6. Follow-up care for differentiated and poorly differentiated thyroid carcinoma – Thyroid Cancer
For patients with differentiated thyroid carcinomas, a long tumor follow-up for at least 10 years is recommended, as local recurrences or distant metastases can still occur even after many years or decades. The frequency and extent of follow-up care are based on the risk assessment of the carcinoma. Prompt detection of tumor recurrence or lymph node metastases enables rapid intervention and therefore offers the best chances of treatment, even in the event of recurrence.
One large unicenter study [569] on the prognosis of 2,011 patients with differentiated thyroid carcinoma with a follow-up period of up to 20 years (median 7.1 years) showed a normal life expectancy for the majority of patients. The initial treatment was thyroidectomy followed by radioiodine therapy. Compared to the normal population in Germany, however, life expectancy was reduced, with the exception of patients < 45 years and a maximum of one lymph node involvement of the cervicocentral compartment. Significant risk factors for reduced life expectancy were: follicular thyroid carcinoma, extrathyroidal tumor growth, cervicolateral lymph node metastases, distant metastases, age > 45 years.
A second unicenter study [792] with 2,476 differentiated thyroid carcinomas showed, with a median follow-up of 6.6 years, a comparable life expectancy compared to the normal German population with the exception of patients > 45 years with distant metastases. In patients with carcinomas < 2 cm without lymph node or distant metastases, life expectancy was even better than that of the general population. Thyroidectomy was performed in 90.4% of these patients, lymph node dissection in 39.9% and radioiodine therapy in 91.1%.
6.1 When does aftercare begin?
According to the definition of this guideline, the follow-up period begins after completion of all primary therapies, in the case of radioiodine therapy including the success control (see Chapter Response evaluation) or after completion of all recurrence therapies with corresponding success control. The diagnostics in follow-up care are used for the early detection of recurrence or progression and end accordingly when recurrence or progression is confirmed.
Follow-up care includes checking and adjusting the thyroid hormone substitution or suppression with medication as well as the diagnosis and treatment of typical complications of the primary therapy. This includes sonography of the thyroid gland and soft tissues of the neck including lymph nodes, determination of the tumor marker thyroglobulin (Tg) and thyroglobulin antibodies (TgAb) as well as laboratory testing of thyroid hormone therapy. Patients are also given the opportunity to express their tumor-related concerns and receive competent answers.
6.2 How should follow-up care be provided for proven differentiated and poorly differentiated thyroid cancer?
Follow-up care for differentiated thyroid carcinoma depends on the risk stratification and is initially based on the initial risk category; later it depends on the progression and response to the initial therapy/therapies. Ideally, this is carried out by appropriately specialized physicians.
A multi-center study [382], which compared 1,624 unifocal papillary carcinomas (PTC) with 1,000 multifocal PTC, described a significantly higher rate of local recurrence for multifocal carcinomas after a median follow-up of 56 months (19.8%, p < 0.001) compared to unifocal carcinomas (13.6%). Thyroidectomy and radioiodine therapy were performed in 83.6% of multifocal and 74.0% of unifocal carcinomas.
An analysis of the American National Cancer Database (NCDB) and the National Cancer Institute's SEER registry of 47,902 patients who underwent surgery for papillary thyroid carcinoma between 1988 and 2006 at the age of < 45 revealed a significant influence of lymph node metastases on overall survival.
In patients who were >45 years old at the time of surgery for papillary thyroid carcinoma, Zaydfudim et al. [793], also in an analysis of the SEER registry of 30,504 patients, found a 46% higher risk of dying from this carcinoma if lymph node metastases were detected than in patients without lymph node involvement.
In a literature analysis by Randolph et al. [605], the frequency of recurrent lymph node metastases in PTC correlates with the histopathological lymph node status at the time of initial surgery. In stage pN0, local recurrence occurred in 2% of patients, whereas in stage pN1 it occurred in 22%. The risk of local recurrence also correlated with the number of tumor-infiltrated lymph nodes at the time of initial surgery (< 5 infiltrated lymph nodes: 4% tumor recurrence, > 5 infiltrated lymph nodes: 19% recurrence).
Two meta-analyses [794], [795] also showed an increased risk of local recurrence in PTC in correlation with the extent of the initial procedure. For patients who underwent thyroidectomy and prophylactic cervicocentral lymph node dissection, the risk of recurrence was reduced by 35% compared to patients who underwent thyroidectomy alone. It must be added that postoperative radioiodine therapy was more frequent in the group with lymph node dissection (71% with versus 53% without lymph node dissection).
Follow-up care for differentiated thyroid carcinoma shall be organized depending on the risk stratification, initially according to the initial risk category, and later depending on the progression, in particular the response to the initial therapy/therapies.
- Consensus
- Strong consensus (100%)
The initial classification of thyroid carcinomas according to the TNM classification is important for the indication of initial therapies and for monitoring the success of the therapies [83], [24]. However, the TNM classification does not allow any statement to be made regarding progression-free survival and overall survival after the treatment(s) [796], [797], [798], [799], [800], [801], [802].
Furthermore, neither surgical outcome, response to radioiodine therapy, nor molecular markers such as BRAF V600E, TERT and TP53 are included in the TNM classification or in other classifications proposed to date.
For example, it was shown that a TERT mutation is an independent factor for increased mortality (hazard ratio [HR]: 10.35; 95% confidence interval: 2.01-53.24) for all differentiated carcinomas. For papillary thyroid carcinoma alone, the risk is even more pronounced (HR: 23.8; 95% confidence interval: 1.36-415.8) [803].
Verburg et al. were able to show that after completion of radioiodine therapy, an inconspicuous success control with diagnostic ¹³¹I whole-body scintigraphy in combination with a non-measurable stimulated Tg value levels the initial risk of recurrence regardless of the TNM stage and that patients in this constellation only have a very low recurrence rate of 3% regardless of the initial risk classification. The long-term mortality rate with a follow-up period of 25 years was 3.4% ± 1.3% in the low-risk arm and 3.7% ± 1.7% in the high-risk arm (p = n.s.) [735].
6.3 Terminology of treatment response and risk assessment for recurrence of DTC
The response to treatment shall be classified as excellent, good or acceptable, biochemically incomplete or structurally incomplete, taking into account clinical, laboratory and imaging findings.
