The adequate risk stratification in thyroid carcinoma is crucial to avoid on one hand the overtreatment of low-risk and on the other hand the undertreatment of high-risk patients. The question how to properly assess the risk of relapse has been discussed during recent years and resulted in a substantial change in our approach to risk stratification in differentiated thyroid cancer, proposed by the newest ATA guidelines. First initial risk stratification, based on histopathological data is carried out just after primary surgery. It should be emphasized, that a high quality of histopathological report is crucial for proper risk stratification. Next, during the follow-up, patients are restratified considering their response to treatment applied and classified to one of the following categories: excellent response, biochemical incomplete response, structural incomplete or indeterminate response. This new approach is called dynamic risk stratification as, in contrary to the previous rigid evaluation performed at diagnosis, reflects a real-time prognosis and thereby substantially influences and personalizes disease management. In this review, we raise some unresolved questions, among them the lack of prospective studies, fulfilling evidence-based criteria, necessary to validate this model of risk stratification. We also provided some data concerning the use of dynamic risk stratification in medullary thyroid cancer, not yet reflected in ATA guidelines. In conclusion, dynamic risk stratification allows for better prediction of the risk of recurrence in thyroid carcinoma, what has been demonstrated in numerous retrospective analyses. However, the validation of this approach in prospective studies seems to be our task for near future.
Jolanta Krajewska, Ewa Chmielik and Barbara Jarząb
Mimi I Hu, Rossella Elisei, Marek Dedecjus, Aron Popovtzer, Maralyn Druce, Ellen Kapiteijn, Furio Pacini, Laura Locati, Jolanta Krajewska, Richard Weiss and Robert F Gagel
Vandetanib is an oral tyrosine kinase inhibitor approved for treatment of advanced symptomatic or progressive medullary thyroid cancer (MTC). The current study (Nbib1496313) evaluated the benefit–risk of two starting doses of vandetanib in patients with symptomatic or progressive MTC. Patients were randomized 1:1 to receive vandetanib 150 or 300 mg daily and followed for a maximum of 14 months (Part A), with the option to then enter an open-label phase (Part B) investigating vandetanib 100, 150, 200 and 300 mg daily doses. Efficacy was assessed in Part A, and safety and tolerability during Parts A and B up to 2 years post randomization. Eighty-one patients were randomized in Part A and 61 patients entered Part B, of whom 37 (60.7%) received 2 years of treatment. Overall, 25% of patients experienced an objective response (OR) at 14 months (OR rate, 0.29 (95% CI, 0.176–0.445) for 300 mg, and 0.20 (95% CI, 0.105–0.348) for 150 mg; one-sided P value approximately 0.43). The most common adverse events (AEs) included diarrhea, hypocalcemia, asthenia, QTc prolongation, hypokalemia and keratopathy, all at generally higher incidence with 300 vs 150 mg (Part A). Part B safety and tolerability was consistent with Part A. OR was observed with both vandetanib doses; the 300 mg dose showed a more favorable trend vs 150 mg as initial dose. Thus, for most patients, 300 mg vandetanib is the most appropriate starting dose; dose reductions to manage AEs and lower initial doses for patients with particular comorbidities can be considered.
Ernst von Dobschuetz, Helena Leijon, Camilla Schalin-Jäntti, Francesca Schiavi, Michael Brauckhoff, Mariola Peczkowska, Giovanna Spiazzi, Serena Demattè, Maria Enrica Cecchini, Paola Sartorato, Jolanta Krajewska, Kornelia Hasse-Lazar, Katarzyna Roszkowska-Purska, Elisa Taschin, Angelica Malinoc, Lars A Akslen, Johanna Arola, Dariusz Lange, Ambrogio Fassina, Gianmaria Pennelli, Mattia Barbareschi, Jutta Luettges, Aleksander Prejbisz, Andrzej Januszewicz, Tim Strate, Birke Bausch, Frederic Castinetti, Barbara Jarzab, Giuseppe Opocher, Charis Eng and Hartmut P H Neumann
The precise diagnosis of thyroid neoplasias will guide surgical management. Primary thyroid paraganglioma has been rarely reported. Data on prevalence, immunohistochemistry (IHC), and molecular genetics in a systematic series of such patients are pending. We performed a multinational population-based study on thyroid paraganglioma and analyzed prevalence, IHC, and molecular genetics. Patients with thyroid paraganglioma were recruited from the European-American-Head-and-Neck-Paraganglioma-Registry. Demographic and clinical data were registered. Histopathology and IHC were re-investigated. All patients with thyroid paraganglioma underwent molecular genetic analyses of the SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, RET, TMEM127, and MAX genes. Analyses included Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) for detection of large rearrangements. Of 947 registrants, eight candidates were initially identified. After immunohistochemical analyses of these eight subjects, 5 (0.5%) were confirmed to have thyroid paraganglioma. IHC was positive for chromogranin, synaptophysin, and S-100 and negative for calcitonin in all five thyroid paragangliomas, whereas the three excluded candidate tumors stained positive for pan-cytokeratin, a marker excluding endocrine tumors. Germline variants, probably representing mutations, were found in four of the five confirmed thyroid paraganglioma cases, two each in SDHA and SDHB, whereas the excluded cases had no mutations in the tested genes. Thyroid paraganglioma is a finite entity, which must be differentiated from medullary thyroid carcinoma, because medical, surgical, and genetic management for each is different. Notably, approximately 80% of thyroid paragangliomas are associated with germline variants, with implications for additional tumors and a potential risk for the family. As opposed to sporadic tumors, surgical management and extent of resection are different for heritable tumors, each guided by the precise gene involved.