We thank Prof Braun for his involved and succinct confirmation of our key messages and agree with him that further discussion of the guideline recommendation regarding calcitonin screening should be continued elsewhere. Prof. Chenot rightly points out the scarce evidence described in the AACE/AME/ETA guideline (1) with regard to follow-up examinations. However, a misunderstanding concerns the facts that the guidelines do not recommend thyroid ultrasonography as a screening examination and that for a patient with thyroid nodules a (low) risk for a false-negative risk stratification is well known, whereas this obviously does not apply to the general population.
With regard to the letter by Kreissl and colleagues, we wish to point out that it was not us but the AACE/AME/ETA guideline that suggested an algorithm (Figure 2). The evidence levels of the publications available for guideline recommendations are known to be different. For this reason, the current AACE/AME/ETA S3 guideline classifies the evidence levels of the consulted publications and classifies the strength of each recommendation according to the evidence—in contrast to, for example, the 10-year-old consensus statement from the German Society of Nuclear Medicine (2), which did not do this.
As no further literature for the sensitivity of scintigraphy was mentioned, we may continue to assume 5% (with a low level of evidence for the respective publications).
We wish to respond to the four further issues raised by Kreissl and coauthors as follows:
First, in order to clarify that initial statements had already been composed a long time before our data collection period, we cited the German Society of Nuclear Medicine’s consensus statement from 1999 and not the, similar, 2003 version (2).
Second, we thought it made more sense to compare the results of our study with the current algorithm from the AACE/AME/ETA guideline than to generate outdated algorithms from an old consensus statement for the purposes of comparison.
Third, the claim that the algorithm suggested in the AACE/AME/ETA S3 guideline (3) (Figure 2), cannot be applied to the situation in Germany can not be substantiated by a 10 year old, unrevised—and therefore according to AMWF rules invalid—consensus statement with 7 references (2). The AACE/AME/ETA guideline (1) is a good example of how the (internationally) published evidence can be interpreted by several scientific societies jointly and under consideration of regionally different epidemiologies. According to Figure 2 and the AACE/AME/ETA guideline (1), an individual nodule >1 cm would not be fine-needle aspirated directly but only after risk stratification using clinical presentation, TSH, calcitonin, and sonographic criteria for malignancy. By applying this strategy, up to 53% of nodules can be spared from FNAC by sonography alone, as shown in Figure 2 (3).
Fourth, because of the publication date, the combination treatment with iodide and thyroxine can only be evaluated in the current guideline update. The discussion of the relevant study was therefore not the topic of our article (4).
Since euthyroid autonomy is common, especially in multinodular goiter (5), the AACE/AME/ETA guideline (1) and our Figure 2, which was taken from the guideline, recommends scintigraphy for all cases of multinodular goiter, among other reasons in order to rule out autonomy from fine-needle aspiration cytology (FNAC), and, so far, for uninodular goiter depending on TSH and clinical presentation. The articles by Görges et al. and Graf et al.—cited by Kreissl and colleagues as well as by Prof. Palmedo and Prof. Türler— only state for 57 of 514 (42% multinodular) or for none of the patients whether a single nodule or several nodules were present.
Evaluations of FNA results do not mention hot nodules as a relevant explanation for follicular proliferations. Furthermore, only 5–10% (4) of thyroid nodules are hot nodules. The use of scintigraphy to reduce the frequency of follicular proliferations in cytology as suggested by Kreissl et al. has therefore not been mentioned in the guidelines.
The false-negative rate of FNA, as mentioned by Prof. Palmedo and Prof. Türler, is reported extremely divergently in the different publications; the guideline reports it to be 1–2% (1). This means that for FNA, as for any investigator-dependent method, quality and quality control of the cytologist and further measures by the aspirator (1) are crucial to reduce false-negative results. The guidelines do not mention technetium-99m-MIBI scintigraphy. We can conclude from our data that, while paying attention to the limitations explained in our article (for example, a lack of clinical symptoms), that in a scenario of guideline conform diagnostic evaluation, diagnostic surgery could have been avoided in most of the patients with operated uninodular thyroids. Very similar results have in the meantime also been reported from Belgium (6).
Most of the topics raised by Popert overlap with those explained above. We did not refer to older US guidelines but to a current and international guideline. Our study objective was to compare healthcare reality with guideline recommendations, and not to discuss guideline recommendations. If reality and guidelines diverge then health services research is required in order to change the evidence base for guideline revisions. Not almost all nodules are cold, but about 45%, and about as many nodules are scintigraphically normal or poorly characterized (3,7).
Prof. Dr. med. Ralf Paschke
Klinik für Endokrinologie und Nephrologie
Conflict of interest statement
The author declares that no conflict of interest exists.
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