- Consensus
- Strong consensus (96,2%)
Table 19: Risk groups after RIT and a follow-up period of 2 years
| Category | Definition | Course of the disease/risks | Follow-up care or therapy |
| Excellent response to therapy (excellent response) |
No tumor is visible on imaging and either Tg value under TSH suppression is < 0.2 ng/ml or TSH-stimulated Tg value is <1 ng/ml |
96 - 99 % of patients remain disease-free 1 - 4 % of patients develop a recurrence within a period of 5 to 10 years, less than 1 % will die from thyroid cancer. |
The intensity and frequency of follow-up should be reduced early and TSH suppression discontinued. |
Good/acceptable response to therapy (indeterminate response) |
- There is no evidence of a local tumor or metastasis of the thyroid carcinoma in the follow-up imaging or there is weak radioiodine storage in the thyroid bed - Tg value under TSH suppression is ≥ 0.2 ng/ml and < 1ng/ml - TSH-stimulated Tg value ≥ 1.0 ng/ml and < 10 ng/ml or - TgAb values are stable or falling, and nothing pathological is seen on imaging |
In 80 - 85% of patients, this condition remains stable or evolves towards excellent response. In 15 - 20%, a tumor is found in follow-up over a period of 5 to 10 years. Risk of dying from this cancer below 1% |
Patients should continue to receive follow-up care with repeated imaging. If non-specific tumors become specific, they should be investigated with further imaging or biopsy. |
| Biochemically incomplete response (biochemical incomplete response) |
There is no evidence of a local tumor or metastasis of the thyroid carcinoma in the follow-up imaging and - Tg value under TSH suppression is ≥ 1ng/ml or - TSH-stimulated Tg value ≥ 10 ng/ml or - Rising TgAb values |
At least 30% will spontaneously become patients who have no signs that they have thyroid cancer; another 20% will become so after additional therapy. In 30%, the condition remains unchanged. 20% percent develop a recurrence, i.e. a tumor is found on imaging. Risk of dying from this cancer is less than 1% |
If the Tg value is stable or falling, patients should continue to be monitored and the TSH value should be suppressed in most patients. |
| Structurally incomplete response | In imaging, there are structural or functional masses (uptake of iodine in RIT or [¹⁸F]FDG in PET/CT) that can be assigned to thyroid cancer. This is independent of the Tg value or whether TgAb is detectable. |
In 15 - 50% of cases, further therapies are successful and the patients can be reclassified. In 50 - 85% of patients, the disease persists despite additional therapies. Around 10% of patients with metastases in the neck and around 50% of patients with distant metastases die from this cancer. |
Patients in this group require further therapy or further observation depending on the clinical and pathological findings, the size and localization, the growth rate, the ability to take up iodine or the uptake of [¹⁸F]FDG in PET/CT. |
Although the initial tumor stage, differentiated histological factors and possibly additional molecular pathological markers influence the initial risk profile and thus the extent of the initial therapy/therapies, the outcome after completion of the initial therapy is decisive for the risk of recurrence (so-called dynamic risk assessment). Several retrospective studies with a total of >5,000 patients have shown that the outcome after completion of initial therapy is a significantly more reliable predictor of recurrence risk than the initial risk classification [735], [543], [544], [804], [805], [806], [807]. Systematic prospective data are lacking. The response to the initial therapy (surgery + RIT) has a direct influence on the risk of recurrence; this has been documented in retrospective studies [735].
There are 4 references in the ATA guideline that describe the risk of recurrence after surgery and RIT as a function of the response achieved to the initial therapy; all of these patients underwent both thyroidectomy and radioiodine therapy [543], [545], [544], [546] - the problem is the transfer to German conditions, as treatment in the USA is usually with only 1.1 GBq ¹³¹I, which is possible on an outpatient basis there. In retrospective studies, the risk of recurrence over a follow-up period of 5-10 years was between 1% and 4% (median 1.8%) in patients who showed an excellent response to therapy 6-18 months after total thyroidectomy. In patients with initial low-risk disease, the recurrence rate was <1% [807], [721], [808], with initial intermediate-risk disease 1-2% [544], [807] and even with initial high-risk disease, a recurrence rate of up to 5% was observed in the majority of studies. Recurrence rates of 14% were only described in individual studies [543], [809]. A reliable indication of the risk of recurrence in initial high-risk patients according to the TNM classification cannot be made with certainty, as these patients only achieved full remission in approx. 20-40% of cases and persistent disease was observed more frequently [543], [544], [810], [546], [545], which was often not consistently differentiated from disease progression requiring treatment in the above-mentioned studies during further follow-up.
In the German study by Verburg et al., the risk of recurrence after thyroidectomy and RIT with 3.7 GBq ¹³¹I and a subsequent excellent response was < 4%, regardless of the initial risk classification, with a median follow-up duration of 60 months, range 4-306 months [735].
A biochemically incomplete response is observed in approx. 10-20% of patients after thyroidectomy and radioiodine therapy, without a significantly different frequency in the various initial risk groups [543], [544], [546], [811]. The majority of these patients show a complete remission or stable elevated thyroglobulin levels during further follow-up [543], [545], [811], [812]. The risk of these patients developing a structural (i.e. image-detectable) disease in the following years has been described as 0-17% [543], [811], [812].
If, on the other hand, only a structurally incomplete remission is achieved after thyroidectomy and radioiodine therapy, this detectable finding persists in around 70% of cases in the following years [543], [544], [807]. The available studies usually only allow a differentiation of a stable, persistent, structurally detectable finding from a progressive finding requiring treatment to a limited extent, as these distinct endpoints were rarely systematically differentiated. When this was differentiated, a variable risk of progressive disease on imaging of <5% [544] to 50% [806], [809], [811] was observed. In addition, a significantly shorter overall survival of patients with structurally incomplete remission compared to patients with only biochemical persistence was reported [809], [545], [811].
The presence of image-detectable distant metastases is a predictor of a less favorable outcome compared to only cervical lesions [811]. Whether patients with an initially high risk and subsequent structurally incomplete response have a higher risk of progression requiring treatment than patients with an initially intermediate risk cannot be answered with the help of the existing literature, as generally either only the initial risk category was differentiated with regard to subsequent progression or only the degree of remission, but not both risk classifiers in combination.
In the patient group classified as "indeterminate response" according to ATA [24] and as "good/acceptable response" in this guideline (suppressed Tg 0.2-1.0 ng/ml; stimulated Tg 1-10 ng/ml; stable/regressingTgAb, possibly unspecific imaging findings), the risk of developing structurally detectable disease within a period of 5 to 10 years is approx. 10-20% [813], [814], [815].
The assessment of the risk of recurrence does not end with the completion of the initial therapy, but is constantly reviewed and, if necessary, adjusted during the entire follow-up, taking into account the dynamics of the findings. For example, the risk of recurrence can be downgraded for patients with an initially biochemically incomplete response who fulfill the criteria for full remission during the course of treatment [543], [545], [811], [812].
Patient age >55 years is well documented as an independent, prognostically unfavorable factor in the initial risk assessment [807]. However, the independent prognostic significance against the background of post-therapeutic dynamic risk stratification has not yet been sufficiently investigated or has not yet been shown to have any independent prognostic significance [807]. The additional prognostic benefit of the BRAF mutation has also not been investigated. Additional prognostic information of the TERT promoter mutation status in addition to dynamic risk stratification was derived based on retrospective data [816], but has not been validated.
6.4 What role do medical history and clinical examination play in the follow-up of patients with differentiated thyroid carcinoma?
A symptom-oriented medical history and physical examination shall be fundamental components of aftercare.
- Consensus
- Strong consensus (96,3%)
There are no controlled studies to answer this question. Both measures are part of the general medical standard.
New onset of cervical tenderness or lymph node swelling may indicate local recurrence or lymph node metastasis.
New focal bone pain may be an indication of skeletal metastasis. In the case of differentiated thyroid carcinomas, however, this is a rare coexistence. Regional or distant metastases are usually asymptomatic at first and are more likely to be diagnosed during imaging examinations, which are initiated when the thyroglobulin level rises.
As part of the follow-up examination, the question of tolerability of thyroid hormone replacement is relevant. To this end, it is important to record hypothyroid and especially hyperthyroid symptoms, including increased sweating, sleep disorders, palpitations and cardiac arrhythmia, unwanted weight changes or digestive problems. Corresponding complaints may be cause for a dose adjustment (see Chapter Follicular carcinomas).
Specific side effects and sequelae of individual therapies are described in the corresponding therapy chapters. Possible side effects of the initial therapy (recurrent paresis, hypoparathyroidism with chronic need for therapy) shall be known or investigated. Reference should be made here to the relevant chapters (see Chapter How should postoperative hypoparathyroidism be treated? and Diagnosis of vocal fold function and management of vocal fold dysfunction).
Aspects of quality of life and psychological well-being are described in Chapter Rehabilitation.
6.5 How should the TSH value be adjusted in the long-term course of patients with differentiated thyroid carcinoma?
The TSH setting shall be adjusted depending on the risk of recurrence or progression, taking into account the individual tolerance of the medication, including the patient's condition, state of health and concomitant diseases (osteopenia/osteoporosis, cardiac arrhythmia, etc.).
