5. Initial therapy of differentiated thyroid carcinoma – Thyroid Cancer
5.1 Resection of the thyroid gland
The terminology of thyroid resection forms applies regardless of dignity for both benign and malignant thyroid diseases [340]. They are defined here for all entities named in this guideline. For most malignant thyroid findings, complete thyroidectomy is required for curative treatment and/or as a prerequisite for radioiodine therapy.
- Enucleation: Excision of a nodule along its capsule.
- Nodal excision: removal of a nodule with a seam of normal thyroid tissue.
- Isthmus resection: Resection of the pretracheal thyroid tissue.
- Subtotal thyroid gland resection: partial removal of a thyroid lobe with a parenchymal remnant of 1 to 4 ml.
- Near-total flap resection: partial removal of a thyroid lobe with a parenchymal remnant of less than 1 ml.
- Lobectomy/flap resection: complete removal of a thyroid lobe including the thyroid isthmus and lobus pyramidalis.
- Surgery according to Riedel-Hartley-Dunhill: Lobectomy with contralateral subtotal resection and a parenchymal remnant at the upper pole or dorsally of 1 to 4 ml.
- Bilateral subtotal resection: partial removal of both thyroid lobes with bilateral parenchymal remnants of 1 to 4 ml each.
- Near-total thyroidectomy: The almost complete removal of the thyroid gland, leaving a unilateral or bilateral parenchymal remnant totaling less than 2 ml.
- Thyroidectomy: The complete removal of both thyroid lobes including the isthmus and the pyramidal lobe without leaving any parenchymal remnants.
The procedures listed under 3-10 are partial or complete extracapsular procedures, the resections listed under 1+2 are intracapsular procedures in which thyroid tissue is removed while leaving most of the thyroid capsule intact. Other procedures not listed here are defined by the indication of the thyroid remnant in the surgical report.
5.2 Resection of the lymph nodes
5.2.1 Terminology of lymph node resection procedures
Various terminologies are used in the literature to describe resection procedures [341], [342]. In many cases, the extent of resection in the lymph node area is combined with that in the area of muscular, nervous and vascular structures in different ways (e.g. radical or modified-radical neck dissection). As the aforementioned resection procedures are based on the terminology and surgical technique of the procedure for squamous cell head and neck tumors, which differ considerably from thyroid carcinomas, these guidelines are based on Dralle's compartment classification (see Figure 2) with regard to the terminology of the resection procedures: Compartment resection cervicocentral (right or left), cervicolateral (right or left) and mediastinal (right or left) [343], [344]. If muscular, nervous or vascular structures are included in the resection, this should be added to the resection definition, as should the access designation (cervical, transsternal). If no compartment resection is performed but selective removal of individual lymph nodes or groups of lymph nodes for local control with a non-curative approach, this should also be indicated (e.g. selective lymph node dissection compartment 1, 2, 3 or 4). Prophylactic compartment resection means lymph node dissection in the absence of clinical evidence of lymph node metastases, therapeutic compartment resection means lymph node dissection in the presence of clinically, imaging or biopsy proven lymph node metastases. As with other oncological procedures, the number of examined and tumor-involved lymph nodes should be specified in the pathological work-up of the compartment resection. The central and mediastinal compartments contain an average of 10 lymph nodes each (5 on each side), the lateral compartments 20 lymph nodes each (58, 62, 66). The lymph node compartments listed are shown schematically in Figure 2a–d and apply to all entities named in this guideline.
5.2.2 Central compartment (C1a, cervicocentral right; C1b, cervicocentral left) (Fig. 2a)
In surgical anatomical terms, the central compartment comprises the entire soft tissue space containing the lymph nodes, which is bounded laterally by the carotids and cranially by the hyoid bone. The caudal boundary is formed on the right by the brachiocephalic trunk and on the left by the V-shaped outlet of the common carotid artery from the aortic arch. The transverse V. brachiocephalica sinistra separates the cervical from the mediastinal lymph node space. The suprabrachiocephalic part of the upper mediastinum is therefore part of the cervicocentral compartment. The midline of the trachea separates the right from the left part of the central compartment without an anatomical fascial boundary comparable to the lateral boundary of the common carotid artery. Within the central compartment, the recurrent nerve divides the right and left central compartments into an antenerval (level 6) and a retronerval part (level 7). The third sub-area of the central compartment is formed by the prelaryngeal lymph nodes ("Delphi").
5.2.3 Lateral compartment (C2, cervicolateral right; C3, cervicolateral left) (Fig. 2b and c)
The lateral compartment extends on both sides of the common carotid artery laterally to the trapezius muscle, cranially to the hypoglossal nerve, and caudally to the subclavian vein. The dorsal boundary is formed by the dorsal cervical fascia. In contrast to the fascicles of the cervicobrachial nerve plexus and the accessory nerve, which pass through the lateral compartment and may therefore be at risk during lateral compartment resection, the phrenic nerve lies under the dorsal cervical fascia. The thyroid lobes and the central compartment are connected to the lateral compartment by lymphatic vessels running parallel to the thyroid veins both in front of and behind the vascular sheath [346], [347].
5.2.4 Mediastinal compartment (C4a, right; C4b, left) (Fig. 2d)
The mediastinal compartment extends seamlessly, i.e. without transverse anatomical fascial boundaries, from the V. brachiocephalica sinistra (cranial boundary) in a bidirectional direction ventrally into the anterior superior mediastinum to the thymus and the preaortic lymph nodes and dorsally to the paratracheal lymph nodes in the posterior superior mediastinum. The lateral borders on both sides are the mediastinal pleural leaves, caudally the pericardium (ventral) and the tracheal bifurcation (dorsal). Dissection of the infrabrachiocephalic mediastinum requires a transsternal approach. In the case of combined cervicocentral and mediastinal compartment resection, the entire lymph node-containing fatty tissue can be removed in an en bloc resection while preserving the vascular and nerve structures due to the lack of an anatomical barrier between the two compartments.
5.2.5 Classification of locoregional lymph nodes
Based on anatomical and clinical examinations, the locoregional lymph nodes of primary malignant thyroid tumors can be assigned to four compartments: central, ipsilateral cervicolateral, contralateral cervicolateral, and infrabrachiocephalic mediastinal [343].
Internationally, the classification of locoregional lymph nodes according to Robbins is preferred [341]. Without lateral allocation, level 1 refers to submental and submandibular lymph nodes, level 2A, 2B to cranial jugular lymph nodes, level 3 to central jugular lymph nodes, level 4 to caudal jugular lymph nodes, level 5A, 5B to lateral jugular lymph nodes, level 6 to central lymph nodes, level 7 to central caudal lymph nodes.
5.3 PTC: Indication and extent of resection
The interdisciplinary tumor board presentation serves to ensure an up-to-date, well-founded and interdisciplinary indication for the individual patient by integrating the expertise of the specialist groups involved [348], [349], [350], [351]. The aim is to develop an interdisciplinary, findings-oriented recommendation for the individual patient based on the current state of knowledge of all specialist groups involved in order to propose an optimal procedure and treatment decision.
5.3.1 Papillary thyroid microcarcinoma (PTMC) (T1a)
5.3.1.1 Observation
An isolated unifocal PTMC without aggressive cytological features and without risk factors can be observed if the patient > 30 years of age decides to do so as part of an informed consent process, taking into account in particular the size and age dependency of the risk of recurrence.
The incidence of papillary thyroid carcinoma has risen sharply in individual countries in recent years and amounted to 4.5% of the total population in the USA in 2013 [354]. In an international comparison, however, the frequency of thyroid carcinomas in Germany is largely stable [355]. Papillary microcarcinomas (PTMC), defined as papillary carcinomas ≤1cm, account for over 80% of all incidentally detected papillary thyroid carcinomas (PTC) [356]. They are rarely diagnosed preoperatively in Germany due to the recommendation not to puncture nodules < 1cm. This recommendation is de facto equivalent to an observation strategy. This has been carried out for solitary PTMC in a normal thyroid gland by some research groups [357], [358], [359], [360].
The study by Miyauchi et al. on 1,211 patients with PTMC aimed to estimate the probability of disease progression over a lifetime, which was 60.3% for 20-29 year olds, 37.1% for 30-39 year olds, 14.5% for 40-49 year olds, 6.6% for 50-59 year olds and 3.5% for over 70 year olds over an observation period of 10 years. Tumor growth and the occurrence of lymph node metastases were seen within 10 years in 46% and 27% of 20-year-olds and in 3% and less than 1% of those over 60. None of the patients who were primarily only observed and later operated on due to progression had developed distant metastases or died from the tumor [352]. An isolated unifocal PTMC without aggressive cytological features (e.g. large cell variant, poorly differentiated variants) and without risk factors (not capsular or on the trachea, no additional nodes, no predisposition, no suspicion of metastasis, no molecular genetic risk profile) can be observed if the patient opts for this as part of an informed consent process [352].
In contrast, Oh et al. demonstrated a 100% higher risk of tumor volume doubling in patients <45 years after [361].
According to Miyauchi, low-risk patients were those who had only a solitary PTMC, no primary lymph node metastases, no infiltration of the thyroid capsule and did not directly border the trachea or the recurrent laryngeal nerve. It must be mentioned here that it is unclear how high the proportion of newly defined NIFTPs is in the patient population, as these cannot be differentiated from papillary thyroid carcinomas in fine needle aspirates.
Sugitani et al. conducted a survey in Japanese clinics, of which over 50% carried out "active observation" without surgery in low-risk patients [362]. Jeon et al. were also unable to demonstrate a negative effect on surgery delayed up to one year after diagnosis compared to patients with PTMC who were operated on immediately [363].
PTMC exhibit different biological behavior. In addition to indolent, slowly progressive forms, aggressive variants can be distinguished. This group includes multifocal PTMC and PTMC with specific genetic characteristics such as BRAF mutations or changes in genes of the stimulated cell cycle and stem cell activation [364], [365], [366], [367].
If a solitary papillary microcarcinoma is confirmed by FNAC and there are no other risk factors, an observation strategy may be an alternative to immediate surgery. However, the patient should be informed about the risk of a possibly necessary extended resection (e.g. thyroidectomy instead of lobectomy and possibly additional lymphadenectomy) if the tumor progresses and about the type, extent and duration of the necessary structured follow-up. The patient should also be informed about the established surgical therapy. The recommendation for conservative treatment should be made by an interdisciplinary tumor board, set out in writing and explained to the patient. Systematic recording of these patients and their progression in established registers is expressly encouraged.
5.3.1.2 Local ablative procedures of the PTMC
Local ablative procedures have a cosmetic advantage over surgery by avoiding a classic cervicotomy. Based on a meta-analysis of 12 studies with over 1,000 patients with PTMC, Tong et al. demonstrated that radiofrequency ablation, microwave ablation and laser ablation can effectively ablate PTMC foci locally [368]. Chen et al. came to the same conclusion, showing 13 studies with various local ablation procedures to be effective and with very few complications [369]. In long-term studies, local ablative procedures appear to have a comparable effectiveness to surgery in the treatment of PMTC, but prospective comparative studies on classic surgical procedures are lacking. A critical point to be made about the studies included in the meta-analysis is that 9 of the studies cited were from China and 3 from Korea. 9/12 studies were retrospective. In 2 studies, including the largest with 412 patients from China, neither the age nor the sex of the patients was known. In only 76% of patients was the thyroid carcinoma no longer detectable after treatment. After MWA, bleeding occurred in 2.8% and partly persistent hoarseness in 4.4%. As no laryngoscopy was performed, the percentage of recurrent paresis may be significantly higher. In addition, the follow-up periods are not yet long enough for a conclusive evaluation of the long-term outcome.
It is essential to inform the patient about the significance of a lack of histology and possible limitations of the sonographic assessment of the course of the disease and to provide information about the established surgical treatment. The decision for local ablative therapy should be made by an interdisciplinary tumor board and ideally only in the context of a study inclusion.
5.3.1.3 Surgery of the PTMC
PTMC without risk factors should be treated surgically by lobectomy.
- Consensus
- Strong consensus (100%)
- References
- [370]
A thyroidectomy should be performed for papillary thyroid carcinomas with a tumor diameter of 10 mm or smaller with risk factors, i.e. multifocal PTMC, histologically higher-risk subtypes of PTC, familial clustering of PTC, lymph node metastases and previous cervical radiation.
With regard to long-term survival, Liu et al. were unable to identify any difference between patients whose PTMC had been treated with a thyroidectomy or with less than a thyroidectomy based on SEER data from 2004-2013 [374]. Chan et al. compared the 10-year survival rates of "low-risk PTC patients", the majority of whom are patients with PTMC, using a meta-analysis of 25 studies with 73,742 patients. According to this, patients after lobectomy showed no difference in survival compared to patients after thyroidectomy [370]. This also corresponds to the results of the study by Zhang et al. on 5,492 Korean patients with PTC, over 50% of whom had PTMC and showed no influence of the primary resection extent on survival. However, since the consensus threshold of ≤ 10 mm for the definition of PTMC reflects a biological continuum, there is a treatment corridor for borderline findings, taking individual risk factors into account. Although it is true for all PTC that the risk quo ad vitam increases with age [375] and that men have a lower probability of survival than women, with a 90% and 96% 10-year survival rate respectively [376], there is no effect of more extensive surgery on the survival of patients with PTMC.
Taking into account the fact that the PTMC threshold of 10 mm is well documented by several studies [377], but reflects a continuum in terms of tumor biology, there is a treatment corridor of alternative treatment options in individual cases of tumors of this size, especially when the diagnosis is only made postoperatively, which must be determined individually on an interdisciplinary basis, taking into account the patient's circumstances. In a study with a follow-up of 35 years, Noguchi et al. showed a recurrence-free survival rate for PTMC < 5 mm: 96.7%, 6-10 mm: 86.0%) [378].
Kim et al. used data from 8,676 patients with PTMC to compare the effect of thyroidectomy versus lobectomy on the need for a new surgery due to tumor persistence or tumor recurrence [373]. In patients with multifocal PTMC, they found a reduced recurrence rate after thyroidectomy compared to lobectomy (0/5,387 vs. 28/3,289 (0.85%)). Kwon et al. found the same in a smaller group of 688 patients [379]. However, the patients with thyroidectomy were more likely to have transient and permanent hypoparathyroidism of 13% and 2%, respectively, compared to 0%.
