Langzeitdiagnostische Genauigkeit der hochsensitiven Thyreoglobulin-Bestimmung bei Patienten mit differenziertem Schilddrüsenkarzinom nach I-131-Ablation

In more recent years, highly sensitive thyroglobulin measurement (hsTg) has found entry into clinical practice in the follow-up of differentiated thyroid carcinoma (DTC). The follow-up of DTC contains nonstimulated as well as TSH-stimulated Tg measurements. Unremarkable stimulated Tg levels, often combined with other follow-up procedures such as neck ultrasound and/or diagnostic I-131 whole body scintigraphy, are a good predictor of excellent prognosis. This prognostic value has been validated in numerous long-term observational cohort studies, usually of a retrospective nature. For hsTg, such long-term outcome studies are not yet available. Our hospital belonged to the early adopters of hsTg measurement, using hsTg for the regular follow-up of DTC from 2004 onwards. As a considerable follow-up time is now potentially available in our patient collective, the primary aim of the present study is to examine the predictive value for long-term patient-relevant outcome measures of unremarkable non-stimulated hsTg measurement. A secondary aim is the further validation of the predictive value of basal, unstimulated hsTg for the results of consecutive stimulated Tg measurement. The population of our study contains 461 patients, thereof 51 patients with a positive thyroglobulin antibody (TgAb) test. As for the total population, the Kaplan-Meier adjusted mortality was 1.1±0.8% at both 5 and 10 years, respectively. The Kaplan-Meier analysis further revealed that an unstimulated Tg threshold of 0.1 ng/ml was not able to significantly discriminate with regard to the risk of DTC related death (p=0.06), but a threshold of 1 ng/ml was. For patients without TgAb we calculated a risk of recurrence after 1, 5 and 10 years of 0.5±0.5%, 0.5±0.5%, and 2.0±1.6%. For patient with TgAb we found out a risk of recurrence at 1, 5 and 10 years of 4.5±4.4%, 0.5±0.5%, and 23.4±17.4%. Moreover, we calculated excellent negative predictive values using 0,1 ng/ml as a threshold for positivity, thus of 97% (85-99%) for patients with TgAb and 97.6% (94.7-99.0%) for patients without TgAb. Comparable studies referred to excellent negative predictive values for non-stimulated Tg-measurements upon available stimulated Tg-values ≥1 ng/ml. We can not only confirm this to our total population but distinguish that the hsTg measurements provides with a threshold of 0,1 ng/ml for positivity negative predictive values of ≥97%. The new highly sensitive thyroglobulin measurements are brilliant at an excellent functional sensitivity and accuracy. During follow up, two patients died from progressive disease of whom both suffered from distant metastases at the time of DTC diagnosis. One of them presented a strong fall of the Tg level after the initial RIT. The only biochemical hint for a persisting disease was a slightly increased TSH-stimulated Tg value of only 1,3 ng/ml in the initial follow-up. Other than that mentioned the necessity of the diagnostic I-131 whole-body scintigraphy (dxWBS) is a subject of debate among experts. On the one hand, the “American Thyroid Association” claims less dxWBS as a matter of routine. On the other hand, in Germany there is still a wide performance of dxWBS. This study provides further support for the idea to preselect patients regarding follow-up procedures. The high negative predictive value allows us to estimate the necessity of a dxWBS. The present results show that in patients without distant metastases at diagnosis, an undetectable hsTg signals an extremely good long-term prognosis with a very low risk of recurrence and negligible risk of DTC-related death. For low risk patients with undetectable non-stimulated hsTg the high negative predictive value means that further invasive procedures, such as TSH-stimulated Tg-measurements and dxWBS, can be left undone. For those patients, a stimulated Tg does not provide any additional value with regard to the risk of recurrence or DTC-related death. As this risk of recurrence is unfortunately not non-existent, it remains advisable nonetheless to regularly perform follow-up at half-yearly to yearly intervals based on unstimulated Tg measurements. Further procedures like the stimulated Tg measurement or dxWBS can be likely reserved for high risk patients with evidence for a present disease or biochemical sign for recurrence. Due to our results the high NPV of nonstimulated hsTg testing means that the dxWBS can be omitted for patients with nonstimulated hsTg values <0,1 ng/ml. Whether ultrasound as a screening method is still needed in the follow-up is however currently subject of debate among experts.