- Consensus
- Strong consensus (100%)
Follow-up care also includes monitoring thyroid hormone levels. If the course of the disease is stable, it should be checked annually.
- Consensus
- Strong consensus (96,2%)
The recommendations mentioned in this chapter are based on current international consensus [24], [817]. In principle, there is insufficient data available for specific TSH target ranges with regard to the risk of recurrence and overall or disease-related survival for specific patient groups, so that targets with regard to TSH adjustment must always be weighed up in terms of tolerability and individual (especially cardiovascular) risk, particularly if TSH suppression is used. Unfavorable effects with regard to the cardiovascular system and bone metabolism must be taken into account.
Adjustment of thyroid hormone replacement both in terms of TSH setting and combination therapy of LT4 and LT3 can improve quality of life and should be carried out in accordance with international guidelines for the treatment of hypothyroidism [818]
In patients with TSH-suppressive thyroid hormone settings who develop hyperthyroid symptoms, the dose of thyroid hormones should first be reduced slightly with the help of specialists and after weighing up the risks. If this does not alleviate the symptoms, taking thyroid hormones in the evening can be tried on an experimental basis in order to achieve a better quality of life [819], [820].
According to a recent meta-analysis, TSH-suppressive medication in post-menopausal women favors lower bone surface density in the lumbar spine compared to a healthy control group. TSH suppression generally meant a TSH value of <0.3 mU/l, in the majority of studies <0.1 mU/l. The duration of TSH suppression was 5-15 years in each case. In contrast, there was no significant difference in bone density in the femur in postmenopausal women and in bone density in the lumbar spine or femur in men. In premenopausal women, bone density in the lumbar spine and femoral neck was significantly increased under TSH suppression [821]. A second recent meta-analysis found significantly lower bone density in postmenopausal women with TSH suppression <0.1 mU/l, but not with a TSH value of 0.1-0.5 mU/l [822]. It must be taken into account that the category "TSH < 0.1 mU/l" also includes all patients with excessive thyroxine administration (individual hyperthyroidism factitia). In a prospective observational study of 686 women >65 years of age, the risk of femoral neck and vertebral body fractures was 3 or 4 times higher with a TSH suppression ≤0.1 mU/l compared to patients with a TSH of 0.5-5.5 mU/l. The risk with a TSH value between 0.1-0.5 mU/l was not clearly increased [823]. Another observational study showed that in women (90% of whom were postmenopausal) on TSH-suppressive medication, a significant decrease in the trabecular bone score (TBS) was observed after 5-10 years at a TSH value of <0.1 mU/l, but not at a TSH value between 0.1-0.5 mU/l [824]. These studies emphasize that long-term TSH suppression in postmenopausal patients <0.1 mU/l should only be carried out with special consideration of the increased risk of osteoporosis.
In a comprehensive observational study (17,684 patients), TSH suppression <0.03 mU/l was significantly associated with increased cardiovascular events (cardiac arrhythmias, morbidity, mortality) after adjustment for age, gender, previous cardiovascular disease, and diabetes. However, this risk was not increased with a TSH value between 0.04-0.4 mU/l compared to patients with TSH 0.4-4.0 mU/l [825]. In a placebo-controlled study in 25 patients with differentiated thyroid carcinoma and normal left ventricular ejection fraction, L-thyroxine-induced subclinical hyperthyroidism (median TSH value 0.015 mU/l, fT4 23.1 pmol/l) led to diastolic dysfunction, which was at least partially reversible after euthyroidism was restored [826]. Another interventional study (18 patients) also showed echocardiographic abnormalities and limitations in physical performance in patients on a fixed dose of L-thyroxine with a median TSH value of 0.05 mU/l compared to a euthyroid control group. These differences were reduced or normalized after individual titration of the L-thyroxine dose with a TSH target value of 0.1 mU/l [827].
In summary, these studies show that side effects of hormone replacement are only observed significantly more frequently in patients with a TSH value <<0.1 mU/l, but not with a TSH value around 0.1 mU/l.
In order to improve the tolerability of thyroid hormone replacement, it is recommended to use the lowest possible dose that allows the respective TSH target range. The respective TSH target ranges shall be aimed for, but do not necessarily have to be achieved, especially if the patient feels understandably more comfortable at a different dose. Frequent dose changes with the aim of reaching the TSH target range should also be avoided if there is otherwise a risk of jeopardizing patient compliance or acceptance. If a dose change is necessary, it should generally be made in small steps.
The TSH ranges mentioned below are target values that should be approximately achieved. Frequent changes in thyroid hormone dosage should be avoided. The following recommendations are summarized in the following two tables 20 and 21.
Initial situation (surgery +/- RIT) until response evaluation
Very low risk
In the case of lobectomy, thyroid hormone replacement can be carried out with the aim of achieving a TSH value within the normal range. In the case of a complete thyroidectomy, a TSH value within the normal range should be aimed for. TSH-suppressive therapy shall not be used.
Low risk
In patients with a low risk of recurrence, a TSH value of 0.5-2 mU/l shall be aimed for in patients with an excellent response (non-stimulated Tg < 0.2 ng/ml) and a TSH of 0.1-0.5 mU/l in patients with an incomplete response (non-stimulated Tg ≥ 0.2 ng/ml).
Medium risk
In patients with a medium risk of recurrence, a TSH value of 0.1-0.5 mU/l shall be aimed for postoperatively.
High risk
In patients with a high risk of recurrence, a TSH of < 0.1 mU/l shall be aimed for postoperatively.
From response evaluation 6-12 months after initial therapy
Excellent response
A TSH value of 0.5 - 2.0 mU/l should be aimed for in patients with an excellent response.
Good/acceptable response
A TSH value of 0.1 - 0.5 mU/l should be aimed for in patients with a good/acceptable response, taking into account possible risk factors.
Biochemically incomplete response
In patients with a biochemically incomplete response, a TSH value of 0.1 - 0.5 mU/l should be aimed for, taking into account possible risk factors.
Structurally incomplete response
In patients with a structurally incomplete response, a TSH value of <0.1 mU/l should be aimed for, taking into account possible risk factors.
- Consensus
- Strong consensus (100%)
The only meta-analysis from 2002 [828] with 10 evaluable, predominantly retrospective studies (a total of 4,174 patients with differentiated thyroid carcinoma) showed an advantage of TSH suppression for recurrence-free survival or overall survival (relative risk: 0.73; 95% confidence interval: 0.6-0.88; p<0.05). It was not possible to differentiate between different risk groups or treatment strategies (extent of surgery, with/without radioiodine therapy) on the basis of the individual studies. The authors of the meta-analysis defined TSH-suppressive medication as a TSH value <0.5 mU/l without hyperthyroid symptoms and with free thyroid hormones in the upper normal range or slightly elevated. In the individual studies, however, the suppression achieved was usually not stated or uniformly defined and did not necessarily correspond to the current definition of TSH suppression due to less sensitive TSH assays. Furthermore, due to the retrospective database, it cannot be ruled out that a bias may exist due to possibly different risk profiles of patient groups with and without TSH-suppressive therapy [828].