Wu et al. showed that 28.5% of patients with a primary diagnosis of a follicular variant of PTMC developed contralateral nodules during the course of the disease [380] and according to Sullivan et al. the vast majority of these (up to 100%) were malignant [371].
Recurrences due to contralateral PTMC foci are therefore more common in primary multifocality and a size of over 5 mm [381][382], [382] and also occur more frequently in patients with BRAF and TERT mutations [383], [384][384], [364], [367] and activation of cell cycle genes [366].
According to Joseph et al., the meta-analysis of 15 studies shows increased regional lymph node metastases and distant metastases in primary multifocality of PTMC, which can ultimately only be detected by thyroidectomy with subsequent radioiodine uptake [372]. Joseph et al. therefore advocate thyroidectomy in patients with multifocal PMTC [372].
5.3.1.4 Central lymph node dissection
In cN1-PTMC, bilateral central compartment resection (level VI) should be performed in conjunction with total thyroidectomy.
- Consensus
- Strong consensus (100%)
Prophylactic central lymph node dissection can be performed in the presence of risk factors (e.g. multifocality, aggressive PTC variants, size (variable: from approx. 8 to 10 mm), capsular infiltration, evidence of a prognostically unfavorable mutation).
- Consensus
- Strong consensus (100%)
- References
- [385]
Clinically inconspicuous lymph nodes show metastases in more than 20% of patients undergoing PTMC surgery with prophylactic central lymph node dissection, despite the good prognosis of the patients, so that bilateral central compartment resection (level VI) should be performed in conjunction with total thyroidectomy to ensure complete tumor removal, reduce the risk of recurrence and improve the chances of survival in cN1 PTMC. Lymph node metastases are increasingly seen in younger patients before the age of 45-55 [386], [387], [388], [389], [390], male patients [388], [389], [390], in tumors over 5 or 7 mm [391], [386], [392], [393], [386], [394], [388], [395], [389], [390], in multifocality of the PTMC [396], [392], [386], [393], [387], [382], [388], [389], [390], [397], [398], in capsular invasion [392], [395], in extrathyroidal growth (ETE) [399], [386], [393], [387], [388], [389], in lymphovascular invasion [400] and in localization of the tumor in the upper pole of the thyroid [401], [395]. In addition, PTMC with BRAF mutations and PTMC with proven Hashimoto's thyroiditis show increased central lymph node metastases [399]. Even skip metastases can occur in the upper pole of PTMC in up to 25% of cases [401]. According to Zheng et al. [397], the incidence of central lymph node metastases increases significantly with multifocality (from 26% with one focus to 29% with two foci, 48% with three foci, and 72% with 4 or more foci).
According to a comparison of over 2,000 patients by Ito et al., prophylactic central lymph node dissection of the affected side of the thyroid gland has no influence on lymph node recurrence [400]. A meta-analysis by Shan et al. [402], which was based on 11 studies and a meta-analysis by Qu et al. with 19 studies and over 8,000 patients [393] also came to the same conclusion. In contrast, Hughes et al. were able to demonstrate on the basis of 14 studies and 3 meta-analyses that thyroidectomy with prophylactic lymphadenectomy results in a reduction in the recurrence rate of PTMC from 6.8% to 4.6% compared to thyroidectomy alone, but that permanent hypoparathyroidism increases from 1.6% to 3.5% [385].
Prophylactic central lymph node dissection is therefore only recommended in the presence of risk factors (multifocality, aggressive PTC variant, size >5-7mm, capsular infiltration, BRAF positivity) and with surgical expertise.
5.3.2 Papillary thyroid carcinoma T1b to T4
5.3.2.1 Thyroidectomy
Thyroidectomy should be performed for PTC > 1cm, for multifocal PTC, for familial PTC, and regardless of the size of the primary tumor for encapsulating and metastatic PTC as well as for histologically more aggressive variants.
In justified cases, lobectomy can be a treatment strategy for PTC pT1b/pT2, provided there are no risk factors such as vascular invasion, lymph node metastases, capsular infiltration, familial predisposition, or previous radiotherapy.
In a retrospective cohort study, Song et al [403] evaluated 318 matched pairs from the Asan Medical Center Korea for the comparison of total thyroidectomy (TT) versus lobectomy. The risk of recurrence after TT was not statistically significantly different in the total group with tumor size 1 to 4 cm compared to lobectomy (HR of 1.35 (0.40 - 1.36)).
Vargas-Pinto et al. [404] analyzed two meta-analyses [405], [406], which included a total of 6 publications, following a systematic literature search. The work by Adam with more than 68,000 patients [405] showed better survival after total thyroidectomy. The survival advantage increases with the length of follow-up. In an analysis of the NCDB database, the survival rate after 14 years for TT is 86.6% compared to 84.4% for lobectomy. This does not take into account whether and how often completion surgeries were performed after primary lobectomy. The mean follow-up period was only 6 to 7 years. There were no statistically significant differences in recurrence-free survival. The results of all the studies cited above do not take into account whether the patients underwent radioiodine therapy after TT or whether the patients underwent completion surgery after lobectomy, so a bias in the results to the disadvantage of TT cannot be ruled out. The studies show advantages of TT over lobectomy with a low level of evidence. In addition, it must be taken into account that TT is a prerequisite for radioiodine therapy and enables highly sensitive recurrence detection with the tumor marker thyroglobulin in follow-up care. However, the stage-specific subgroup analysis shows a superiority of TT in each case, without reaching statistical significance. The above reasons lead to the recommendation to use TT as the standard procedure, but also to the recommendation to forego it in favor of lobectomy in a favorable constellation.
5.3.2.2 Central lymph node dissection
In cN1-PTC, a central compartment resection (level VI) should be performed in conjunction with total thyroidectomy, regardless of the size of the primary tumor and based on frozen sections.
- Consensus
- Strong consensus (100%)
In the case of clinically recognizable lymph node metastases (cN1) in the central compartment, a central compartment resection should be performed regardless of the size of the primary tumor in order to reduce the risk of recurrence and improve survival prospects, avoid recurrence surgeries that are prone to complications, and save the radioiodine activity that may be required for radioiodine therapy of central lymph node metastases [256], [60], [24]. Confirmation should be made in the frozen section. Central compartment resection during the initial procedure does not significantly increase the surgical risk. The number of tumor-involved lymph nodes has prognostic relevance [407]. Whether compartment resection can be limited to the affected side for oncological reasons in the case of unilateral lymph node involvement [408], in order to avoid the complication risk of the contralateral cervicocentral side, has not yet been proven by studies [409], [410], [411]. A recent meta-analysis identified age < 45 years, tumor size > 1 cm, male gender, extrathyroidal growth and ipsilateral lymph node metastases as prognostic factors for contralateral lymph node involvement [412].
To avoid a surgical risk that may not be commensurate with the low oncological risk, a prophylactic compartment resection in cN0-PTC > 1 cm should only be performed if justified and with appropriate surgical expertise.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus (100%)
- References
- [413]
If a cN0-PTC is only diagnosed postoperatively and there is no evidence of residual tumor, a complete prophylactic central compartment resection should not be performed after total thyroidectomy.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus (100%)
- References
- [413]
Prophylactic lymph node dissection is defined as lymph node dissection without clinical evidence of lymph node metastasis (cN0). For cN0 low-risk PTC < 2.5 cm, an analysis of 5 RCTs with 763 patients showed no advantage of prophylactic central lymph node compartment resection (PCND) for recurrence reduction [413]. Most of the included studies had a low risk of bias. No differences were found for both structural and biochemical recurrence no difference RD -0.00; p=0.95 in the groups with or without PCND. The rate of permanent hypoparathyroidism was 3% higher with additional PCND (CI 0%-6%). Comparing the risk difference of thyroidectomy vs. additional PCND, the complications were comparable for the recurrent recurrence rate RD=0.01; p=0.73, the permanent recurrence rate RD -0.00, for transient hypoparathyroidism RD=0.04; p=0.20 and postoperative hemorrhage RD=0.00; p=0.87. In contrast, the permanent hypoparathyroidism rate was significantly increased with PCND with RD=0.03; p=0.02.
With very good quality of evidence, PCND shows no oncological advantage with an increased risk of transient and permanent damage, which is why a negative recommendation is issued.
However, 30-60% of intraoperative central lymph node metastases found preoperatively as cN0 [385] and less than 30% of central lymph node metastases are clinically detected intraoperatively [414].
5.3.2.3 Lateral lymph node dissection
If the PTC primary tumor is located in the upper pole or PTC with extensive central lymph node involvement and in the case of clinical suspicion or histological evidence of lateral lymph node metastases, a primary lateral compartment resection of the tumor-bearing side should be performed, and if necessary also of the contralateral side in the case of extensive central lymph node involvement.
Lateral lymph node metastases are found in around 25 % of PTC patients [418], [419]. If metastases are suspected/detected preoperatively by palpation, sonography, biopsy, or intraoperatively by macroscopic or frozen section histology, a primary lateral compartment resection of the affected compartment is recommended [420], [24], [421], [60], [418], [422], [423]. Whether lateral compartment resection can be restricted to certain regions of the lateral compartment [424], [415] has not yet been sufficiently clarified by studies, so that a complete compartment resection is generally indicated. In the case of extensive central lymph node involvement (> 5 lymph node metastases), both the ipsilateral and contralateral lateral compartments are affected in over 70% of cases [418], so that a primary unilateral or bilateral lateral compartment resection is justified in order to minimize the risk of recurrence and avoid re-surgeries. Alternatively, a sequential procedure (decision on lateral compartment resection after radioiodine therapy or other imaging) can be chosen. In principle, lateral compartment resection can be performed in two stages if indicative factors have not been clarified at the time of surgery.
If there is no evidence of lateral lymph node metastases and no or only minimal central lymph node involvement, there is insufficient evidence to recommend a prophylactic lateral compartment resection, particularly in terms of surgical morbidity (shoulder-arm syndrome, lymphatic fistula) [425], [426], [427], [428], [429], [423], [416].
In PTC, so-called "skip" metastases are present in the ipsilateral lateral compartment in 1.6 - 21.8 % of cases without simultaneous central lymph node metastases [430], [431], [432], [433], [434], [435]. This metastatic pathway is preferentially observed in primary tumors in the upper pole of the thyroid gland [433], [436], [437],[434].
5.3.2.4 Mediastinal metastases
Mediastinal lymph node metastases in PTC are rare (< 5 %) [407] but can be treated surgically with curative intent in the absence of distant metastases. If infrabrachiocephalic retrosternal lymph node metastases are suspected on preoperative imaging or detected intraoperatively, the indication for transsternal (or minimally invasive video-assisted) mediastinal compartment resection should therefore be considered, taking into account the general condition of the patient and the overall tumor burden. If distant metastasis is present, the curative approach is not applicable and mediastinal lymph node dissection is used to treat locoregional symptoms or to prevent secondary complications caused by the mediastinal lymph node metastases. There is no indication for prophylactic mediastinal dissection due to the increased risk of complications [417], [438], [439].
5.3.2.5 Completion surgeries
When is completion surgery for papillary thyroid carcinoma indicated?
Completion surgery with removal of the residual thyroid gland is indicated for papillary thyroid carcinomas > 1 cm in diameter, intrathyroidal spread with R1 resection or multifocal carcinomas in order to enable radioiodine therapy. A meta-analysis consisting of 13 studies including 8 cancer registry studies [440] examined the survival time of patients with papillary thyroid carcinoma and a tumor diameter between 1.0 and 4.0 cm who had undergone thyroidectomy or lobectomy. Overall, no clear difference was found between the two surgical procedures in terms of recurrence-free survival and overall survival. What was striking in all studies with the inclusion of > 16,000 patients was that the percentage of lobectomies in the total patient population was only 6% - 36%, and that these groups were obviously very selective. Two very large studies from the National Cancer Database (NCDB) [441], [442] showed a significant survival advantage for patients with a PTC who had undergone thyroidectomy when 52,173 patients and 22,899 patients were included. Bilimoria et al. described that lobectomy alone in PTC > 1 cm led to a higher risk of local recurrence and a lower survival rate [441]. Rajjoub et al. also found a survival benefit for PTC with a diameter of 2.0 - 3.9 cm when a thyroidectomy was performed as opposed to a lobectomy [442].
A further meta-analysis of 6 studies that analyzed the rate of local recurrence of 2.939 PTC after thyroidectomy versus lobectomy [443], after a follow-up period of 10.9 years, showed a significantly lower rate of local recurrence (4.4% after thyroidectomy, 8.3% after lobectomy) and tended to show better survival rates (mortality after thyroidectomy 0.3%, after lobectomy 1.1%, n.s.) when thyroidectomy was performed.
In multifocal PTC, thyroidectomy reduces the risk of tumor persistence or recurrence in the contralateral thyroid lobe [196]. In a recent single-center study, Harries et al. [270] found no difference in the examined survival rates (survival with contralateral PTC-free thyroid lobe (CLPFS), recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS)) of 849 patients with unifocal or multifocal papillary pT1/pT2 carcinomas, 85% of whom, however, were classified as "low risk" according to the ATA classification. Limiting factors of this study, which covered a period of 30 years, were the exclusion of 40 patients who underwent completion surgery just a few days postoperatively, patients with lymph node metastases, and a median follow-up period of only 58 months.
In the case of incompletely resected PTC (R1/R2 resections), completion surgery should be performed for oncologically adequate surgical therapy. Exceptions to this are very small tumor remnants that are directly adherent to the recurrent laryngeal nerve, the trachea, or the esophagus. In these cases, radioiodine therapy and follow-up can be performed first.
In the case of complete thyroidectomy, prophylactic follow-up surgery in the area of the locoregional lymph nodes is not recommended. If indicated, completion surgery should be performed at the earliest possible time, if possible within the first four postoperative days or after an interval of 3 months [444], as the period between the 4th postoperative day and 3 months has proven to be particularly risky.
In the case of postoperative incidental findings of a PTC, a completion surgery should be performed if the primary surgery did not correspond to the resection procedure appropriate for the primary tumor spread.
