrence of persistent/recurrent disease. In patients with persistent/recurrent disease hematoxylin-eosin-stained slides of the primary tumors and/or metastatic lesions were also reviewed for histological features including immunostains for Tg.
During follow-up, 8 out of 94 (8.5%) patients showed persistent/recurrent disease: in the course of the disease two patients showed Tg positivity, three showed Tg antibody (TgAb) positivity, and the other three showed persistently undetectable Tg and TgAb. Patients who developed Tg and/or TgAb positivity during follow-up had a significantly shorter disease-free survival period when compared with patients with persistently undetectable Tg and TgAb (P<0.006). Histological features were not able to predict the recurrent status.
Follow-up of Tg and TgAb in patients with initially negative Tg and TgAb is useful since a number of patients had shown detectable Tg or TgAb during follow-up indicative for persistent/recurrent disease. Tg and TgAb negativity at the time of ablation is not a predictive determinant for future recurrent status.
Edward Buitenwerf, Tijmen Korteweg, Anneke Visser, Charlotte M S C Haag, Richard A Feelders, Henri J L M Timmers, Letizia Canu, Harm R Haak, Peter H L T Bisschop, Elisabeth M W Eekhoff, Eleonora P M Corssmit, Nanda C Krak, Elise Rasenberg, Janneke van den Bergh, Jaap Stoker, Marcel J W Greuter, Robin P F Dullaart, Thera P Links and Michiel N Kerstens
A substantial proportion of all pheochromocytomas is currently detected during the evaluation of an adrenal incidentaloma. Recently, it has been suggested that biochemical testing to rule out pheochromocytoma is unnecessary in case of an adrenal incidentaloma with an unenhanced attenuation value ≤10 Hounsfield Units (HU) at computed tomography (CT).
We aimed to determine the sensitivity of the 10 HU threshold value to exclude a pheochromocytoma.
Retrospective multicenter study with systematic reassessment of preoperative unenhanced CT scans performed in patients in whom a histopathologically proven pheochromocytoma had been diagnosed. Unenhanced attenuation values were determined independently by two experienced radiologists. Sensitivity of the 10 HU threshold was calculated, and interobserver consistency was assessed using the intraclass correlation coefficient (ICC).
214 patients were identified harboring a total number of 222 pheochromocytomas. Maximum tumor diameter was 51 (39–74) mm. The mean attenuation value within the region of interest was 36 ± 10 HU. Only one pheochromocytoma demonstrated an attenuation value ≤10 HU, resulting in a sensitivity of 99.6% (95% CI: 97.5–99.9). ICC was 0.81 (95% CI: 0.75–0.86) with a standard error of measurement of 7.3 HU between observers.
The likelihood of a pheochromocytoma with an unenhanced attenuation value ≤10 HU on CT is very low. The interobserver consistency in attenuation measurement is excellent. Our study supports the recommendation that in patients with an adrenal incidentaloma biochemical testing for ruling out pheochromocytoma is only indicated in adrenal tumors with an unenhanced attenuation value >10 HU.
Sophie J van Asselt, Adrienne H Brouwers, Hendrik M van Dullemen, Eric J van der Jagt, Alfons H Bongaerts, Klaas P Koopmans, Ido P Kema, Bernard A Zonnenberg, Henri J Timmers, Wouter W de Herder, Wim J Sluiter, Elisabeth G de Vries and Thera P Links
Patients with von Hippel-Lindau (VHL) disease are prone to develop pancreatic neuroendocrine tumors (pNETs). However, the best imaging technique for early detection of pNETs in VHL is currently unknown. In a head-to-head comparison, we evaluated endoscopic ultrasound (EUS) and 11C-5-hydroxytryptophan positron emission tomography (11C-5-HTP PET) compared with conventional screening techniques for early detection of pancreatic solid lesions in VHL patients.
We conducted a cross-sectional, prospective study in 22 patients at a tertiary care university medical center. Patients with VHL mutation or with one VHL manifestation and a mutation carrier as first-degree family member, with recent screening by abdominal computed tomography (CT) or magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS), were eligible. Patients underwent EUS by linear Pentax echoendoscope and Hitachi EUB-525, and 11C-5-HTP PET. Patient-based and lesion-based positivity for pancreatic solid lesions were calculated for all imaging techniques with a composite reference standard.
In 10 of the 22 patients, 20 pancreatic solid lesions were detected: 17 with EUS (P < 0.05 vs CT/MRI+ SRS), 3 with 11C-5-HTP PET, 3 with SRS, 9 with CT/MRI, and 9 with CT/MRI + SRS. EUS evaluations showed solid lesions with a median size of 9.7 mm (range 2.9–55 mm) and most of them were homogeneous, hypoechoic, isoelastic, and hypervascular. Moreover, EUS detected multiple pancreatic cysts in 18 patients with a median of 4 cysts (range 1–30).