It is therefore recommended that the TSH setting be risk-adapted. In an observational study with 366 patients, a TSH threshold value of 2 mU/l was best suited to differentiate between patients who remained tumor-free and those with a recurrence or tumor-associated mortality [829]. There are no valid data to justify TSH suppression below the normal range in patients with a very low risk of recurrence, which is why a TSH value between 0.5 and 2.0 mU/l is recommended. Since the data on the risk of recurrence is not consistent for patients with an excellent response but initially high risk (see background text to Chapter Resection of the lymph nodes), it may be considered to aim for a TSH target range of 0.1-0.5 mU/l in the first 5 years of follow-up. If the good/acceptable response remains unchanged or the biochemical response is incomplete, a TSH value in the lower reference range can be aimed for after 5 years
In patients with a biochemically incomplete response, the risk of recurrence is variable, but on average increased (Chapter Resection of the lymph nodes), which is why a TSH target of 0.1-0.5 mU/l is recommended. If the patient achieves an excellent response in the further course of follow-up, the TSH setting could be adjusted accordingly.
In the case of structurally incomplete response, the risk of recurrence is sometimes significantly increased, and disease-related mortality is also increased on average (Chapter Resection of the lymph nodes). For this reason, TSH-suppressive therapy with a target value of around 0.1 mU/l is recommended. Retrospective data suggest that an even significantly lower TSH value (<0.03 mU/l) does not improve disease-specific survival [830].
For patients without radioiodine therapy, a randomized controlled trial on the influence of TSH suppression on disease-free survival of 433 patients with papillary thyroid carcinoma is available. The patients underwent surgery (>80% no total thyroidectomy), no patient received radioiodine therapy. Approximately 90% of the patients were assigned to the low-risk group according to the AMES classification [831]; however, patients with microcarcinomas or distant metastases were excluded. Thus, a selected patient collective was available. In this collective, disease-free survival after 5 years was comparable between patients with TSH-suppressive therapy (median TSH: 0.07) and patients without suppression (median TSH: 3.2) at 91 vs. 89% and was not different even after a maximum of 12 years of follow-up [832]. In this respect, a TSH target range of ≤0.5 mU/l or ≤0.1 mU/l is only recommended for patients without radioiodine therapy if there is an incomplete response.
There are no dedicated data for the subgroup of patients with lobectomy that justify a different recommendation.
Provided there are no contraindications, suppressive thyroid hormone treatment appears appropriate until the first post-therapeutic follow-up. The risk assessment is subject to continuous reassessment during the course of treatment. In particular, the initial risk can be downgraded if the findings of a biochemically or morphologically incomplete response remain constant over the long term.
Table 20: Recommended TSH target ranges in the period after inital therapy until response evaluation after 6 months
|
|
TSH target range |
|||
|
Very low risk |
Low risk* |
Medium risk* |
High risk* |
|
|
Excellent response** (non-stimulated Tg <0.2 ng/ml) |
0.5 - 2.0 mU/l |
0.5 - 2.0 mU/l |
0.1 - 0.5 mU/l |
<0.1 mU/l |
|
Incomplete response** (non-stimulated Tg >0.2 ng/ml) |
0.1 - 0.5 mU/l |
|||
|
* after total thyroidectomy ** in addition to the biochemical response, the structural response is also relevant |
||||
Table 21: Recommended TSH target ranges according to the response after inital response evaluation after 6-12 months
|
TSH target range |
|||
|
excellent |
good/acceptable* |
biochemically incomplete** |
structurally incomplete*** |
|
0.5 - 2.0 mU/l |
0.1 - 0.5 mU/l |
0.1 - 0.5 mU/l |
<0.1 mU/l |
|
* at age > 60 years, osteoporosis or atrial fibrillation: TSH target ranges 0.5 - 2.0 mU/l ** in addition to the biochemical response, the structural response is also relevant without risk factors such as postmenopause, tachycardia, osteopenia/osteoporosis, age > 60 years: TSH target range <0.1 mU/l *** for atrial fibrillation: TSH target range 0.1- 0.5 mU/l |
|||
6.6 Laboratory diagnostics (thyroglobulin)
The determination of the thyroglobulin (Tg) value in combination with the determination of thyroglobulin antibodies (TgAb) shall be carried out as part of follow-up care using a quality-assured, highly sensitive assay. If TgAb is elevated, a negative Tg shall not be considered diagnostically usable. This applies in particular to a Tg that cannot be detected with an immunometric assay.
- Consensus
- Strong consensus (95,7%)
Once therapy evaluation has been completed, no further tumor diagnostics should be performed if the serum Tg concentration is below 0.1-0.2 ng/ml (depending on the functional assay sensitivity) and the neck sonography is normal, given the high negative predictive value.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2a
NPV
- Consensus
- Strong consensus (96%)
- References
- [733]
Endogenous or exogenous TSH stimulation alone for Tg determination shall not be performed in tumor aftercare.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 2a
NPV
- Consensus
- Strong consensus (100%)
- References
- [733]
The protein thyroglobulin (Tg) is synthesized exclusively by thyrocytes and can be detected as a tumor marker in serum. However, it is not possible to differentiate between malignant and benign thyroid tissue as the source of Tg. The use of Tg as a sensitive tumor marker therefore requires the complete removal of the thyroid gland, which is usually achieved by total thyroidectomy and adjuvant radioiodine therapy. The detection of Tg in serum can be disturbed by anti-Tg antibodies. These must therefore also be determined in parallel with the Tg determination. If TgAb is detectable, the validity of the Tg determination (in terms of reflecting the tumor burden) cannot be guaranteed. Otherwise, Tg is a very sensitive tumor marker in the tumor follow-up of differentiated thyroid carcinomas. Reliable sensitive Tg tests are commercially available and have a limit of quantification (LoQ) of 0.1 to 0.2 ng/ml, sometimes even lower.
After a lobectomy, Tg can be measured due to the residual thyroid tissue, but its significance as a tumor marker is then limited. After a lobectomy, the Tg value alone is therefore not suitable for detecting a recurrence [833], [834], [835].
After the systematic literature search, the evidence assessment was based on the meta-analysis by Giovanella [733]. Eight publications with a total of 1,568 patients were included. The result of the determination of thyroglobulin serum concentration (Tg value) under thyroid hormone medication was compared with various imaging procedures, sonography, chest X-ray, CT, MRI, fine needle aspiration cytology, 99mTc-MIBI scintigraphy and FDG-PET/CT. The overall sensitivity was 83.4% (73.4 - 90.1), the specificity 79.9% (63.0% - 90.3%). The positive predictive value was only 21.3% (11.9 - 30.7), while the negative predictive value was extremely high at 99.4% (89.9% - 99.9%). The sole use of the Tg determination under thyroid hormone medication can therefore largely rule out a recurrence, provided the Tg determination is valid. Despite the low to moderate confidence in the quality of the evidence, the two strong negative recommendations can therefore be issued.
The above evidence-based recommendations make no statement on the value of Tg determination for the detection of recurrence. There is a consensus among the experts that the absolute Tg values are of less importance than the progressive increase in Tg values. The mostly retrospective studies provide only very weak evidence on the question of how a progressively increasing Tg value should be defined and what diagnostic and/or therapeutic consequences should be drawn when. The PPVs range from 8% [836] to 40% [837] and depend on the previous therapies, the selected criteria and not least on the quality of the Tg determination.
6.7 What role does neck sonography play in the follow-up of patients with differentiated thyroid carcinoma?
Neck sonography shall be part of every follow-up examination and shall include a systematic examination of the thyroid bed and the central and lateral lymph drainage areas of the thyroid region.
- Consensus
- Strong consensus (100%)
Sonography is one of the central examination methods in the aftercare of thyroid cancer. It is largely risk-free and inexpensive. In both older [796] and more recent studies [674], [838], sonography has demonstrated its diagnostic value for detecting persistence or recurrence in various situations in the follow-up of thyroid cancer.
There are three scenarios for sonography in the follow-up of thyroid cancer: timely postoperative sonography, postoperative sonography for sonomorphological characterization of treatment response and risk stratification, and long-term follow-up.