- Consensus
- Strong consensus (100%)
The timing of the completion surgery should be determined taking into account the extent of the primary surgery, the prognosis of any existing recurrent paresis, any residual tumor and surgical expertise. Given the paucity of literature data on this question, the time 3-5 days and again from 3 months after the initial surgery has proven to be clinically appropriate if the previously operated side needs to be reopened, as adhesions are still minor to moderate or have regressed [421]. This recommendation on the timing of a completion surgery does not apply if only the unaffected opposite side needs to be operated on and is qualified if the risk profile of the tumor or the local situation makes prompt re-surgery appear more favourable.
The necessity of referral to an appropriately profiled center should be examined. The positive correlation between the better quality of results in thyroid surgery and the surgical volume of the individual surgeon, but also of a center, has been proven many times. So-called high-volume surgeons achieve significantly better results in the measurable quality parameters (recurrence savings rate, hypocalcemia rate, postoperative bleeding rate, general complications). In thyroid cancer surgery in particular, studies show a positive correlation between high-volume thyroid surgery and complete tumor resection, low complication rates and lower postoperative radioiodine storage and tumor marker burden according to [445], [446], [447], [448], [449]. Following evidence research by the European Society of Endocrine Surgeons (ESES) on the volume-outcome association in thyroid surgery, a consensus conference defined that a high-volume surgeon performs >50 thyroid procedures per year and that >100 surgeries per year are performed in a thyroid surgery center [450].
In the case of complete thyroidectomy with evidence of a PTC, prophylactic follow-up surgery of locoregional lymph nodes should not be performed (see [5.6]).
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus (100%)
- References
- [413]
Sanabria et al. [413] evaluated five randomized controlled trials in their meta-analysis. The studies compared the surgical outcome of thyroidectomy alone (n=354) versus thyroidectomy plus central lymph node dissection (n=409). Most of the included studies had a low risk of bias. No differences were found between the two groups for either structural or biochemical recurrence. The rate of permanent hypoparathyroidism was 3% higher with additional central lymph node dissection (CI 0% - 6%). In summary, as there was no benefit for prophylactic lymph node dissection but an increased risk of harm with high confidence in the study results, a negative recommendation was made.
5.3.2.6 Cross-organ PTC
Resection of cervicovisceral tumor infiltrations can be performed if the appropriate conditions are met (general condition, absence of progressive distant metastases, resectable lesion, surgical experience with surgical and perioperative management).
The widely invasive extrathyroidal extension is a significant risk factor for systemic and locoregional metastasis and local recurrence [454], [455], [456], [457]. In the rare presence of surgically resectable invasion of the tumor into adjacent cervicovisceral structures (esophagus, trachea, dorsal neck muscles) (approx. 5 - 7 %), radical resection may be indicated in the absence of progressive distant metastases and with appropriate surgical expertise [458], [459], [460], [461], [451], [452], [453]. Alternative procedures to segmental resection or fenestration of the trachea are so-called shaving (tumor resection while leaving the tumor-infiltrated wall of the larynx, trachea or esophagus) or non-surgical palliative procedures in conjunction with adjuvant measures (e.g. radioiodine therapy, external radiotherapy, antineoplastic drug therapy such as tyrosine kinase inhibitors, etc.). A shaving procedure is not recommended for transmural tumor infiltration [462].
5.3.3 PTC in childhood and adolescence
The diagnosis and treatment of thyroid carcinomas in children and adolescents requires special expertise in surgical management, histopathological diagnosis and postoperative follow-up care and should therefore be reserved for designated centers.
- Consensus
- Strong consensus (100%)
- References
- [463]
Thyroid carcinomas in children and adolescents are more often bilateral (30%) and multifocal (65%) [464], [465], [466]. In a retrospective study with a follow-up of 40 years, thyroidectomy showed a significantly lower local recurrence rate of 6% compared to 35% in 215 children with papillary thyroid carcinoma [467]. It should be noted that most patients in the thyroidectomy group received RIT. Histological subgroups, which are associated with a higher risk, have a proportion of 15 to 37%: tall-cell variant 7-13%, diffuse sclerosing variant 7-16%, solid/trabecular variant 1-4% [468]. In contrast to the significantly increased risk of local recurrence of these subtypes in adults, there does not appear to be an increased risk in children compared to classic PTC [469]. Despite lower overall tumor-related morbidity and mortality compared to PTC in adults, the rate of lymph node and distant metastases in children and adolescents is significantly higher than in adults [470], [471], [472]. Lymph node metastasis rates of 60% are reported [471]. Significant differences in locoregional metastatic behavior between children and adolescents could not be demonstrated [473], [474].
Since the staging criteria of the TNM system are based on the primary tumor size of adults [475], the age-independent use of the primary tumor size for the extent of resection in children and adolescents may lead to an underestimation of the risk of metastasis and recurrence. In conjunction with the overall higher rate of locoregional lymph node metastases in both the central and lateral compartments, careful preoperative and intraoperative clarification of the lymph node status should therefore be performed in children and adolescents in order to adequately determine the extent of resection of the thyroid gland and the locoregional lymph nodes. Weighing up the benefits and risks and assuming appropriate surgical expertise, prophylactic central compartment resection in PTC > 1 cm appears to be sensible [467]. Thyroid surgery in children and adolescents should only be performed by high-volume surgeons in appropriately profiled centers due to the particular vulnerability, the difficulty in identifying and protecting the parathyroid glands and the frequently advanced and aggressive thyroid carcinomas [446], [476], [450].
5.4 Follicular carcinomas
Follicular thyroid carcinoma (FTC) is less common than PTC, accounting for approx. 10 - 15 % of all thyroid carcinomas in Germany [477]. The incidence is higher in iodine-deficient areas than in areas with sufficient iodine supply. With an age peak at around 50 years, FTC occurs significantly later than PTC. As with PTC, women are affected about 5 times more frequently than men.
Clinically, prognostically and therapeutically, minimally invasive FTC with and without vascular invasion must be distinguished from broadly invasive FTC due to their different tumor biology and prognosis and the resulting different treatment strategy [478], [274], [172], [253]. In the 2017 WHO classification, the previous division into minimally invasive and broadly invasive follicular carcinomas is abandoned and a new division into 3 groups is carried out [172]:
Follicular carcinomas ≤1 cm are a rarity in contrast to PTMC [479], the diagnosis should therefore be checked by a reference pathologist due to the different surgical treatment for FTC and PTC.
5.4.1 Minimally invasive follicular thyroid carcinoma (MIFTC) without vascular invasion
For solitary MIFTC without histologically detectable vascular invasion, only lobectomy should be performed for tumor size < 4cm, but not routine primary or secondary total thyroidectomy.
In the case of a histopathological diagnosis of vascular invasion, a total thyroidectomy should be performed.
- Consensus
- Strong consensus (95,7%)
- References
- [253]
5.4.2 Minimally invasive follicular thyroid carcinoma (MIFTC) with vascular invasion
In MIFTC with vascular invasion, a prophylactic lymph node dissection can be performed.
- Consensus
- Strong consensus (100%)
Around two thirds of follicular carcinomas are MIFTC [480]. Differentiation from follicular adenomas and the follicular variant of PTC or NIFPT is generally possible neither cytologically nor by frozen section, but predominantly histologically on the paraffin section based on nuclear morphology and evidence of minimal capsular and/or vascular invasion [482], [483]. As frozen section examinations only provide histological evidence of a MIFTC in exceptional cases [484], [485], [486], the use of frozen section histology for cytologically follicular neoplasia is more likely to serve the purpose of detecting other tumor entities [484], [487], [488].
In contrast to broadly invasive FTC, lymph node metastases are found in less than 10 % of cases (in patients with vascular invasion) in MIFTC [480], [489]. Prophylactic lymph node dissection is not indicated [24], [490], [60], [258]. In a prospective study by Asari et al., 14% of patients had distant metastases, of which 9.1% at diagnosis and 4.7% during the first postoperative year [480]. Long-term studies have demonstrated a very good overall prognosis for MIFTC [491].
5.4.3 Widely invasive follicular thyroid carcinoma (WIFTC)
The widely invasive follicular carcinoma can be recognized macroscopically by its blurred borders and usually pronounced invasion into the surrounding thyroid tissue and can usually be confirmed by a frozen section examination. Due to the risk of metastasis in around one third of cases [480], the prognosis of WIFTC is less favorable than that of MIFTC, and the average age and tumor size are significantly higher than for MIFTC [491], [492]. WIFTC often metastasize primarily hematogenously and are then diagnosed through the detection of distant metastases [480]. Due to the regularly detected vascular invasion, a total thyroidectomy with postoperative RIT including diagnostics should always be performed, i.e. especially in the case of primary distant metastasis [24], [318], [60], [420], [493], [494], [495], [496], [497], [498], [499], [500]. This requires a completion thyroidectomy if the diagnosis is only made postoperatively after a primary non-total thyroidectomy. Lymph node metastases are detected in around 20 % of cases of WIFTC, usually in conjunction with distant metastases [480], [501]. The indication for compartment resection is therefore generally only given in cases where lymph node metastasis has been detected preoperatively or intraoperatively. The extent of the compartment resection should be based on the local findings. The same treatment principles apply to organ-transcending FTC as to PTC. If distant metastasis is present at the time of surgery, a prophylactic central compartment resection can be performed [24], [318], [258].
5.5 Oncocytic thyroid carcinoma
If an oncocytic carcinoma (non-encapsulated, possibly with vascular invasion) is detected preoperatively or intraoperatively, a thyroidectomy should be performed in conjunction with a central compartment resection.
- Consensus
- Strong consensus (100%)
- References
- [258]
Oncocytic thyroid carcinoma (synonyms: oxyphilic carcinoma, Hürthle cell carcinoma) is a rare (< 5 %) histological variant of differentiated, mostly follicular, rarely papillary carcinomas. Oncocytic carcinomas are characterized by the presence of at least 30% oncocytic cells in the tumor and show a more aggressive tumor biology with an increased rate of lymph node and distant metastases and a lower radioiodine uptake than PTC and FTC [506], [507], [508], [502], [503], [504], [505]. Due to the less favorable tumor biology compared to classic FTC and PTC, a total thyroidectomy with postoperative radioiodine ablation should be performed primarily or secondarily in oncocytic carcinoma, regardless of the primary tumor size [258].
Due to the rarity of oncocytic carcinomas, no major studies are available on the question of the prognostic advantage of prophylactic compartment resection or completion surgery following lobectomy. However, due to the frequency of lymph node metastases and the limited radioiodine uptake capacity, a routine central compartment resection is recommended at least in the case of a preoperative or intraoperative diagnosis [258]. In the case of postoperative diagnosis after lobectomy, completion surgery can be dispensed with in individual cases if there are no risk factors (e.g. R0, encapsulated, lack of vascular invasion, cN0) and clinical follow-up is confirmed. If non-encapsulated oncocytic carcinoma is detected postoperatively, completion and compartment resection should only be performed if thyroglobulin is elevated or there is clinical evidence of lymph node metastases [258]. After primary total R0 thyroidectomy without central lymph node dissection, a completing compartment resection should only be performed if thyroglobulin is elevated or there is evidence of lymph node metastases. Follow-up care, recurrence therapy and distant metastasis surgery correspond to the therapy principles of PTC.
5.6 Poorly differentiated papillary carcinomas (PDTC)
Poorly differentiated thyroid carcinomas (PDTC) are tumors with a significantly poorer prognosis than differentiated PTC and FTC [515]. They were first defined in 2004 by the WHO [478] as an independent entity with a prognosis between that of differentiated and undifferentiated carcinomas. The frequency of these tumors is stated to be around 0.7-5 % of all clinically manifest thyroid carcinomas [478], [516].
Based on the Turin criteria, the WHO defines PDTC as a thyrocytic neoplasm with limited follicular cell differentiation and a morphological as well as clinical intermediate position between PTC and FTC on the one hand and undifferentiated (anaplastic) carcinomas on the other [252]. Solid/trabecular/insular growth, necrosis and an increased mitotic rate are typical of PDTC [261], [517], [518], [519]. For the diagnosis of PDTC, it is sufficient if 10 % of the tumor exhibits the typical morphological characteristics of PDTC [520], [521]. PDTCs are rarely smaller than 3 cm at the time of diagnosis, often show locally invasive growth, lymph node metastases (64 %) and not infrequently distant metastases (50 %) in the lungs, liver and bones [522], [521], [520], [523], [524], [487], [510].
Due to the more aggressive growth behavior compared to PTC and FTC and the lack of radioiodine uptake in 20 % of resectable tumors, a total thyroidectomy with radical tumor resection should be performed primarily or secondarily even in an M1 situation [510], [509], [145], [451], [514]. In a study by Walczyk et al., the tumor size of > 4cm, pT3-4, extensive extrathyroidal growth, R1 resections, TNM stages III-IV showed a significantly poorer survival rate for patients [511], [525]. Due to the frequent primary lymph node metastasis, the indication for systematic lymphadenectomy or compartment resection of the affected compartments is usually given. There are currently no studies on the question of prophylactic lymph node dissection in PDTC. However, if the diagnosis of PDTC has already been made preoperatively or intraoperatively, it is recommended to perform at least a central lymph node dissection/compartment resection due to the high risk of lymph node metastases. Radioiodine uptake is often limited. The detection of a TERT promoter mutation appears to be significantly associated with radioiodine refractoriness [526]. Ho et al. described a 10-year survival rate of 45.1% [527].
5.7 Quality assurance
5.7.1 Volume and outcome
Thyroid carcinomas should be operated on by surgeons experienced in thyroid surgery.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2a
- Consensus
- Strong consensus (100%)
- References
- [450]
Numerous studies have shown that "hospital and surgeon volume" have a significant influence on the complication rates of thyroid surgery. The evidence report includes a review of meta-analyses [450], which evaluates the publications [446], [528], [529], [530], [531], [532], [533]. The overall data situation is heterogeneous, particularly with regard to the requirements for the individual surgeon, which is not least due to the fact that the studies do not always explicitly differentiate between thyroidectomies and thyroid surgery. With overall low confidence in the quality of the evidence, the recommendation is made. On the basis of the data, the requirement of a minimum number of 100 thyroidectomies per year in the institution and more than 50 thyroidectomies per surgeon per year appears appropriate [450].