EUS is superior to CT/MRI + SRS for detecting pancreatic solid lesions in VHL disease.11C-5-HTP PET has no value as a screening method in this setting. EUS performs well in early detection of pNETs, but its role in VHL surveillance is unclear.
Annika M A Berends, Michiel N Kerstens, Janne W Bolt, Thera P Links, Esther Korpershoek, Ronald R de Krijger, Annemiek M E Walenkamp, Walter Noordzij, Boudewijn van Etten, Gursah Kats-Ugurlu, Adrienne H Brouwers and Anouk N A van der Horst-Schrivers
PET with 6-[18F]fluor-l-3,4-dihydroxyphenylalanine (18F-FDOPA) has been shown to be a useful imaging tool with a high sensitivity for the visualization of neuroendocrine tumors (NETs). 18F-FDOPA uptake in tumors other than NETs has been suggested previously, but data on this phenomenon are limited. We therefore studied the non-physiological, false-positive uptake of 18F-FDOPA in a large population of patients with a NET or with a high clinical suspicion of harboring a NET.
Patients and methods
Retrospective single-center study among adult patients in whom 18F-FDOPA PET scintigraphy was performed between January 2004 and December 2014. The original scan report was compared with the original pathology report corresponding with the 18F-FDOPA PET-positive lesion. In case this was inconsistent with the diagnosis of a NET, both the scan and the pathology slides were reassessed. Specimens of these non-NET tissues were immunohistochemically stained for AADC.
1070 18F-FDOPA PET scans from 705 patients were evaluated. Focal or multiple 18F-FDOPA-avid lesions were described in 709 18F-FDOPA PET scans (66%). Histology of these 18F-FDOPA PET-positive lesions was present in 508 (72%) cases. In seven cases, the histopathology was not compatible with NET but showed squamous cell carcinoma of the cervix, multiple myeloma (two cases), hepatocellular carcinoma, Schwannoma, adrenocortical carcinoma and a skeletal myxoid chondrosarcoma, with positive immunohistochemical staining for AADC in 67%.
Pathological uptake of 18F-FDOPA does not always indicate the presence of a NET. The possibility of 18F-FDOPA uptake by tumor types other than NETs, although rare, should be considered.
Marloes Nies, Bernadette L Dekker, Esther Sulkers, Gea A Huizinga, Mariëlle S Klein Hesselink, Heleen Maurice-Stam, Martha A Grootenhuis, Adrienne H Brouwers, Johannes G M Burgerhof, Eveline W C M van Dam, Bas Havekes, Marry M van den Heuvel-Eibrink, Eleonora P M Corssmit, Leontien C M Kremer, Romana T Netea-Maier, Heleen J H van der Pal, Robin P Peeters, John T M Plukker, Cécile M Ronckers, Hanneke M van Santen, Anouk N A van der Horst-Schrivers, Wim J E Tissing, Gianni Bocca and Thera P Links
The impact of childhood differentiated thyroid carcinoma (DTC) on psychosocial development has not yet been studied. The aim of this study was to evaluate the achievement of psychosocial developmental milestones in long-term survivors of childhood DTC.
Design and methods
Survivors of childhood DTC diagnosed between 1970 and 2013 were included. Reasons for exclusion were age <18 or >35 years at follow-up, a follow-up period <5 years or diagnosis with DTC as a second malignant neoplasm. Survivors gathered peer controls of similar age and sex (n = 30). A comparison group non-affected with cancer (n = 508) and other childhood cancer survivors (CCS) were also used to compare psychosocial development. To assess the achievement of psychosocial milestones (social, autonomy and psychosexual development), the course of life questionnaire (CoLQ) was used.
We included 39 survivors of childhood DTC (response rate 83.0%, mean age at diagnosis 15.6 years, and mean age at evaluation 26.1 years). CoLQ scores did not significantly differ between survivors of childhood DTC and the two non-affected groups. CoLQ scores of childhood DTC survivors were compared to scores of other CCS diagnosed at similar ages (n = 76). DTC survivors scored significantly higher on social development than other CCS, but scores were similar on autonomy and psychosexual developmental scales.
Survivors of childhood DTC showed similar development on social, autonomy, and psychosexual domains compared to non-affected individuals. Social development was slightly more favorable in DTC survivors than in other CCS, but was similar on autonomy and psychosexual domains.