A timely postoperative sonography (i.e. within the first 3 months postoperatively) is not generally useful, as the assessability and informative value are limited. Exceptions may be [839]: There is no preoperative sonography and the diagnosis was made incidentally by histology, the preoperative sonography is not conclusive or not complete with regard to possible lymph node metastases, activity outside the thyroid bed is seen in the scintigraphy after RIT following total thyroidectomy or there are discrepantly high Tg values compared to the accumulation in the thyroid bed in the postablative scintigraphy. For patients who have initially received radioiodine therapy, cervical sonography is already described in Chapter Diagnostics before radioiodine therapy as part of the imaging preparation for radioiodine therapy.
Postoperative sonography is an important examination for the sonomorphological characterization of the response to therapy. Although prospective studies on the question of the best time for sonography checks are lacking, they are recommended 6-12 months postoperatively [83], [24]. Retrospective studies have found evidence that too early risk stratification after total thyroidectomy and radioiodine therapy has no advantage for this assessment [544], [806].
A separate situation with an early need for monitoring after 3 months arises for findings that may indicate renewed surgical therapy [24], [839]. These include organ-transcending growth (pT3/pT4), R1/R2 resections and histological evidence of lymph node metastases. In practice, the latter results from the fact that suspicious lymph nodes detected preoperatively by sonography often cannot be reliably assigned to the corresponding histological findings. Postoperative sonography 3 - 4 months after surgery was also the most sensitive method for detecting cervical tumor manifestation in a study [674].
Postoperative sonographic findings can only be interpreted with precise knowledge of the clinical, laboratory, histopathological and other imaging findings.
Standardized protocols and documentation of sonography are quality criteria for medical findings. They standardize sonographic findings and improve comparability. A complete sonography must include the examination of the thyroid bed [799], [800] as well as the cervical and lateral lymph node stations [83], [24].
After thyroidectomy, echo-rich scar tissue in the thyroid bed is typically observed on sonography as a result of the connective tissue reaction following surgery [799]. After successful radioiodine therapy of residual thyroid tissue, this may subsequently remain as inhomogeneously hypoechoic tissue, which is typically without detectable perfusion in color-coded duplex ultrasonography [799], [840]. Criteria for suspicious lesions in the thyroid bed after thyroidectomy are comparable to the general malignancy criteria for thyroid lesions (details in the "Diagnostics" chapter). In summary, these include hypoechogenic, nodular lesions (especially those that are larger in anteroposterior diameter than in lateral diameter ("taller than wide" [799]) or cystic or blurred or more vascularized or size-progressive lesions or those with calcifications [799], [841], [842].
Patients with initially low or intermediate risk and excellent as well as good and acceptable response to primary therapy occupy a special position here. The risk of recurrence is very low at <1%, meaning that abnormal findings in sonographic follow-up are more often false positives [842], [843], [844], [845]. It is therefore justified to dispense with further routine sonographic checks in these patients after 5 years of inconspicuous follow-up care [846]
The sonography of lymph nodes in the drainage area of the thyroid gland is also described in detail in the "Diagnostics" chapter (Chapter Sonography), also with regard to technical aspects. In summary, it makes sense to classify lymph nodes into the categories normal, indeterminate or suspected malignancy using evaluated sonomorphological criteria (cystic changes, echogenic foci, loss of the hilar sign, atypical peripheral vascularization [97], [90]). In addition, the localization of the lymph nodes in the central and lateral compartments according to an evaluated classification is necessary to ensure the reproducibility of the findings.
6.8 How often should outpatient or inpatient follow-up examinations take place?
Patients who have undergone surgery and radioiodine therapy should be followed up every 6 months for the first 5 years to determine the Tg and TgAb values, and have a neck sonography scan. After 5 years, the follow-up should take place every 12 months, after 10 years every 12-24 months.
- Consensus
- Strong consensus (100%)
Patients who have undergone surgery without radioiodine therapy should always undergo sonography in addition to the determination of Tg and TgAb. Depending on the risk of recurrence, the follow-up intervals should be individualized.
- Consensus
- Strong consensus (96%)
In the case of unclear or suspicious findings in the routine follow-up examinations, individualized, shorter examination intervals should be defined.
- Consensus
- Strong consensus (100%)
The majority of recurrences of differentiated thyroid carcinomas are observed within the first 5 years of follow-up [847], [848], [849][849], so that consistent follow-up examinations are particularly important during this period. However, studies with longer follow-up periods show that there is no follow-up period after which subsequent recurrences can be reliably ruled out. Extensive retrospective data [850], [851] and prospective long-term data from the HiLo study [852] show that even in low-risk patients, recurrences continue to occur after >5 years and the recurrence rate is steadily increasing. However, these long-term surveys lacked additional information on the response achieved by these patients at risk of recurrence after initial therapy.
As shown in detail in Chapter Patients with complete treatment success after initial adjuvant radioiodine therapy, the risk of recurrence is clearly determined by the response achieved after completion of the initial therapy in addition to the initial risk category (low, intermediate, high risk) [853], [848], so that adjusted follow-up intervals according to the initial risk category and the response achieved are justified [838]. For all other patients (i.e. initial high risk or incomplete response), ongoing sonographic follow-up examinations are recommended even after 5 years of follow-up, whereby the examination intervals can be extended with increasing follow-up duration.
In patients with total thyroidectomy without radioiodine therapy, the unstimulated Tg value often falls into the unmeasurable range [854] over the course of the follow-up years and can be considered a reliable indicator of normal follow-up in these cases. Nevertheless, sonographic follow-up examinations [797][797] help to detect cervical recurrences and should therefore be performed routinely. The data on "correct examination intervals" is insufficient, so that the above-mentioned examination intervals are based on clinical experience.
In patients who have undergone lobectomy, the Tg value is an unreliable follow-up parameter and is only partially sensitive for the detection of recurrences or carcinoma lesions in the remaining thyroid lobe [833]. At the same time, recurrences are also observed more frequently in small carcinomas after lobectomy than after total thyroidectomy [851], which is why regular sonographic follow-up examinations are important.
6.9 Diagnostic ¹³¹I whole-body scintigraphy
¹³¹I whole-body scintigraphy with a usual activity of 350 - 400 MBq, if necessary carried out with higher, also therapeutic activity depending on weight, is used in follow-up care to detect or exclude iodine-storing recurrences and/or metastases in all forms of differentiated and poorly differentiated thyroid carcinoma [855]. The individual indication for the administration of ¹³¹I must be given by a doctor with the appropriate specialist knowledge (Radiation Protection Act, Guidelines on Radiation Protection in Medicine). For contraindications, see Chapter Preparatory measures for radioiodine therapy.
The following indications are explicitly not considered in this chapter, as they have been assigned to the chapter on radioiodine therapy.
6.9.1 Patients with complete treatment success after initial adjuvant radioiodine therapy
If the success check shows negative findings ≥ 6-12 months after the initial RIT, no further diagnostic ¹³¹I whole-body scintigraphy shall be performed if the follow-up is normal.
- Consensus
- Strong consensus (95,7%)
Irrespective of the initial TNM tumor classification of thyroid carcinomas, the probability of recurrence is very low in the case of an unremarkable success control of radioiodine therapy (no evidence of residual thyroid tissue or metastases). The disease-related mortality rate is <1 % [807], [721], [808] and the probability of recurrence is <5 % [735], [544], [805], [807], [838]. To avoid radiation exposure without subsequent clinical consequences, further diagnostic ¹³¹I whole-body scintigraphy shall therefore be avoided.