5.7.2 Neuromonitoring
Intraoperative neuromonitoring (IONM) shall be used for bilateral thyroid surgery, preferably in the form of continuous neuromonitoring (CIONM) in the case of special risk constellations.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1a
- Consensus
- Strong consensus (100%)
- References
- [534]
Intraoperative neuromonitoring (IONM) does not replace the gold standard of visual nerve imaging, but is used in addition to it. The identity of the recurrent laryngeal nerve can be reliably confirmed and nerve function can be demonstrated by stimulating the superior vagus nerve after resection. A meta-analysis [534][534] of 5 RCTs - 4 of them with very low certainty of evidence - with 1,558 patients (781 randomized IONM, 777 visual nerve identification) showed no significant advantage of IONM to avoid permanent recurrent nerve palsy (RR 0.77, 95% CI 0.33 - 1.77; 4 studies 2,895 nerves at risk. In contrast, there is a tendency towards an advantage for the avoidance of transient recurrent nerve palsies when using IONM (RR 0.62, 95% CI 0.0 -1.08;). It must be taken into account that studies are generally carried out by particularly experienced surgeons and that the success of IONM is presumably less clear as a result. Only IONM makes it possible to review the strategy (e.g. two-stage surgical approach, which can reduce the risk of bilateral recurrent nerve palsy) if bilateral surgery is planned and the signal is lost on the first side. For this reason, and since there are no disadvantages associated with IONM, a strong positive recommendation is made.
5.8 Radioiodine therapy
5.8.1 Radioiodine therapy - definition
Definition: Radioiodine therapy (RIT) is the systemic application of ¹³¹I (as sodium iodide) for the selective internal irradiation of benign or malignant iodine-storing thyroid tissue. RIT has a wide therapeutic range and is used as an adjuvant, curative or palliative treatment.
Malignant tumors that can be treated with RIT due to their ability to accumulate and store iodine include PTC with its histological subtypes and FTC, oncocytic thyroid carcinoma (historic name: Hürthle cell tumors) and PDTC (= poorly differentiated thyroid carcinoma). The probability and ability to accumulate radioiodine and thus respond to RIT differs between these histological types. Oncocytic thyroid carcinomas and PDTC respond less well on average to RIT.
The aim of initial adjuvant radioiodine therapy (RIT) is to eliminate occult iodine-storing tumor tissue (metastases, residual tumor or secondary tumors) after thyroidectomy. Non-iodine-storing tumor tissue located in residual thyroid tissue can also be killed. Dosimetry is not possible as the tumor volume is usually not known. A risk-dependent standard activity is used. Adjuvant RIT also ablates the remaining postoperative thyroid tissue. This increases the diagnostic value of both subsequent radioiodine diagnostics (RID) and thyroglobulin determination. The term "ablative" RIT is often used in the international literature. This means that the elimination of residual tissue is the sole therapeutic goal. The literature results (see section Endogenous versus exogenous stimulation (hypothyroidism versus thyrotrophin alpha) for "ablative" therapy should therefore only be applied with caution to adjuvant therapy. An increase in thyroglobulin indicates a recurrence of thyroid cancer. The detection of newly occurring pathological iodine stores is evidence of a recurrence.
Radioiodine therapy (RIT) can be used for both curative and palliative treatment of iodine-enriched metastases. The distinction between curative and palliative is not disjunctive in thyroid cancer and RIT. Several non-curative radioiodine therapies can delay the course of the disease so that the thyroid cancer is not life-limiting.
5.8.2 Indications for radioiodine therapy (RIT)
The recommendation for radioiodine therapy shall be made on the basis of the clinical and histopathological findings in an interdisciplinary tumor board.
- Consensus
- Strong consensus (100%)
To prevent the development of hypothyroidism, patients who can, should or are due to undergo radioiodine therapy should be placed on L-thyroxine replacement therapy following the operation, or should be presented to a nuclear medicine therapy ward promptly after surgery (before hypothyroidism develops) for consultation, information about radioiodine therapy and determination of the therapy concept. The indication for RIT is determined by a doctor with specialist knowledge in radiation protection & nuclear medicine [535], [536], [537]. The patient shall be appropriately involved in the treatment decisions [538].
Krajewska et al. point out the influence of the time latency between surgery and RIT. Patients at low risk of recurrence who received RIT up to 9 months after surgery had a significantly lower risk of recurrence than patients who received RIT between 9 and 24 months or after more than 24 months since DTC diagnosis, namely 0%, 5.5% and 7.1% respectively [539]. Yu et al. also reported poorer treatment outcomes with delayed RIT, although a 3-month latency between surgery and RIT was reported here [540].
The TNM stage plays a key role in determining the indication for RIT. This classification is supplemented by an extended histopathological classification, so that the extent of extrathyroidal spread can be depicted, supplemented by a description of lymph node metastases, which are associated with a poorer prognosis [541], [542]. The classification into risk classes is initially concerned with the risk of recurrence (see table Classification of risk classes) [60], [24], [543], [544], [545], [546]. Other factors are relevant for the treatment decision, such as overall survival with versus without RIT [547], [548] and the simplicity of follow-up if an excellent response is subsequently achieved through the combination of surgery and RIT. This risk assessment is also important for the surgical procedure, in particular for the question of completion surgery and the indication for radioiodine therapy.
In addition to the staging system based on the TNM system and the prognosis groups I-IV of the UICC/AJCC derived from it, taking into account patient age, a whole series of other systems for estimating the prognosis of thyroid cancer are described in the international literature, mainly developed in the USA [549], [550]. In addition to the TNM prognosis groups, these systems take into account gender, tumor invasiveness parameters, and follow-up data from surgery and/or RIT as well as imaging and/or thyroglobulin levels after primary therapy in different ways for risk classification; they are therefore not comparable or only comparable to a limited extent and have not been evaluated in Germany.
Table 16: Classification of the risk classes for papillary and follicular thyroid carcinomas with regard to the risk of recurrence. The percentages are averaged values from the literature; the individual risk of recurrence may differ.
| Risk of recurrence | Extended pTMN classification |
| Very low risk (≤2%) |
Papillary thyroid carcinoma
|
| Follicular thyroid carcinoma, minimally invasive, without vascular invasion | |
| Low risk (≤5%) |
Papillary thyroid carcinoma pT1b, pT2, N0/pN1*, M0
|
| PTMC (multifocal +/- BRAF V600E mutation) | |
| Follicular thyroid carcinoma intrathyroidal FTC with capsular invasion or with minimal (≤ 2 foci) vascular invasion |
|
| Intermediate risk (5-25%) |
Papillary thyroid carcinoma
|
| High risk (> 15 - > 25%) |
Papillary thyroid carcinoma pT3, pT4, N1, M1
|
| Follicular thyroid carcinoma, grossly invasive with extensive vascular infiltration (> 2 foci) |
The WHO classification of DTC (differentiated thyroid carcinoma) is changed approximately every 10 years. This makes it considerably more difficult to compare study results and transfer them to clinical application. A new histopathological classification was published in 2022. The latest, 8th edition of the UICC/AJCC TNM classification from 2017 brought significant changes to the risk groups compared to the previous version on the basis of published studies on the influence of clinical data on prognosis, resulting in a "downstaging" of approx. 30% of patients with DTC: the age limit was increased from 45 to 55 years; the criterion of minimal extrathyroidal tumor invasion was dropped; N1 cases are no longer classified in a higher stage, stage III; DTC > 4 cm are classified as pT3a; DTC of any size with macroscopic extrathyroidal growth are classified as pT3b; pN1b cases are no longer assigned to stage IV; distant metastases are grouped as stage IVB (previously IVC) [172]. These changes are based on retrospective studies of large patient cohorts, primarily from the USA [551]. This classification led to the vast majority of patients with DTC being assigned to the low-risk group in stage I (assumed tumor mortality 0-2%). However, the American literature emphatically points out that patients < 50 years of age in prognosis group I have "the full spectrum of recurrence risk", as it includes patients with lymph node metastases (prognosis group I) and distant metastases (prognosis group II) [552]. In a study on tumor-related mortality based on 85,740 DTC cases from the SEER database from 1973-2009, it is pointed out that there is no clear age limit in the range of 35 - 55 years [553]. A study from the Netherlands and Germany [554] on 3,074 patients with a higher proportion of follicular thyroid carcinomas than is typical for the USA (23% FTC and 77% PTC) focuses on age-dependent tumor-related mortality. The study confirms an age-dependent "threshold value" of approx. 50 years for papillary thyroid carcinoma. However, for FTC, which is considered separately here, this threshold is 10 years lower at around 40 years [554]. These two studies should give rise to a differentiated view of the age limit of 55 years recently raised in the 8th edition of the UICC/AJCC.
The classification of tumors > 4 cm or with infiltration in the neck muscles (regardless of age) in "intermediate" prognosis group II with an assumed tumor mortality of 5-15% also appears questionable with regard to the risk of recurrence. Prognosis groups with a high (mortality) risk of >20% are group III, which only includes patients older than 55 years with tumors infiltrating locally into the neck structures, and group IV, which also refers to older patients with tumors with even more aggressive local tumor growth (mortality risk > 50%). It must also be emphasized that this classification completely ignores the high risk of recurrence compared to mortality and the impairment of quality of life associated with recurrence therapy.
The risk stratification according to the 8th edition of the TNM system of the UICC/AJCC and the dependent restrictive indication for RIT by the ATA has been criticized by European experts [555], [556]. At a consensus conference in Martinique at the end of 2015, an attempt was made to identify international commonalities in the indication of RIT. These included the statement that "there is no one right way to treat patients" and that "local factors such as the quality of preoperative and postoperative diagnostics, the quality of thyroglobulin determination and radioiodine diagnostics, the experience of the operating surgeon and clinical aspects of local care by the treatment team must be taken into account when determining the indication for RIT [552]. The American approach of reducing or abolishing the indication for RIT should be questioned, if only because, in contrast to Germany, mortality from DTC has risen in the USA in recent years [557].
In addition to the histopathological findings, patient-specific aspects must be taken into account when determining the indication for RIT. These include the completeness of the resection (R0 versus R1 versus R2), lymph vessel or vascular invasion, multifocality of the tumor, aggressive tumor behavior, molecular genetic characteristics, lymph node and distant metastases and their localization. In their analysis of the National Cancer Database with 45,415 patients, Pontius et al. pointed out that 11.6% of patients had lymphatic infiltration. These patients had more frequent lymph node metastases (74.1% versus 32.5%, p< 0.01) and also distant metastases (3.0 versus 0.5%, p < 0.01). The treatment of patients with lymph vessel infiltration with radioiodine significantly reduced their mortality (HR=0.43, p<0.01) [558].
Additional molecular genetic characteristics of the tumors listed in this classification (such as BRAF V600E mutations, TERT mutations, etc. [559] can play an additional role in the individual risk assessment for the indication. However, Li et al. were able to show that RIT after surgery is no less effective in patients with BRAF V600E mutations than in wild-type patients [547], which is why such a mutation is by no means a reason to exclude RIT [560].
The classification of differentiated thyroid carcinoma into risk classes for the probability of recurrence has changed over time. The American Thyroid Association (ATA) distinguishes between patients with low, intermediate, and high risk of recurrence. Papillary microcarcinomas (PTMC or PTC pT1a) are not listed as a separate risk category, but are integrated into the low-risk category. There is no consensus on the percentage value for a recurrence at which a transition to the next higher risk category should take place. The choice of a percentage value such as very low risk (probability of recurrence after oncology-oriented surgery < 2%), low risk (2 - <5%), intermediate risk (5 - 15/20%), high risk (> 15/20%) is a possible but ultimately arbitrary classification. When assessing the risk, it should be borne in mind that both classifications are based on different WHO classifications that are no longer up to date. Not least the introduction of NIFTP ("noninvasive follicular thyroid neoplasms with papillary-like nuclear features"), which are not considered malignant, has led to a risk migration and the tumors now classified as DTC are associated with a higher risk. The assignment of a patient to a risk class with regard to the risk of recurrence of the DTC must not be done statically and only once postoperatively. It is a dynamic process in which therapeutic measures and the response to them must be regularly taken into account [552].
Adjuvant RIT reduces the recurrence rate and mortality (HR of thyroid cancer-related mortality) with an HR of 0.53 - 0.79, depending on the study; for T3 tumors with an HR of 0.43; for T4 tumors with an HR of 0.29 [561], [562], [563]. Due to the high benefit of RIT at high risk of recurrence and the extrapolation into the low risk range, RIT has established itself as the standard procedure for low, medium and high risk of recurrence of differentiated thyroid carcinoma - not only in Germany.
Sawka et al. published systematic reviews and meta-analyses on the effectiveness of RIT in patients with papillary and follicular thyroid carcinoma in the periods 1966-2002 in the first publication [561] and 2002-2007 in the second publication [562]. Bilateral resection was the guideline for patient selection with regard to thyroid surgery. The minimum follow-up period allowed for inclusion of publications in the review was 5 years. Outcomes examined were tumor-specific survival, tumor recurrence or late lymph node/distant metastases. In studies with overlapping patient cohorts, only the publication with the largest number of patients was evaluated. It should be critically noted that Sawka et al. [561] stated that the selection of "low-risk" patients was based on the 4th edition of the UICC/AJCC TNM system [549]. Patients with UICC/AJCC stages I and II were then assigned to the "low-risk" group. At that time, the age limit for classification was 45 years and not 55 years as in the current 8th edition. The changed age limit means that patients aged 45-55 years with an age-related higher risk are now included in group II.
The pooled analysis of 13 selected cohorts mainly from the USA of the first review [561] showed statistically significant, favorable effects of RIT in the 10-year course with regard to locoregional recurrences (clear effect, relative risk 0.31, 95%CI 0.2-0.49) and metachronous distant metastases (weak effect, reduction of the absolute risk by approx. 3%, 95% CI 1-4%). However, the results were inconsistent between centers, and the additional benefit of RIT in low-risk group I patients was considered inconclusive [561].
The second review by the same first author used exactly the same selection criteria as the previous publication [562]. This review included 21 publications from the first review and 7 new publications. The heterogeneity of the data from international centers in North America, Europe, and Asia made pooled data analyses difficult. However, with regard to tumor-related mortality, data pooling of 11 studies was possible. There was a significant reduction in the recurrence rate: in the collectives with PTC and PTC/FTC (Figure 2 of the publication), 248/2,121 patients with RIT (11.7%) and 583/3,005 patients without RIT (19.4%) had a recurrence. Significantly fewer distant metastases occurred in the group treated with RIT, namely 28/1,107 in the RIT group and 45/1,156 without RIT (p = 0.02). For recurrence-free survival, 5 studies with the largest number of patients (n=3,474) showed a considerable reduction in the risk of recurrence from 24.2% recurrence rate without RIT to 12.5% recurrence rate with RIT [562].
An analysis of 2,936 DTC patients in the National Thyroid Cancer Therapy Cooperative Study Group (NTCTCS) showed an improvement in disease-specific and overall survival in patients with advanced tumor disease and regional lymph node and/or distant metastases who received postoperative RIT [564]. A later analysis of 4,941 patients in the NTCTCS trial with a median follow-up of 6 years (range 0 - 25 years) confirmed an improvement in overall survival in stage III and IV patients and also showed an improvement in disease-free survival in stage II patients after surgery and RIT [565].
The benefit of postoperative RIT was demonstrated in patients with locally advanced tumor disease and/or distant metastases: In 11,832 patients from the National Cancer Database, USA, Yang et al published that RIT was associated with significantly better 5- and 10-year survival in both PTC and FTC patients with stage IV A, B, or C disease, in contrast to a non-radioiodine-treated control group and also to external beam radiotherapy [566]. Mortality in the PTC cohort (n=10,796) at 5 and 10 years was 11% and 14% for patients who received RIT compared to 23% and 26% for patients who did not receive RIT. Mortality in the FTC cohort (n=1,036) at 5 and 10 years was 29% and 37% in patients receiving radioiodine therapy compared to 46% and 51% in patients not receiving RIT. These survival rates were also significantly better than those of patients who received external beam radiotherapy as an alternative, where the mortality rate was between 47% and 60% [566].
In 2018, the European Association of Nuclear Medicine (EANM) commissioned a literature study on adjuvant RIT for thyroid cancer from the German Agency for Quality in Medicine, Berlin (ÄZQ). This study was reported on in the EANM journal [556]. As part of the preparation of this guideline, Cochrane Cancer was commissioned to review the literature published between 2015 and the end of 2018 using the same search criteria as the ÄZQ. This identified 12 publications, including 5 that were already included in the ÄZQ report. The 7 "new" publications included 6 register studies and one systematic review with a meta-analysis. One study had to be subsequently excluded as it focused on the safety rather than the effectiveness of RIT. The review and two other studies dealt exclusively or predominantly with papillary microcarcinoma. At a 10-year follow-up, there were no survival benefits from RIT in this group. Disease-free survival, which is actually more relevant as an outcome parameter, was not investigated. Two registry studies in the SEER database investigated the effectiveness of RIT in low-risk cases of UICC/AJCC Group I (<55 years) and II (≥ 55 years) with regard to central lymph node metastases. While one study demonstrated a clear survival benefit of RIT in stage pN1a in terms of reduced overall mortality (HR=0.54, P < 0.001) [563], the second study on the same data set found a similar effect only if the later pathologically-anatomically proven lymph node metastases pTN1 had not been clinically detected (cNx/0) [567]. The last study identified by Cochrane deals with the clinically important question of which prognostic factors play a role in patients with stage pT2-4. First, it was shown that RIT significantly improves disease-specific survival in patients with tumors > 2cm (HR = 0.60, P< 0.01) if one of the additional risk factors age > 45 years, locally invasive tumor growth, lymph node or distant metastases is present [568].
As data from RCTs on the benefits of RIT in low and intermediate stages are lacking worldwide, data from clinical follow-up registries must be used as a substitute. The Würzburg Thyroid Cancer Registry has been collecting clinical follow-up data on around 3,000 DTC patients since 1980. A prospective observational study from this registry on 2,011 DTC patients of all tumor stages from 1980-2011 (median follow-up 7.1 years) allows indirect conclusions to be drawn about the effectiveness of RIT in terms of survival in the intermediate stages pT1b-4a pN0-1 M0 [569]. Despite the higher risk, the 10-year survival probability of this group treated with radioiodine does not differ from that of the "very-low" risk patients pT1aN0M0 who did not receive RIT and a matched comparison group from the general German population without DTC: The 10-year survival rates of the DTC patients with low and intermediate risk, who made up 86% of the total collective, and that of the comparison group from the general German population was 95%. Patients older than 45 years with advanced tumor disease in stage pT4a, b or c (according to the 7th edition of the UICC classification), patients with lymph node metastases in the lateral neck compartment or with distant metastases had poorer long-term survival. Of the patients with tumor stage IVc, only around 30% were still alive after 20 years [569].
There are analyses from Europe [556] and the USA, particularly from their national cancer registries, which show a clear benefit of RIT in higher, but also in intermediate and low stages [570], [553], [548], [571]. Orosco et al. determined a benefit for RIT in 199,371 patients from the NCDB database and 77,187 patients from the SEER database across all stages with the exception of papillary microcarcinoma. In the group treated with RIT, there was a lower overall mortality (NCDB: RAI hazard ratio (HR) 0.55, P<0.001; SEER: HR 0.64, P<0.001) as well as a reduction in cancer-specific mortality (SEER: HR 0.82, P=0.029) [548].
Recent publications also demonstrate the benefit of RIT in low and intermediate stages [572], [573]. Zhao et al. reported in a multivariate Cox regression model that low to intermediate risk PTC patients had better OS when RIT was performed. Subgroup analysis showed that RIT predicted better OS in patients ≥55 years, AJCC stage II and extracapsular extension with HR (95% CI) of 0.57 (0.45-0.72), 0.57 (0.45-0.72) and 0.68 (0.51-0.91), respectively. Patients with at least 2 cervical lymph node metastases or multifocal tumors or extracapsular extension treated with surgery and RIT had better survival than those treated without RIT [574].
Sutton et al. analyzed treatment decisions of surgery and RIT according to patient age. age dependence. 72,368 were young adults aged 18-54 years; 23,726 were middle-aged adults aged 55-64 years; 18,119 were older adults aged 65-79 years and 2,885 were very old adults aged over 80 years. With increasing age, the rate of patients operated on (99.0%, 98.4%, 97.4%, and 89.1%; p < 0.001) or treated with RIT (48.7%, 42.5%, 39.7%, and 30.7%; p< 0.001) decreased. Middle-aged, older and very old adults had a higher risk of death from differentiated thyroid cancer (HR: 4.0, 95%CI: 3.2-4.8, p < 0.001; HR: 7.6, 95%CI: 6.3-9.1, p < 0.001; and HR: 17.2, 95%CI: 13.8-21.3, p < 0.001). In multivariable Cox regression adjusting for clinicopathologic factors, treatment was a significant prognostic factor (surgery HR: 0.26, 95%CI: 0.22-0.32, P < 0.001; and no RAI HR: 1.42, 95% CI: 1.25-1.67, P < 0.001) [575].
5.8.2.1 Papillary micro-carcinoma PTC pT1a (= PTMC) N0 M0: Papillary thyroid micro-carcinoma (PTMC)
PTC pT1a is described in section statistics with up to 36% and thus represents a very frequent incidental finding ("incidental PTC") [576]. Papillary microcarcinoma (PTC pT1a, i.e. a PTC ≤ 10 mm) is usually detected as an incidental finding after (lobectomy or) thyroidectomy of a goiter. In its guideline published in 2014, the British Thyroid Association (BTA) devoted considerable space to risk assessment and personalized decision-making in the treatment of PTMC (PTC pT1a) [60], in particular with data on metastasis. The prevalence of nodal micrometastasis is given as 12 - 50%. On the basis of 15 studies with 4,096 patients and a follow-up of 3.7-11.2 years, the BTA calculated a probability of 0.4% for distant metastasis in PTMC and, after analyzing 16 studies with 5,256 patients, put the risk of locoregional recurrence at 2.5%. The previous therapies were very heterogeneous and in some cases also included radioiodine therapy [60].
In the case of a postoperative incidental finding of a papillary microcarcinoma (unifocal PTMC, PTC pT1a) with no evidence of locoregional or distant metastases and no other risk factors, no further ablative therapy (surgical therapy or radioiodine therapy) shall be performed.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 1b
- Consensus
- Consent (93%)
- References
- [577]
In their meta-analysis of papillary microcarcinoma, Hu et al. found no advantage for RIT in reducing the risk of recurrence at a follow-up period of 10 years [577]. Nineteen retrospective cohort studies comparing patients with RIT with those without RIT met the inclusion criteria of this publication. A multivariate analysis of the efficacy of RIT in relation to recurrence or thyroid cancer-related mortality in patients with papillary microcarcinoma was performed in several studies, of which only one study yielded a positive result. In PTMC patients treated by total or near-total thyroidectomy (TT/NT) with or without RIT, the meta-analysis found that RIT did not significantly reduce the 10-year risk of tumor recurrence (relative risk [RR] 0.96; 95 % confidence interval [CI] 0.63-1.48; P = 0.87), nor locoregional recurrence (RR 1.15; 95 % CI 0.75-1.76; P = 0.51), distant metastases (RR 0.32; 95 % CI 0.08-1.32; P = 0.11) or thyroid cancer-related mortality (RR 0.76; 95 % CI 0.22-2.63; P = 0.66). With low confidence in the quality of the evidence, this justifies the negative recommendation.
In PTC in stage pT1a with risk factors (e.g. multifocality, aggressive subtype, organ capsule infiltration, genetic risk profile, percutaneous pre-irradiation of the head/neck region), radioiodine therapy can be offered after an individual risk/benefit assessment if a thyroidectomy has been performed.
- Recommendation grade
- 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
- Level of evidence
- 2a
- Consensus
- Consent (92%)
- References
- [574]
If risk factors are present, the prognosis is also worse in the pT1a situation. Risk factors for the increased probability of lymph node metastases are multifocality, aggressive subtype, low degree of differentiation, infiltrative tumor growth with infiltration of the thyroid capsule, but also surrounding desmoplastic fibrosis [578], [579], a tumor diameter of 6 mm or more, familial clustering or a history of percutaneous pre-irradiation of the head and neck region [580], [581], [582], [583], [60].
Shattuck et al. published an important aspect of multifocality, namely that in multifocal PTC the individual tumors arise from independent tumor clones, so that in multifocal PTC RIT (if necessary after completion surgery) was advised to prevent the development of a new tumor in the residual thyroid tissue [584].
Genpeng et al. reported on 285 patients with multifocal PTC. Multifocal PTC had a higher rate of capsular invasion, extrathyroidal extension, N+ stage and local recurrence and therefore received RIT more frequently. Capsular invasion (hazard ratio [HR], 1.589; 95% confidence interval [CI], 1.352-1.984), advanced pathologic T classification (HR, 3.582; 95% CI, 2.184-5.870), and pathologic N+ stage (HR, 1.872; 95% CI, 1.278-2. 742) were associated with an increased risk of multifocality and there was a significantly increased HR for central cervical lymph node compartment involvement in male sex (HR, 2.694; 95% CI, 1.740-4.169), advanced pathologic T classification (HR, 2.403; 95% CI, 1.479-3.907), and multifocality (HR, 1.988; 95% CI, 1.361-2.906). Genpeng therefore recommend a total thyroidectomy with prophylactic bilateral central lymph node dissection for multifocal PTC in view of the increased probability of lymph node metastases in level VI [585].
Zhao et al. [574] investigated whether patients benefit from radioiodine therapy if they have a papillary microcarcinoma with an intermediate risk of recurrence. Zhao et al. identified 8 studies that matched the search strategy and a total of 2,847 patients were analyzed. The analysis of PTMC patients with intermediate risk of recurrence showed that patients without RIT had a higher rate of cancer recurrence than those who had undergone RIT (RR 0.23, 95% CI 0.11-0.49, P = 0.0001). Patients with risk factors for lymph node metastases (RR 0.16, 95% CI 0.06-0.42, P = 0:0002), microscopic extrathyroidal extension (RR 0.19, 95% CI 0.06-0.60, P = 0:005) and multifocality (RR 0.13, 95% CI 0.04- 0.45, P = 0.001) had a significantly higher risk of recurrence without RIT. RIT reduces the cancer recurrence rate over 5 years in PTMC patients with risk factors such as lymph node metastases, microscopic extrathyroidal extension and multifocality.
If these risk factors are present, RIT can be performed in the case of a total thyroidectomy after individual risk-benefit assessment and patient information. In the prospective ESTIMABL2 study, in which RIT was not performed for low PTC tumor stages, patients with aggressive histological subtypes of PTC were excluded [586].
With low confidence in the quality of the evidence, recommendations were made with appropriate strength for the different risks,
5.8.2.2 Papillary thyroid carcinoma with preoperatively diagnosed LN or distant metastases, PTC pT1a N1 and/or M1 (papillary thyroid microcarcinoma = PTMC ≤ 10 mm)
In the case of initially lymphogenous or hematogenous metastasized PTC pT1a (PTMC), radioiodine therapy shall be carried out after thyroidectomy.
The publication by Zhao et al. identified the presence of lymph node metastases in patients with papillary microcarcinoma as a risk factor for recurrence, meaning that these patients benefit from radioiodine therapy [574].
For papillary microcarcinoma diagnosed preoperatively, a meta-analysis by Mehanna et al. showed a 14.7-fold higher probability of recurrence compared to histopathologically incidentally detected microcarcinoma [583].
In a retrospective cohort study from Seoul, Korea, Kwon et al. investigated the effect of radioiodine therapy on papillary microcarcinoma. Of a total of 1,932 patients, 1,648 had received radioiodine therapy and 284 had not received RIT after total thyroidectomy. The risk of recurrence was identical at a mean follow-up time of 8.3 years, but only on condition that the patients had no lymph node metastases in the lateral neck compartment and no distant metastases [587].
Al-Qahtani et al. investigated the benefits of radioiodine therapy in patients with papillary microcarcinoma in a retrospective cohort study conducted between 2000 and 2012[588]. 326 patients had papillary microcarcinoma, of whom 144 patients received radioiodine therapy and 182 did not receive radioiodine therapy. During the median follow-up period of 8.05 years, 23 recurrences occurred, 8 (4.4%) in the radioiodine-treated group and 15 (10.4%) in the patients who had not received radioiodine therapy. The presence of lymph node metastases was a statistically highly significant risk factor for disease-free survival in the univariate and multivariate analysis (univariate analysis LN positive 4.45 versus LN negative 1.17, p < 0.0001 and multivariate analysis LN positive 3.74 versus LN negative 1.01, p < 0.0001).