According to the dynamic risk stratification, patients with persistent iodine storage in the thyroid gland in the sense of residual thyroid tissue are also classified in the group of full remission in the absence of imaging evidence of tumor lesions and an undetectable tumor marker. This does not result in an indication for further radioiodine whole-body scintigraphy or radioiodine therapy [735], [856]. If there is a clinical suspicion of tumor recurrence (e.g. clinic, increase in thyroglobulin, imaging), a ¹³¹I whole-body scintigraphy for staging and clarification of a possible indication for surgery is advisable, provided that metastases that are primarily accessible to radioiodine therapy are unlikely.
6.9.2 Patients with increased TgAb or impaired recovery
In the case of persistently elevated or increasing TgAb, a ¹³¹I whole-body scintigraphy can be performed even if the Tg is negative.
- Consensus
- Strong consensus (100%)
In immunometric assays, TgAb can lead to falsely low Tg values. An elevated Tg level indicates tumor persistence regardless of interfering TgAb or impaired recovery. However, if TgAb is detected, the level of the Tg serum concentration can no longer be used for follow-up and a negative Tg is not proof of a complete remission [857], [858]. Antigen presence should be assumed in the case of increasing or newly occurring TgAb during the course [859]. In the case of complete thyroid ablation, persistence/recurrence is therefore suspected. According to a recent meta-analysis, persistently elevated TgAb is also associated with an increased risk of persistent or recurrent tumor disease [860]. Therefore, if TgAb or impaired recovery is detected, an individualized approach is necessary and diagnostic ¹³¹I whole-body scintigraphy may be indicated as part of follow-up care due to the inability to assess the course of Tg. TgAb levels that fall significantly (by >50%) over the course of treatment indicate a good/acceptable response to therapy, even if a plateau develops [861].
The following diagram shows the procedure for detecting TgAb as recommended in this guideline:
6.9.3 Patients with suspected recurrence
Diagnostic ¹³¹I whole-body scintigraphy shall not be performed to assess therapeutically useful iodine storage in cases of suspected recurrence; radioiodine diagnostics with therapeutic activity is the preferred procedure here.
- Consensus
- Strong consensus (100%)
A diagnostic ¹³¹I whole-body scintigraphy incl. SPECT/CT for metastasis localization shall only be performed if the possibility of local therapy is discussed in the tumor board.
- Consensus
- Consent (84,6%)
After therapeutic measures (surgery, further RIT, percutaneous RTx), a diagnostic ¹³¹I whole-body scintigraphy may be indicated for control purposes in the case of previously iodine-positive metastases.
- Consensus
- Strong consensus (100%)
Patients who are suspected of having a recurrence after complete remission should undergo comprehensive diagnostics. Due to the unfavorable effect of a metastasis search with ¹³¹I on a subsequent RIT [724], [862], [863], this should be omitted and RIT should be performed directly. In addition to the beneficial therapeutic effect, the sensitivity for the detection of iodine-storing metastases is also higher when using a therapeutic activity [864].
The collection of pre-therapeutic dosimetric data can enable an individualized therapy concept for subsequent radioiodine therapies (blood dosimetry with small amounts of ¹³¹I, lesion dosimetry with ¹²⁴I, see Chapter Patients with suspected recurrence), especially in patients with recurrence [865].
In the context of an individual indication, diagnostic ¹³¹I whole-body scintigraphy to search for metastases as part of re-staging to clarify an indication for surgery, possibly with intraoperative use of a gamma probe [866], may be useful. The use of diagnostic ¹³¹I whole-body scintigraphy to monitor the therapeutic measures can also serve to monitor success in individual cases.
6.9.4 TSH stimulation
The TSH stimulation required for radioiodine diagnostics can be exogenous (preferred) or endogenous.
- Consensus
- Strong consensus (100%)
In preparation for a diagnostic ¹³¹I whole-body scintigraphy, exogenous or endogenous TSH stimulation is required. Prospective comparative studies for the stimulation methods in the specific context of diagnostic ¹³¹I whole-body scintigraphy in follow-up care do not exist. The two methods of TSH stimulation are described in Chapter TSH stimulation of the current guideline on radioiodine therapy. The aim is to induce a high TSH serum concentration. It is not known exactly what influence the duration of the hypofunction has, nor the level of the maximum TSH concentration. According to convention - based on radioiodine therapy - a basal TSH serum concentration >30 mU/l is required. However, with regard to the diagnostic accuracy of a diagnostic ¹³¹I whole-body scintigraphy, there are no reliable data available to justify a specific threshold [867]. In the case of endogenous stimulation, a serum TSH concentration >30 mU/l is generally considered desirable and sufficient. However, this threshold is based on observations from a single study with only 7 patients. Alternatively, exogenous stimulation with recombinant TSH has been established [868].
In the case of contraindications to endogenous stimulation, exogenous stimulation is the method of choice. Other concomitant circumstances and concomitant diseases that may also argue in favor of exogenous stimulation are listed in Chapter TSH stimulation.
6.10 PET/CT in the follow-up of differentiated and poorly differentiated thyroid carcinoma
6.10.1 PET/CT with [¹⁸F]FDG
A [¹⁸F]FDG-PET/CT should be performed if Tg or TgAb is elevated, if morphological recurrence is suspected, or if the tumor is Tg-negative.
- Consensus
- Strong consensus (96%)
A meta-analysis of 17 studies with 1,195 patients showed a high diagnostic accuracy of [¹⁸F]FDG-PET/CT in the detection of recurrent and/or metastatic disease in DTC patients with hTg elevation (usually stimulated >2 ng/ml) and negative ¹³¹I whole-body scintigraphy. The pooled sensitivity was 86% (95% confidence interval: 0.79-0.91), the specificity 84% (95% confidence interval: 0.72-0.91), whereby no significant advantage for previous TSH stimulation could be evaluated in the analysis [869]. In contrast, a meta-analysis of seven prospective studies with 168 patients on [¹⁸F]FDG-PET/CT with and without rhTSH stimulation showed that significantly more patients with rhTSH stimulation had true positive lesions detected than without TSH stimulation (odds ratio: 4.92, 95% confidence interval: 2.70-8.95). This changed the clinical management in 9% of patients compared to [¹⁸F]FDG-PET/CT without rhTSH stimulation [870]. However, the individual studies included only a few patients and the results have not yet been confirmed. It is therefore not possible to derive a recommendation that [¹⁸F]FDG-PET/CT examinations should always be performed under TSH stimulation.
In a meta-analysis of 9 studies ([¹⁸F]FDG-PET: 3 studies; [¹⁸F]FDG-PET/CT: 6 studies) with 515 patients, the pooled sensitivity was 84% (95% confidence interval: 0.77-0.89), the specificity 78% (95% confidence interval; 0.67-0.86) [871].
¹⁸F]FDG-PET/CT is more sensitive in patients with an aggressive histologic subtype, including poorly differentiated thyroid carcinoma, the tall cell variant and Hürthle cell tumor [872], [241], [240]. ¹⁸F]FDG PET/CT in patients with metastatic DTC is an important negative predictor of response to radioiodine therapy and an independent prognostic factor for survival [873], [874]. PET/CT is able to identify lesions with high [¹⁸F]FDG accumulation (quantification by SUV), which may correspond to a more aggressive subtype and should be treated specifically or monitored more closely. Even if ¹³¹I-enrichment is detectable in metastases, [¹⁸F]FDG-PET/CT is valuable as a complementary cross-sectional diagnostic, as it can detect neoplastic foci that do not show ¹³¹I-enrichment.
6.10.2 PET/CT with ¹²⁴I
¹²⁴I-PET/CT imaging with or without dosimetry can be performed as an alternative to ¹³¹I whole-body scintigraphy as part of the diagnostic procedure.