These publications justify the recommendation of radioiodine therapy for papillary microcarcinoma in the presence of lymph nodes and distant metastases.
Further publications deal with the question of how frequent lymph node metastases are in papillary microcarcinoma and how often disease persistence occurs at this tumor stage.
In a meta-analysis by Qu et al., a probability for the presence of lymph node metastases in the central compartment of 30.2% (847/2,801 patients) for unifocal PTMC and 47.7% (460 / 964 patients) for multifocal PTMC was extracted from 11 studies. Risk factors were male gender, younger age of onset < 45 years, tumors > 5 mm, multifocality and extrathyroidal extension [393]. In unifocal papillary carcinoma, the probability of lymphogenic micrometastases increased with increasing tumor diameter, depending on the tumor diameter, even below 10 mm (tumor diameter 6 to 10 mm).
Goran et al. found similar figures for lymph node metastases in a total of 237 PTMC patients. Lymph node metastases were found in 33% of patients. The distribution was 27% in the central lymph node compartment and 20% in the lateral lymph node compartment; skip metastases were found in 6%. A PTMC diameter of 5 mm or more was a risk factor: PTMC ≤ 5 mm had LN metastases in 20.3% (521/2,570 patients) and PTMC > 5 mm in 36.3% (1,457/4,012 patients) [589].
Gao et al. confirm that PTMC does not always follow a favorable course. 40/358 patients (14.3%) developed disease persistence. The variables male gender, initial tumor size >5 mm, lymph node metastases and a stimulated thyroglobulin level ≥ 10 μg/L were associated with disease persistence in univariate regression analysis. A post-stimulation thyroglobulin level ≥ 10 μg/L was the only independent prognostic variable that predicted disease persistence in multivariate regression analysis (odds ratio: 36.057, p = 0.000) [590]. Accordingly, a PTMC is not always considered a clinically or prognostically favorable tumor, with Gao et al. reporting distant metastases in only 1/280 patients (0.4%) [590]. Based on their analysis, Gong et al. therefore suggested a diameter of 8.5 mm as the best cut-off between "indolent" and lymphogenously metastasized tumors [591].
Al-Qurayshi et al. also investigated whether papillary microcarcinoma always presents as "indolent". Of a total of 30,180 adult patients with PTMC from 2010 to 2014 in the National Cancer Database, 5,628 patients (18.7%) were identified as having advanced tumor characteristics, including central lymph node metastases (8.0%), lateral LN metastases (4.4%), microscopic extrathyroidal extension (6.7%), grossly invasive extrathyroidal extension (0.3%), lymphatic vessel invasion (4.4%), and distant metastases (0.4%) [592]. Huang et al. published on the frequency of lymph node metastases: Of 484 patients with PTMC, 49.6 % had central and 9.1 % lateral lymph node metastases [593].
5.8.2.3 Papillary thyroid carcinoma in stages with low and medium risk of recurrence, PTC pT1b, pT2 and pT3
Patients with PTC pT1b pN0 without risk factors should not undergo radioiodine therapy if an excellent result has already been achieved by surgery, otherwise the advantages and disadvantages of radioiodine therapy should be discussed individually.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 1b
- Consensus
- Consent (87%)
- References
- [586]
Leboulleux et al. published a prospective randomized study (ESTIMABL2) on the benefit of RIT in patients with tumor stages pT1aN0, pT1aNx, pT1bN0 and pT1bNx [586]. In this French prospective ESTIMABL2 study, PTC patients in these stages underwent thyroidectomy and were then randomized into 2 groups: 389 patients received RIT and 387 patients did not receive RIT. The surgeries had already been planned primarily as oncological surgeries and were performed in 35 selected expert centers. In both groups, 44% of patients had undergone lymphadenectomies as part of the thyroidectomy. Patients with aggressive tumor histologies were excluded. Information on the side effect profile (recurrent paresis, hypoparathyroidism) is missing in the publication. After 3 years, the results were comparable in both groups, whereby a composite endpoint was examined, namely the occurrence of functional, structural or biochemical abnormalities. More than 95% of patients had an unremarkable course and the advantage for RIT was only 0.3% (with a small number of cases, p = n.s.). During the follow-up period, abnormal findings occurred in 16/367 patients (4.4%) in the observation group and in 15/363 patients (4.1%) in the radioiodine-treated group. The endpoints were defined differently in the groups. In the radioiodine-treated group, iodine accumulations outside the thyroid bed were counted as events, which, as expected, was not possible in the non-radioiodine-treated group. This means that the more sensitive method was used in the radioiodine-treated group. In the radioiodine-treated group, findings requiring treatment were found in 10 patients; this was the case in only 4 patients in the observation group. The results suggest that the benefit of RIT in oncologically oriented surgery is limited to a small number of patients and that the decision to use RIT at this tumor stage depends on multiple factors. It should be critically noted that the follow-up period of 3 years was very short and that many more recurrences were diagnosed in the radioiodine-treated group. This suggests that radioiodine therapy has enabled more sensitive follow-up. RIT was carried out with the low activity of 1.1 GBq, which was determined à priori. Results with higher activities are therefore not available. It is also noteworthy that the risk profile was less favorable in the group of patients receiving radioiodine therapy. Taking into account the points of criticism and the sometimes very critical international view [594], it should be noted that the occurrence of functional, biological and structural events in the patient group of pT1a and pT1b tumors (with a high rate of lymph node dissection) with and without RIT appears to be comparable over three years. However, it is also conceivable that the sensitivity of the diagnosis is worse without RIT, which is why the recurrences were not detected within 3 years. If there is little confidence in the quality of the evidence, a negative recommendation is made.
The following criteria can be used to define an excellent result after a thyroidectomy:
- The removal of a representative number of lymph nodes from the central compartment without evidence of tumor (the guideline value is 6 removed and histopathologically processed lymph nodes in tumor stage pT1b).
- A low postoperative serum Tg value, measured 3-4 weeks after surgery (guideline value < 0.5- 1ng/ml). There are no reliably defined limit values for thyroglobulin. In the ESTIMABL2 study, the recurrence rate with a Tg value of >1ng/ml was 14.6%.
- No Tg antibody detection. If this is the case, the Tg value may be falsely negative.
In patients with PTC pT1b pN0/Nx and patients with PTC pT2 pN0 with prophylactic compartment resection, the advantages and disadvantages of radioiodine therapy shall be discussed individually.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- ⊕⊕⊝⊝
OS
- Consensus
- Consent (91%)
- References
- [572]
At higher tumor stages and in the presence of lymph node metastases, patients benefit from radioiodine therapy. Liu et al. investigated the effect of radioiodine therapy on survival depending on the 7th and 8th edition of the AJCC/TNM stages [572]. They analyzed 89,204 patients from the SEER database in the period from 2006 to 2015. In particular, patients in T-stages pT2, pT3 and pT4 benefited from radioiodine therapy in terms of overall survival according to both the 7th and 8th editions of the classification. Hazard ratios were between 0.293 and 0.575 in the 7th edition and 0.132 and 0.443 in the 8th edition (95%CI all less than 1). The benefit of radioiodine therapy also applied to patients with lymph node metastases and even more clearly to distant metastases (HR of 0.332, 95% CI 0.269-0.410 after the 7th edition and HR of 0.272, 95% CI 0.207-0.358 after the 8th edition for patients with distant metastases).
Zhao et al. [595] analyzed patients in the SEER database from 2004-2018 according to a propensity score matching analysis. A total of 15,179 patients were included, including 3,387 (22.3%) who underwent total thyroidectomy only and 11,792 (77.7%) who received total thyroidectomy and radioiodine therapy. Subgroup analysis showed that RIT in patients ≥55 years, American Joint Committee on Cancer (AJCC) stage II and extracapsular extension resulted in a significantly better prognosis for survival with hazard ratios (HR) (95% CI) of 0.57 (0.45-0.72), 0.57 (0.45-0.72) and 0.68 (0.51-0.91), respectively. The data from Liu et al. and Zhao et al. justify recommendations 5.36 and 5.37.
Based on the SEER database (USA) from the survey years 1973-2009, Orosco et al. were able to show in a collective of 6,049 patients that not undergoing RIT increases carcinoma-specific mortality. For patients with tumor stage pT2 N0 M0, < 45 years, male, of Caucasian descent without adjuvant RIT, a significantly higher hazard ratio of 1.3 (p < 0.0002, confidence interval 95% of 1.1-1.5) was calculated in comparison to a corresponding reference collective in which adjuvant RIT had been performed [548].
Ruel et al. analyzed the data from the National Cancer Database (USA) from 1998-2006 with a focus on the risk of recurrence at pT3 N0 M0 or pT1-3 N1 M0 (intermediate risk group) on the basis of 21,870 patients [571]. The multivariate analysis showed a 29% reduction in mortality for patients with adjuvant RIT compared to patients without adjuvant RIT. This clear effect was found despite the fact that the group of patients who underwent RIT had a statistically more advanced tumor spread at diagnosis than the patients without adjuvant RIT (non-randomized design): Thus, compared with the non-adjuvant treatment group, multifocality at initial diagnosis existed in 51% versus 47% of patients receiving adjuvant therapy, lymph node metastasis in 74% versus 68%, and R1 resection in 19% versus 15% of patients. However, the decision in favor of adjuvant RIT more than compensated for the more advanced tumor stage and improved mortality. Adjuvant RIT also reduced mortality in the subgroup < 45 years (n = 12,612, p = 0.002, mortality reduced by 36%) and in the subgroup > 65 years (n = 2,122, median OS 140 versus 128 months, p = 0.008). In the NCDB analyzed by Ruel et al. the recurrence rate is not recorded, which is why there is no statement on this. It must be taken into account that in the U.S. no distinction is made between adjuvant and ablative RIT (potentially underdosed with RIT at 1.1 GBq).
In a non-systematically reviewed study, Sun et al. compared two groups of patients, each with 12,128 patients, who were treated once with thyroidectomy alone and the other time additionally with RIT [563]. The patients without RIT had a statistically significantly worse overall survival, especially in the group > 55 years. The improvement in overall survival with thyroidectomy and RIT was highly significant for patients in T-stage T3 with an HR of 0.34 (95% CI = 0.27 - 0.43; p < 0.001) and for patients with lymph node metastases who had received RIT: pN1a HR = 0.30 (95%CI = 0.25 - 0.36; p < 0.001) and pN1b HR 0.56 (95% CI = 0.44 - 0.71; p < 0.001). This highly significant benefit of RIT was found both in patients with 1 - 4 lymph node metastases (HR = 0.40, 95% CI = 0.33 - 0.48; p < 0.001) and in patients with ≥ 5 lymph node metastases (HR = 0.46, 95% CI = 0.37 - 0.57; p < 0.001). In absolute numbers, there were 383 deaths in the thyroidectomy group with 1-4 lymph node metastases and 221 deaths with ≥ 5 lymph node metastases. The number of deaths was lower in the group additionally treated with RIT: 175 for 1-4 lymph node metastases and 139 for ≥ 5 lymph node metastases.
When deciding for or against radioiodine therapy, it is important to consider the risks associated with lymph node metastases and the certainty of an "N0" diagnosis.
In most lymphogenously metastasized PTC tumors, a clinical N0 situation is found preoperatively on ultrasound. On histopathology, however, lymph node metastases are found in approx. 20 - 80% of PTC patients (if a sufficient number of lymph nodes have been removed) [596].
Wang et al. found more than 5 lymph node metastases in the central compartment in 67/611 cN0 patients (11%), each with a tumor size of ≥ 2 mm [597]. Lei et al. found "skip metastases" in the lateral neck compartment in 39/450 patients (8.7%) who had undergone both central and lateral neck lymph node dissection for PTC, [598]. Nie et al. reported a probability of skip metastases of 15% (30/203 patients) [599].
The probability of detecting existing lymph node metastases histopathologically depends on the number of lymph nodes removed at thyroidectomy and examined histopathologically [600], [60], [601], [602].
Robinson et al. stated that in order to exclude lymph node metastases with a 90% probability, 6 lymph nodes would have to be examined histopathologically for pT1b tumors, 9 for pT2 tumors and 18 for pT3 tumors [603]. See also background text to recommendation [4.5].
Randolph et al. published a comprehensive analysis of the risk of recurrence depending on detailed descriptors of lymph node metastasis [604], [605]. With less than 5 LN metastases ≤ 0.2 cm, the risk of recurrence is given as less than 5%, whereas the risk of recurrence increases to up to 19% if more than 5 LN metastases are detected. In the clinical N1 situation, the risk of recurrence is up to 22% and up to 33% for macroscopic LN metastases of > 3 cm.
Table 17: Advantages and disadvantages of radioiodine therapy
| Radioiodine therapy | No radioiodine therapy | |
| Elimination of residual thyroid tissue | yes | no |
| Significance of the Tg value in tumor aftercare | yes | no (at least limited) |
| Detection of iodine-avid lymph node metastases | yes | no |
| Detection of iodine-avid distant metastases | yes | no |
| Elimination of tumor tissue | yes | no |
| Certainty of tumor stage | high | low |
| Radiation exposure | existent | not existent |
| Benefit on recurrence-free survival (PFS) | no direct comparative studies of patients with versus without RIT on recurrence risk | |
| Benefit on overall survival (OS) | retrospective studies show benefit, particularly with a follow-up period of 10 years or more | |
5.8.2.4 Papillary thyroid carcinoma in stages with a high risk of recurrence or in the metastatic situation, PTC pT4, M1
T4 and M1 patients have reduced tumor-specific survival [606].
Liu et al. [572] examined PTC patients from the SEER database from 2006 to 2015. Of the total 89,204 patients, 944 patients in the T4a and T4b stages had not received radioiodine therapy and 1,764 patients had received radioiodine therapy. The hazard ratio (improvement in survival) due to radioiodine therapy was 0.489 (95% CI 0.392-0.609) for T4a patients and 0.372 (95%CI 0.284-0.487) for T4b patients (7th edition of the TNM classification); for metastatic patients, the hazard ratio was 0.332 (95% CI 0.269-0.409).
Orosco et al. [548] also analyzed the SEER database and the NCDB database with a total of 276,558 patients. Patients who had radioiodine therapy had an improvement in all-cause mortality in almost all cohorts. High-risk metastatic patients had the greatest benefit. For metastatic patients, the hazard ratio for overall survival was 0.51 (95% CI 0.42-0.61, n=1532) according to the NCDB database and 0.39 (95% CI 0.29-0.52, n=564) in the SEER database. The significant results justify the strong positive recommendation.
5.8.2.5 Special histologies of the PTC
Aggressive subtypes of PTC (including the large cell, columnar cell, and hobnail variants) should be treated with radioiodine therapy.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2b
OS
- Consensus
- Strong consensus (96%)
- References
- [607]
Histological features such as vascular and/or lymphatic invasion, angiogenesis, multifocality, high cell proliferation rate, dissemination of neoplastic cells and histological variants, together with clinical factors such as age, gender, and tumor size, indicate a poor prognosis [608]. Subentities of PTC with a poorer prognosis include the columnar cell variant and the encapsulated variant [609].
Holoubek et al. [607] recorded a total of 155,940 patients with papillary thyroid carcinoma, 4,011 patients with tall cell carcinoma and 507 with diffuse sclerosing carcinoma in the National Cancer Database. Overall survival was compared for matched cohorts of patients who received radioiodine therapy or no radioiodine therapy after total thyroidectomy. The median duration of follow-up was only 4.3 years. For tumor sizes 20 mm and larger, a significant (p=0.004) survival advantage was found for the radioiodine-treated group, 83.4% versus 70.0% in 338 patients. For tumors between 10 and 20 mm, the corresponding values were 88.1% versus 72.7% (n.s.) in 520 patients. Although there is only a low level of confidence in the quality of the evidence, a statistically proven survival benefit from radioiodine therapy was already evident in the comparatively short follow-up period
Cribriform variant of the PTC
Compared to classic papillary thyroid carcinoma, lymph node metastases (12 %) and distant metastases (3 %) are observed less frequently in the rare cribriform variant at primary presentation. In addition, the recurrence rate (8.5 %) and mortality rate (2 %) are lower [610]. The recommendations of the classic PTC can be applied to this variant. In around 40% of cases, it is associated with a germline mutation, which is also the cause of familial adenomatous polyposis [611]. A corresponding clarification should be arranged.
Follicular variant of the PTC
Based on 10,740 patients from the SEER database, the follicular variant of papillary thyroid carcinoma resulted in a metastatic pattern between classic papillary thyroid carcinoma and follicular thyroid carcinoma and the long-term outcome was similar to that of classic papillary carcinoma [612]. Therefore, the recommendations for classic papillary thyroid carcinoma can in principle be transferred to the follicular variant. In the publication by Yu et al., 58% of patients with classic PTC and 56% of patients with the follicular variant of PTC received radioiodine therapy. The overall survival of both variants was practically identical (10-year and 15-year survival for both PTC entities 93% and 89% respectively) and significantly better than the survival rate of patients with an FTC (10-year survival 87% and 15-year survival 79%). The multivariate analysis showed a significant effect for patients with classic PTC (hazard ratio 0.7 [0.5 - 0.8]). For patients with follicular variant of PTC, a trend-like advantage could be proven with only half the number of cases (HR = 0.9 [0.6 - 1.4]) [612].
Diffuse sclerosing variant of PTC (PTC-DSV)
PTC-DSV is a rare histologic subgroup of PTC with a frequency of 0.7 - 6.6% of PTC cases. This variant predominantly affects adolescents and young adults and accounted for over 40% of thyroid carcinomas in the age group < 20 years in a retrospective analysis from South Korea [613]. Whether this distribution is transferable to Germany has not yet been investigated. This subtype is associated with therapeutic external cervical irradiation, has a higher rate of lymph node metastases at diagnosis and distant metastases in around 5% of cases, and showed a recurrence rate of 14% and a mortality rate of around 3% in a study by Pillai et al. [579]. In the study by Fukushima et al., disease-free survival in this group was worse than in the matched control group of classic PTC, which the authors attributed to the non-routine implementation of adjuvant radioiodine therapy in this group [614]. Assuming more aggressive treatment with additional surgery and/or radioiodine therapy, the outcome of these patients is comparable to the high-risk group of the classic PTC [615]. The recommendations for classic PTC can therefore be transferred to PTC-DSV.
Solid variant of PTC (PTC-SV)
The solid variant of PTC is one of the rarest subtypes, accounting for only 3% of all PTCs [616], [617]. PTC-SV frequently occurred in children after the Chernobyl accident and accounted for over 30% of PTC variants in this group [618]. Despite advanced disease in some cases, this group showed a very good prognosis with a very low mortality rate of less than 1% in some cases [619]. However, a meta-analysis by Vuong et al. found that sporadic PTC-SV tends to occur in older patients compared to classic PTC and that the disease-free survival rate is lower than that of classic PTC [620]. As a limitation, however, it should be noted that the authors point out that the overall result was dominated by a single Japanese study [620]. Individual studies in this group also reported higher rates of lymph node metastases and distant metastases [617], [621]. However, Chang et al. did not find an increased risk of lymph node or distant metastases or an increased recurrence rate in their small group [622]. Data regarding the prognosis of PTC-SV therefore remain partly contradictory due to insufficient data. Overall, the recommendations for classic PTC should be applied to PTC-SV.
Tall cell variant of PTC (PTC-TCV)
The tall cell variant of PTC is regarded as an aggressive subtype of PTC, which has been attributed a poorer prognosis in various studies [623], [624], [625], [626], [627]. Compared to classic PTC, this group of patients more frequently exhibits extrathyroidal spread, macroscopic or microscopic residual tumor tissue, lymph node or distant metastases, as well as significantly shorter disease-free survival [624], [625], [626]. The published 10-year survival rates are between 50% and 80% [625], [628]. Surgery and radioiodine therapy significantly improved survival in this group [624]. In the comparative study by Holoubek et al., patients with a PTC-TCV who were treated more aggressively overall (total thyroidectomy and radioiodine therapy) showed a similar overall survival to the group of matched classic PTC [629]. In a further analysis, the same author found no improvement in patients with tumors up to 2 cm, whereas RIT improved survival in the group with tumors between 21 and 40 mm (83.4% vs 70%, p = .004) [607]. Overall, the prognosis in this group worsens as soon as invasive features are present [630]. In contrast, Regalbuto et al. were able to show that the treatment results of PTC-TCV patients were not worse than in the overall group of classic PTC patients. The treatment results of PTC-TCV patients were also better than those of patients with a classic "high risk" PTC [631]. In general, PTC-TCV have lower sodium iodide symporter expression [632]. These patients often require higher cumulative therapeutic activities to improve prognosis and are also more likely to be radioiodine refractory [632], [633]. However, it is important to note that the WHO modified the morphological criteria for the large cell variant of PTC in 2017 [634]. Among other things, ≥ 50% large-cell cells were previously required; in the updated version, ≥ 30% is sufficient. It is therefore assumed that this change will lead to an approximate tripling of the incidence of this variant [634]. Further studies using these new criteria are therefore needed to investigate and better assess the outcome of these patients. Currently, patients with PTC-TCV should be treated similarly to "high risk" PTC patients.
Columnar cell variant of PTC (PTC-CCV)
The columnar cell variant of PTC can be divided into two groups. On the one hand, there is the clinically indolent tumor type, which mainly affects younger patients (median 38 years) and predominantly women with smaller (mean 2.1 cm), encapsulated or well-circumscribed tumors and, on the other hand, the aggressive carcinomas, which occur in older, predominantly male patients (median 60 years) and have larger tumors (mean 6.7 cm) with diffuse infiltrative growth and extrathyroidal spread as well as lymph node and distant metastases [635], [636]. In their study, Song et al. showed that patients with PTC-CCV had a significantly shorter disease-free survival compared to classic PTC [637]. In addition, this PTC-CCV represents an independent risk factor for structurally persistent or recurrent disease [637]. Based on an analysis of the SEER database, it was shown that PTC-CCV is an independent predictor of tumor-specific mortality and that survival is significantly shorter than with classic PTC [638]. In their study, Wenig et al. concluded that although PTC-CCV is a distinct morphologic type, it is not a distinct clinical type of PTC and that treatment should therefore be based on the clinical stage and not the morphologic picture [639]. In view of this unfavorable histology, RIT is recommended [638].
Hobnail variant of PTC (PTC-HV)
The hobnail variant of PTC was first systematically described by Asioli et al. in 2010 and only recently included in the 2017 WHO classification of endocrine tumors [636], [640], [641]. Compared to patients with a classic PTC, this group often shows extrathyroidal spread (58% [642]), lymph node (75% [643]) and distant metastases (23%-44% [636], [644]) and responds only moderately to radioiodine therapy, which also leads to increased mortality overall [644]. However, in a study by Morandi et al. 6/18 patients showed a good response to RIT. 5/6 patients showed a recurrence 50 months after initial response to RIT. 7/18 patients showed a partial response to RIT [645], [644]. In the study by Asioli et al. the 10-year survival rate of these patients was only 64% [642]. Patients with PTC-HV should therefore be treated similarly to classic "high risk" PTC patients. In their review article, Donaldson et al. confirm the aggressive histology with the development of lymph node metastases in 66% of patients and distant metastases in 23% of patients in a follow-up period of 50 months [644].
Oncocytic variant of PTC (PTC-OV)
In the past, the oncocytic variant of PTC was often presented as a more aggressive and invasive variant of PTC [646], [647], [648]. However, other studies have concluded that PTC-OV has a similar prognosis to classic PTC after adjustment for risk factors [649], [650], [651]. In general, patients with PTC-OV are older [647], [650], [651] and have a larger tumor size [652], [651]. Wenter et al. [651] found a recurrence rate of 9% in the PTC-OV group, which was significantly lower than in other studies (19%-31%) [648], [653]. The authors [651] attributed the lower recurrence rate to the multimodal therapy. In contrast to the study by Hong et al. [648], in which only 50% of patients received radioiodine therapy, this was routinely carried out in the group of Wenter et al. Overall, the recurrence rate in patients with PTC-OV after adequate surgical treatment and adjuvant radioiodine therapy is low, which underlines the indication for RIT in patients with this entity.
5.8.2.6 Follicular thyroid carcinoma (FTC)
Minimally invasive, follicular thyroid carcinoma without vascular invasion that has been confirmed by quality-assured histopathology should not undergo radiotherapy.
- Consensus
- Strong consensus (95%)
In minimally invasive, follicular thyroid carcinoma with vascular invasion, radioiodine therapy should be performed.
- Consensus
- Strong consensus (96%)
Radioiodine therapy shall be carried out for grossly invasive follicular thyroid carcinoma.
- Consensus
- Strong consensus (100%)
FTC (MIFTC without and with vascular invasion and grossly invasive FTC)
In follicular thyroid carcinomas, a distinction is made between minimally invasive follicular thyroid carcinoma (MIFTC) with the subgroups without and with vascular invasion and grossly invasive follicular thyroid carcinoma.
Cipriani et al. reported that the histopathologic classification of follicular thyroid carcinoma (FTC) can be difficult. In a retrospective analysis, the initial histopathologic diagnosis was revised in 47/66 FTC patients (71%). Survival in the FTC group was 77% after 10 years and 34% after 20 years [654]. The number of proven vascular invasions required to separate the entities has long been the subject of debate. Earlier work from the Sloan Catering Hospital described a maximum of 4 vascular invasions. Yamasaki et al. analyzed the data of 303 patients with encapsulated angioinvasive FTC from 2005 to 2014. 13/303 patients (4.3%) already had metastases at the time of diagnosis. In the remaining 290 M0 patients, the 10-year disease-free survival was 85.6%. Patients with a single (n = 131) vascular invasion had a 10-year disease-free survival of 94.9%. With 2 or more vascular invasions (n = 159), this fell to 77.9% (p < 0.001). An age of 55 years or older was an additional unfavorable prognostic factor. Patients aged 55 years or older with at least 2 vascular invasions had a disease-free 10-year survival of 66.4%. (p < 0.0001) [655].
Based on the SEER database, among 1,200 patients with MIFTC in 2000-2009, lymph node metastasis was observed in 0.9% and distant metastasis in 0.5% of patients, with 53.3% of patients having received RIT [259]. MIFTCs without vascular invasion, in which the classification as malignant is based solely on infiltration of the tumor capsule, have a favorable prognosis. In this case, thyroidectomy is not considered mandatory. Due to the low risk, RIT does not appear to offer a convincing advantage in this entity, although there is little data available. However, the observational study by O'Neill et al., in which the majority of patients with MIFTC without vascular invasion (43/61 patients, 70.5%) received RIT, showed that a lower rate of lymph node (n = 1) and distant metastases (n = 2) as well as tumor-associated deaths can also be expected in this tumor entity [481]. Disease-free survival with a median follow-up time of only 40 months was better in the group of MIFTC without vascular invasion (97%) than in patients with MIFTC with vascular invasion (81%) or in patients with grossly invasive FTC (45%) [481].
Ito et al. pointed out the significant impact of distant metastases in MIFTC and reported disease-specific 10-year survival rates of 99% for MIFTC patients without, as opposed to only 22% with, metastatic disease [656]. D'Avanzo et al. described distant metastases in only 1 of 45 patients (2.2%) with MIFTC without vascular invasion [657]. Recurrence occurred in 11% of these patients, most of whom were treated by lobectomy, and 8.8% died of tumor-related causes [657], [658].
Wu et al. reported on the poor prognosis of patients with FTC and distant metastases. 7-23% of FTC patients have distant metastases. 190 patients were followed up for a mean of 7.7 years, of which 29 patients already had metastases at the time of diagnosis and 14 patients developed metastases during the course of the disease. Patients with FTC that was already metastatic at diagnosis had the lowest cancer-specific 10-year survival rate (26.0%), followed by those who developed metastatic disease only after initial treatment (76.6%), while patients without metastases all survived (100%) (p ≤ 0.002 for all comparisons) [659].