- Consensus
- Strong consensus (100%)
¹²⁴I emits positrons and thus enables PET/CT imaging in patients with DTC. ¹²⁴I PET/CT can be used both as a dosimetric and diagnostic tool for localizing iodine-avid lesions. However, ¹²⁴I is neither available for purchase as an approved radiopharmaceutical nor is it widely available. According to two prospective studies with a total of 45 patients, the diagnostic sensitivity of ¹²⁴I-PET/CT under rhTSH stimulation is significantly higher at 78-99% than that of diagnostic planar ¹³¹I whole-body scintigraphy with low activity of 37-74 MBq ¹³¹I (22-49%) [864], [875], [876]. According to several prospective studies, the sensitivity of ¹²⁴I-PET/CT under rhTSH stimulation or hormone deprivation (57-100%) is also comparable to post-therapeutic ¹³¹I whole-body scintigraphy with 3.7-11.1 GBq (70-100%) [864], [875], [877], [878], [879]. One exception is disseminated or micronodular lung metastasis, which frequently leads to false negative results of ¹²⁴I-PET/CT compared to post-therapeutic ¹³¹I whole-body scintigraphy [878]. Simplified imaging protocols have been developed and feasibility evaluated for ¹²⁴I-PET/CT for lesion dosimetry prior to radioiodine therapy [880], [881], [882], [883].
6.10.3 PET/CT with somatostatin receptor-affine radiopharmaceuticals
PET/CT with somatostatin receptor-affine radiopharmaceuticals ⁶⁸Ga-DOTANOC/DOTATOC/DOTATATE etc.) can be performed in cases of increased Tg or TgAb in the search for metastases of a differentiated thyroid carcinoma in the absence of detection with other nuclear medicine or morphological imaging methods.
- Consensus
- Strong consensus (100%)
Differentiated thyroid carcinomas express somatostatin receptors (SSTR) to varying degrees, predominantly SSTR 2, 3 and 5 [884], [885] and can therefore potentially be detected with SSTR-affine radiopharmaceuticals. In a prospective pilot study, metastases were detected in 14 of 15 patients with PTC (60% of whom had aggressive subtypes) and hTg increase with negative ¹³¹I whole-body scintigraphy using ⁶⁸Ga-DOTATATE-PET/CT both under TSH suppression and after endogenous TSH stimulation with a sensitivity of 91% and 100% respectively. The other available imaging (CT/MRI, [¹⁸F]FDG-PET/CT) served as a reference. Under endogenous stimulation conditions, more cervical and distant lymph node metastases tended to be detected, but with lower specificity due to a higher detection rate of false positive lymph nodes (an inflammatory genesis was postulated). It can therefore be assumed that the higher sensitivity is the result of a more aggressive diagnosis with correspondingly lower specificity. There was no difference to suppressed TSH in the detection of local recurrence or lung or skeletal metastases [886].
Another prospective study compared ⁶⁸Ga-DOTANOC-PET/CT with [¹⁸F]FDG-PET/CT in patients with differentiated thyroid carcinoma and negative ¹³¹I whole-body scintigraphy despite elevated Tg values. Patient-related sensitivity and specificity were comparable at 78% and 100% (⁶⁸Ga-DOTANOC) and 86% and 91% ([¹⁸F]FDG), respectively, but [¹⁸F]FDG-PET/CT detected more lesions (168/186) than ⁶⁸Ga-DOTANOC-PET/CT (121/186). Only 55% of all lesions (103/186) were concordant, so that ⁶⁸Ga-DOTANOC-PET/CT partly provided supplementary information compared to [¹⁸F]FDG-PET/CT [887].
PET/CT with DOTA-conjugated peptide radioreceptors can also be considered against the background of a theranostic approach with optional specific and systemic DOTA-conjugated peptide radioreceptor therapy.
6.11 Functional cross-sectional imaging diagnostics
If the sonography diagnosis is inconclusive, the ¹³¹I storage is negative and the [¹⁸F]FDG-PET is unremarkable and the Tg serum level or TgAb value continues to rise, additional morphological localization diagnostics should be performed using diagnostic CT or MRI.
- Consensus
- Strong consensus (100%)
The use of PET/CT for the localization of non-iodine-storing tumor parts (Chapter PET/CT in the follow-up of differentiated and poorly differentiated thyroid carcinoma) and iodine whole-body scintigraphy of iodine-storing tumor parts has been discussed in Chapter Diagnostic ¹³¹I whole-body scintigraphy. Computed tomography (CT) and magnetic resonance imaging (MRI) are complementary morphological methods to [¹⁸F]FDG-PET/CT. However, after performing a PET/CT with diagnostic CT, an additional CT would be redundant and not necessary.
The question of which of these two procedures, CT or MRI, should be preferred for an individual patient cannot be adequately answered, as comparative and tumor-specific studies are lacking. Instead, the decision shall be made on an individual basis, taking into account the suspected tumor location.
Due to the higher soft tissue contrast, MRI shows advantages over CT in tumor detection of deep cervical lymph nodes as well as liver and brain metastases [888]. This contrasts with the higher spatial resolution, speed and lower susceptibility to artifacts of CT, which leads to better detection rates for small lung metastases [889].
An indication for CA-supported CT is only given if radioiodine therapy is not planned or foreseeable in the next few months.
6.12 Further procedures
A chest X-ray shall not be performed as a routine follow-up examination.
- Consensus
- Strong consensus (100%)
The chest X-ray examination is not sensitive enough as a search method for the detection of lung metastases in the context of follow-up care and is clearly inferior to Tg determination. If there is a concrete suspicion of lung metastases, chest X-ray is also not recommended, as it is considerably inferior to CT even in low-dose mode (here detection of lung foci < 3mm is possible [890]).
If pulmonary filiae are suspected, a diagnostic CT of the thorax should be performed (with contrast medium if necessary, after ruling out the possibility of radioiodine therapy).
- Consensus
- Strong consensus (100%)
If pulmonary filiae are suspected, diagnostic CT of the thorax is the most sensitive method of assessment. Pulmonary foci with a size of 2 mm and less can be detected here if performed adequately [890]. Before the examination, it should be checked in detail whether the administration of a contrast agent can be expected to provide relevant additional information (e.g. for the assessment of vascular and mediastinal structures), as this interferes with any radioiodine therapy that may be required. In many cases, a native CT without contrast agent is sufficient.
Skeletal scintigraphy (incl. SPECT or SPECT/CT) shall not be used to search for metastases of DTC.
- Consensus
- Strong consensus (96%)
To date, there are no clear recommendations as to when skeletal scintigraphy can or should be performed in cases of osseous filiae. 17 studies on skeletal scintigraphy were analyzed in comparison to other methods for the detection of bone metastases.
The data analysis showed that planar skeletal scintigraphy without the use of SPECT has a significantly lower sensitivity and specificity [245], [244], [891], [892], [893], [894], [895], [896], [897], [898], [899] compared to other methods (¹³¹I whole-body scintigraphy with SPECT, whole-body MRI, [¹⁸F]fluoride PET/CT and [¹⁸F]FDG PET/CT). Without additional SPECT images, the probability of detecting osseous metastases is significantly limited, especially in the more osteolytic filiae typical of differentiated thyroid carcinoma [245], [900]. The specificity and diagnostic accuracy increase in relation to planar skeletal scintigraphy and also in comparison to SPECT when hybrid SPECT/CT imaging is used [893], [895], [899], [901], [902], [903], [904]. Osteo-CT is the superior procedure for this issue.
There is no routine indication for skeletal scintigraphy as part of follow-up care [905]. As extra-osseous metastases may be present in addition to osseous filiae, [¹⁸F]FDG-PET/CT examination is the diagnostic method of choice in this situation.
6.13 Should a fine needle aspiration be performed for suspicious cervical lesions discovered during follow-up care?
In patients with a suspicious cervical lesion, fine-needle aspiration cytology with Tg determination from the punctate can be performed if therapeutically appropriate.
- Consensus
- Consent (92,3%)
There are no controlled studies regarding the value of fine-needle aspiration in suspected recurrence of known differentiated thyroid carcinoma. Retrospective surveys with small numbers of cases showed a diagnostic sensitivity of between 75-85% for fine needle aspiration with cytologic examination of suspicious cervical lymph nodes alone [906], [907], [908]. Fine-needle aspiration of suspicious cervical lymph nodes or lesions can therefore be considered if the result is of potential therapeutic consequence (e.g. decision on surgery). Several retrospective studies have shown that the determination of Tg from the aspirate improves the diagnostic sensitivity on average compared to cytological assessment of the material alone [907], [909], [211], [910], [911]. A meta-analysis of a total of 1,007 lymph nodes in patients after thyroidectomy for differentiated thyroid carcinoma showed a pooled sensitivity of 97% (95% confidence interval: 95-98%) and a specificity of 94% (92-96%) for Tg determination from the aspirate [912].
The determination of Tg from the aspirate requires special calibration and quality control of the kit used with regard to this specific question.
6.14 How should postoperative hypoparathyroidism be treated?
Postoperative hypoparathyroidism shall be monitored and treated as required.
- Consensus
- Strong consensus (96%)
- References
- [913]
Postoperative hypoparathyroidism can occur both temporarily and persist permanently. In this context, timely recognition and initiation of therapy during the inpatient stay with adequate treatment are important. Subsequent determination of serum calcium and parathyroid hormone is required; medication with calcium and highly active vitamin D analogs should be reduced or discontinued if the serum calcium value is in the lower normal range or PTH > 15 pg/ml. The management of hypoparathyroidism in the postoperative setting is illustrated in the S2k guideline "Operative therapy of benign thyroid diseases" [913].
Patients with long-standing hypoparathyroidism have a significantly increased risk of developing kidney stones (nephrocalcinosis/nephrolithiasis) and cataracts as well as neurological symptoms (e.g. depression etc.) and neuromuscular symptoms (e.g. paresthesia, cramps etc.). Therefore, an optimal setting is necessary. To date, there are no data on optimal serum calcium levels in the treatment of hypoparathyroidism. In order to minimize renal calcium excretion, a serum calcium level in the lower normal range or slightly lower should therefore be aimed for. However, some patients require higher values in order to achieve freedom from symptoms. As long as calcium in the 24-hour urine remains within the normal range, serum calcium can be increased until the patient is symptom-free.
Few studies exist on endpoints such as mortality, quality of life, risk of hypercalcemia, kidney stones, tetany and cardiovascular events. An improvement in quality of life under treatment with a recombinant parathyroid hormone [914] could not be reproduced in comparison with a placebo preparation in a randomized controlled trial [915]. With regard to cardiovascular risk under recombinant parathyroid hormone, 2 studies were published [916], [917], in each of which a serious cardiovascular event was described in the recombinant parathyroid hormone group (122 patients in total) compared with no serious cardiovascular event in the placebo group. Convulsions and tetany were not quantitatively evaluated in the majority of studies. Although nephrocalcinosis/kidney stones have been frequently described in hypoparathyroidism, different treatment regimens have not yet been compared in terms of frequency.
With regard to the treatment of chronic hypoparathyroidism in adults, reference is made to published recommendations [918], [919], [920]. There are also several statements from American expert groups [918], [921][921], [922].
6.15 Diagnosis of vocal fold function and management of vocal fold dysfunction
Before and after each thyroid surgery, a laryngoscopic check of the respiratory mobility of the vocal folds shall be carried out and subjective vocal, breathing and swallowing difficulties shall be recorded.
- Consensus
- Strong consensus (96%)
If postoperative vocal fold mobility is restricted, a phoniatric examination should be performed.
- Consensus
- Strong consensus (100%)
In the case of a voice disorder, the indication for voice function therapy should be checked.
- Consensus
- Strong consensus (100%)
The indication for phonosurgical treatment should be examined in the case of persistent voice disorders or dyspnoea. When phonosurgical procedures are indicated in cases of insufficient vocal fold closure or dyspnoea, it shall be considered whether respiratory mobility can still be expected to return.
- Consensus
- Strong consensus (100%)
Dysphonia, i.e. impaired vocal tone or vocal performance, can be caused by unilateral or bilateral paresis of the two laryngeal nerves (recurrent/inferior laryngeal nerve or superior laryngeal nerve) or impaired function of the straight neck muscles following thyroid surgery. In 2-12% of patients with thyroid carcinoma, a voice disorder is already present pre-therapeutically, usually due to paresis of the recurrent/inferior laryngeal nerve [923]. As 20-30% of patients with unilateral paresis do not experience a voice disorder [924], [925], [926], the motility of the vocal folds should be checked preoperatively [927]. Pre-existing, previously asymptomatic functional dysphonia can be unmasked by surgical interventions on the neck organs. Damage to the superior laryngeal nerve or the straight neck muscles can be further causes of voice disorders and can be observed in 27% of patients with preserved respiratory mobility of the vocal folds [928]. For this reason, not only shall a laryngoscopic check of the respiratory mobility of the vocal folds be performed after every thyroid surgery, but subjective voice complaints (preferably using the standardized Voice Handicap Index, VHI), breathing and swallowing difficulties should also be recorded [927], [929]. If there are limitations in vocal function, breathing or swallowing, a phoniatric examination should be carried out and the next steps determined.
According to two reviews, early recurrent paresis after thyroid surgery is found in 5-8% and 0.8-10.5% respectively, permanent paresis in 0.3-3% and 0-1.5% [930], [931].
In the case of dysphonia, voice function therapy is usually indicated. Direct therapy methods focus on voice and speech technique in order to optimize breathing, resonance, phonation and articulation. Indirect therapies focus on those factors that can cause and maintain a voice disorder, e.g. unfavorable room acoustics, dehydration, laryngo-pharyngeal reflux as well as stress and strain factors [932], [933], [934], [935]. Disorders of vocal fold movement with incorrect position and/or tension of the vocal folds can also be treated by phonosurgery [936], [937], [938], [939], [940]. The indication should be based on extensive phonosurgical experience and the timing should be determined according to the prognosis [941].
6.16 Other side effects/long-term consequences
In the treatment and aftercare of patients with thyroid cancer, aspects of quality of life, as well as physical, social and psychological well-being should be recognized and addressed in the interaction with the patient.
- Consensus
- Strong consensus (100%)
Several surveys on quality of life in patients with thyroid cancer have shown that, compared to the general population, a reduced quality of life was reported on average after adjustment for important covariates [942], [943], [944], [945], with these impairments covering various dimensions. These included impairments in psychological well-being (e.g. fatigue, anxiety and depression), in physical functioning [945] and role functions as well as in the general perception of health. In addition, specific somatic complaints such as musculoskeletal or neurological symptoms, e.g. migraine-like headaches, were reported [946] as well as signs of thyroid dysfunction (e.g. dry skin, hair loss, concentration problems, sleep disorders, heat/cold intolerance, palpitations, digestive problems and weight changes) [946]. Patients also complain about the trivializing categorization of thyroid cancer as a "good cancer" in the face of psychological, social and physical stress [947].
In several surveys, fatigue was reported as one of the primary symptoms by approx. 40% of patients with thyroid cancer [948], [949], [950] and thus as frequently as by patients with other cancers [948]. In a single randomized controlled trial with 36 patients, fatigue was reduced by physical exercises under supervision (aerobic training and stretching exercises) [951] (see also Chapter Rehabilitation and Chapter Psychosocial aspects).
References
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