In one of the few studies that examined the survival of a larger number of patients with follicular thyroid carcinoma (FTC), Yang et al. conducted a retrospective analysis of 1,036 FTC patients from the National Cancer Database [566]. The survival rates for patients treated with RIT were significantly better than for patients who had only undergone surgery or external radiotherapy. In the univariate analysis, the hazard ratio for 5-year mortality with or without RIT in stage pT4aN0-1M0 was 0.54 (95% CI = 0.41 - 0.70; p < 0.001), in stage pT4bN0-1M0 0.31 (95% CI = 0.12 - 0.80; p < 0.05) and in stage pT1-4N0-1 M1 0.54 (95% CI = 0.38 - 0.76; p < 0.001). The hazard ratio for 10-year mortality in stage pT4aN0-1M0 was 0.62 (95% CI = 0.53 - 0.72; p < 0.001), in stage pT4bN0-1M0 0.35 (95% CI = 0.19 - 0.64; p < 0.001) and in stage pT1-4N0-1 M1 0.61 (95% CI = 0.46 - 0.81; p < 0.001). In FTC patients with stage pT1-4N0-1 M1, there was a clear difference in survival depending on the treatment modality: In the group treated with external beam radiation therapy (EBRT), mortality was 51% after 5 years and 60% after 10 years. Mortality in the group without adjuvant therapy was 46% after 5 years and 51% after 10 years. The group treated with radioiodine had the lowest mortality at 29% after 5 years and 37% after 10 years. Yang et al. were thus able to show that RIT in stage IV leads to both improved 5-year and 10-year overall survival.
5.8.2.7 Oncocytic thyroid carcinoma
In patients with oncocytic thyroid carcinoma, it should be checked once whether there is a therapeutically useful radioiodine storage or whether it can be treated with radioiodine.
The exceptions are encapsulated oncocytic thyroid carcinomas with few capsular perforations and no vascular invasion, which are adequately treated by lobectomy.
- Consensus
- Consent (95%)
According to the latest version of the WHO classification of endocrine tumors, oncocytic thyroid carcinoma (also known as oxyphilic or Hürthle cell carcinoma) is listed as an independent variant of differentiated carcinomas [660]. Oncocytic thyroid carcinoma is characterized by the fact that the sodium iodide symporter may be non-expressed or only very weakly expressed, whereas thyroglobulin production may be preserved. Patients with this histology should not be excluded from RIT from the outset. It should be checked at least once whether a therapeutically useful radioiodine storage is present or whether it is possible to treat with radioiodine. In addition, any tumor remnants/nests in the residual thyroid tissue can be eliminated by intensive co-irradiation in the crossfire.
Exceptions are encapsulated oncocytic carcinomas with few capsular perforations and no vascular invasion, which are adequately treated by lobectomy.
The recurrence rate of oncocytic thyroid carcinoma varies between 6% (12/207 patients, mean follow-up 55 months) [661] and 12.1% (239 patients, mean follow-up 91 months) [662].
The extent to which follicular oncocytic thyroid carcinoma behaves more aggressively than classic follicular thyroid carcinoma is still the subject of controversy. Hundahl et al. were able to show that after 10 years there is a significantly lower overall survival in the group with Hürthle cell carcinoma (76% vs. 85%) [663]. However, other studies conclude that the prognosis of Hürthle cell carcinoma and classic FTC is similar, provided the risk factors are matched [664], [665], [651].
López-Penabad et al. showed in a subgroup analysis that overall mortality was lower in patients who received adjuvant RIT compared to patients who did not receive adjuvant RIT or received RIT only in the case of persistent disease (p=0.0022 and Fig. 3 in the publication) [666]. Of the 37 metastatic patients with Hürthle cell carcinoma, 14 patients with metastases (38%) showed radioiodine accumulation [666]. In their study, Jillard et al. were able to show that the 5- and 10-year survival rates were significantly higher in patients after RIT compared to patients without RIT (88.9 vs. 83.1% and 74.4 vs. 65.0%) [667].
5.8.2.8 PDTC (poorly differentiated thyroid carcinoma)
In patients with poorly differentiated thyroid carcinoma (PDTC) and differentiated high-grade thyroid carcinoma (DHGTC), it should be checked once whether there is a therapeutically useful radioiodine storage or whether it can be treated with radioiodine.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2b
OS
- Consensus
- Consent (92%)
- References
- [668]
Poorly differentiated thyroid carcinoma is a rare but aggressive variant of thyroid carcinoma. PDTC most frequently metastasizes to the lungs and bones [522], [669], [513]. Apart from anaplastic thyroid carcinoma, poorly differentiated thyroid carcinoma accounts for the largest proportion of thyroid carcinoma-associated deaths [669], [513]. The survival rate is 72% after 5 years and 46% after 10 years [640].
Poorly differentiated thyroid carcinoma is characterized by the fact that the sodium iodide symporter may be absent or only weakly expressed, whereas thyroglobulin secretion is well preserved.
Xu et al. [668] conducted a retrospective cohort study and included a total of 882 patients from the SEER database with poorly differentiated thyroid cancer and compared the overall survival of patients with and without radioiodine therapy. The hazard ratio in favor of radioiodine therapy was 0.57 (0.44 - 0.75; P <0.001). It should be noted that the risk profile was less favorable in the radioiodine therapy group, which means that the actual positive effect of radioiodine therapy is not fully captured. In the case of low confidence in the quality of evidence of the study, which also proves a survival advantage for radioiodine therapy for the PDTC, the recommendation arises to at least check the iodine storage capacity of a PDTC.
Differentiated high-grade thyroid carcinoma was an undefined subgroup of PDTC before the new WHO classification in 2022. A differentiated consideration of the subgroups has not yet taken place. DHGT should therefore continue to be considered in the same way as PDTC.
5.8.3 Postoperative thyroglobulin value
A postoperatively low basal thyroglobulin value (< 2ng/ml) does not rule out lymph node and distant metastases and shall therefore not be used as the sole parameter for further treatment decisions.
- Consensus
- Strong consensus (100%)
After complete thyroidectomy and RIT, thyroglobulin (Tg) is usually no longer measurable or is below 0.5 ng/ml (calibrated to the European standard), making it an excellent tumor marker. After incomplete thyroidectomy, however, the significance of the Tg determination is limited. The thyroglobulin determination has a high clinical value in follow-up care.
A low basal thyroglobulin level after thyroidectomy alone cannot be used to rule out metastases. For example, in the study by Park et al. [670], iodine-avid metastases were found in 6.3% of patients (52/824) after thyroidectomy for thyroid carcinoma despite a postoperatively low thyroglobulin level < 2 ng/ml without antibodies against thyroglobulin. A similar observation for patients with an intermediate risk of recurrence and a postoperative Tg level < 0.6 ng/ml comes from the Memorial Sloan-Kettering Cancer Center in New York. Post-therapeutic ¹³¹I-SPECT/CT identified iodine-storing metastases in 17/146 patients (12%); lymph node metastases were predominant [671].
Prabhu et al. reported that a stimulated thyroglobulin value without interfering antibodies < 1 ng/ml largely excludes metastases, whereas a value of > 5 ng/ml has a 26% probability of metastases [672]. In this study, however, planar whole-body scintigraphy, which is no longer adequate today, served as a reference. Other authors come to the opposite conclusion - also on the basis of planar whole-body scintigraphy [673]. Matrone et al. showed in 505 patients after thyroidectomy that metastases could be detected despite a low thyroglobulin value: 15/287 (5%) patients with a thyroglobulin value ≤ 1 ng/ml and 11/68 patients (16.2%) with a thyroglobulin value > 1 ng/ml had metastases [674].
Campenni et al. reported in 570 DTC patients at low and intermediate risk of recurrence that posttherapeutic radioiodine imaging including SPECT/CT identified 82 patients (14.4%) with metastases, of whom 73 patients (90.2%) had a non-stimulated Tg ≤ 1 ng/ml after surgery. In addition, 44 patients (54 %) of 82 metastatic patients had a stimulated Tg ≤ 1 ng/ml [675].
5.8.4 Diagnostics before radioiodine therapy
CT, MRI, [¹⁸F]FDG-PET/CT, or [¹⁸F]FDG-PET/MRI examinations should be reserved for special questions and can be carried out after radioiodine therapy if necessary.
- Consensus
- Consent (95%)
If imaging using iodine-containing contrast agents is indicated, this examination shall be performed after ¹³¹I whole-body scintigraphy, if clinically justifiable.
- Consensus
- Strong consensus (96%)
After thyroidectomy and before radioiodine therapy, TSH and thyroglobulin including TgAb shall be determined. Other laboratory parameters (blood count, kidney function) should be known.
- Consensus
- Strong consensus (100%)
A lung function test can be performed in the case of multiple or disseminated lung metastases.
- Consensus
- Strong consensus (100%)
As a rule, the postoperative presentation for RIT takes place shortly after the surgery. Examinations prior to RIT are used to detect residual thyroid tissue and to plan RIT.
Scintigraphy
Postoperative functional residual thyroid tissue can be detected by scintigraphy if this is of clinical relevance for planning the further therapeutic procedure. Scintigraphy with a suitable radiopharmaceutical (e.g. ¹²³I, ¹³¹I in low activity) is used to visualize functional residual thyroid tissue and possibly lymph node metastases. This is the case in special situations when relevant thyroid remnants or lymph node metastases are suspected after surgery that would prevent radioiodine therapy. In the study by Mallick et al., ⁹⁹ᵐTc scintigraphy (pertechnetate scintigraphy) was performed prior to RIT in order to visualize thyroid remnants. 2.3% of patients had a large remnant [676]. If diagnostics are performed with ¹³¹I, the lowest possible activities ≤ 15 MBq ¹³¹I may be used to avoid interference in subsequent therapy.
Examinations prior to RIT for suspected or known lung metastases
If a CT scan is planned for suspected lung metastases, this must be performed without iodine-containing CA, i.e. natively. If X-ray contrast medium has been used, RIT will be postponed by at least 2-3 months. In the case of pronounced lung metastasis, a pulmonary function test serves to document the functional lung status prior to RIT and is a starting point for any follow-up examinations. Forensic considerations also speak in favor of this.
CT, MRI, [¹⁸F]FDG-PET/CT, or [¹⁸F]FDG-PET/MRI examinations
Further imaging with CT, MRI or PET is generally not required at the time of the immediate postoperative presentation.
Laboratory
The determination of TSH and thyroglobulin using a modern assay with a low lower detection limit (≤ 0.2 ng/ml) is mandatory and is part of the standard examination in combination with Tg antibodies. The biological half-life of Tg is approx. 1 to 2 days, which must be taken into account when interpreting the measured values. The bone marrow dose is not only influenced by the applied ¹³¹I activity, but also by the kidney function. A differential blood count and the creatinine value are therefore usually determined before RIT.
The measurement of iodine excretion in urine is suitable for identifying patients with high iodine incorporation.
5.8.5 Special aspects of pre-therapeutic iodine imaging/dosimetry
Pre-therapeutic iodine imaging and dosimetry may be performed in individual cases.
- Consensus
- Strong consensus (100%)
For valid dosimetry, the use of[124I]-PET/CT is to be regarded as a superior method. This method is only available to a few centers. Stunning is not to be expected due to the low required activities (25-50 MBq) of the positron emitter. Dosimetry enables an individual treatment decision to be made in the case of detectable metastases. If iodine uptake is low, RIT can be dispensed with or - if possible - the planned focal dose can still be achieved by increasing the activity [677], [678], [679].
In a retrospective, monoinstitutional study from the USA, an improvement in survival was shown for patients with lymph node metastases and distant metastases through individual dosimetry [680]. There is a lack of prospective, randomized data showing that pre-therapeutic dosimetry has a clear beneficial effect on the response rate for metastases as measured by response criteria (RECIST 1.1) or on the survival rate compared to the use of standard activities.
The pre-therapeutic use of ¹²³I or ¹³¹I is not a standard procedure, but can be used in individual case indications [681]. As there are no outcome-based data on dosimetry prior to adjuvant RIT, no general recommendation can be made for such a procedure. Regular pre-therapeutic dosimetry is not necessary, but in individual cases it can be helpful in determining treatment activity. The caution with regard to iodine imaging prior to RIT is shared by experts [682].
5.8.6 Preparatory measures for radioiodine therapy
5.8.6.1 Pregnancy exclusion before RIT
Pregnancy shall be ruled out before radioiodine therapy.
- Consensus
- Strong consensus (100%)
Pregnancy is an absolute contraindication for RIT and must therefore be ruled out before RIT in order to prevent therapeutic irradiation of the embryo or fetus.
5.8.6.2 Weaning and radioiodine application
There should be a latency of at least 8 weeks, but preferably 6 months, between weaning and radioiodine application.
- Consensus
- Strong consensus (100%)
The lactating breast accumulates radioiodine to a considerable extent. Robinson et al. calculated that after administration of 4.0 GBq ¹³¹I the lactating mamma receives 1.6 Gy dose [683]. Breastfeeding should be stopped at least 8 weeks before a ¹³¹I application in order to limit the radiation exposure of the mammae [683]. An increased mammary uptake may still be detectable 3 - 4 months after discontinuation of breastfeeding, so that an appropriate latency phase until RIT should be considered on an individual basis. If necessary, mammary iodine retention can be checked pre-therapeutically with a low activity of ¹²³I. The actual risk of additional radiation exposure can only be estimated theoretically. For a woman without a disease-related reduction in life expectancy whose breast is exposed at the age of 30 years, the expected additional lifetime risk of radiation-induced breast cancer is 0.3% per 100 mGy [684].
5.8.6.3 Relative contraindications
Relative contraindications shall also be taken into account when determining the indication for radioiodine therapy.
- Consensus
- Strong consensus (96%)
Relative contraindications to RIT include
- Severe bone marrow depression if high-dose therapy is planned.
- Significant impairment of lung function if relevant pulmonary storage is to be expected.
- Symptomatic spinal or cerebral metastases that pose a risk of progressive compression symptoms under RIT.
- Pre-existing significant xerostomia with proven symptomatic functional impairment of the salivary glands must be considered as an additional risk when determining the indication for RIT
5.8.6.4 Contraception after RIT
After radioiodine therapy, patients of childbearing age should avoid pregnancy for 6 to 12 months.
- Consensus
- Strong consensus (96%)
Schlumberger et al. [685] reported on 2,113 pregnancies in women with thyroid carcinoma. Before any therapy, the rate of miscarriage was 11%, after thyroidectomy 20% regardless of RIT. However, 4/10 women who had RIT one year before conception suffered a miscarriage. There was no increase in the incidence of premature birth, low birth weight, malformations, or infant death [685].
Metallo et al. reported no fertility impairment in women who had been treated with radioiodine for DTC in childhood or adolescence. 30 pregnancies after RIT were found in patients from the > 3.85 GBq group and 10 in patients from the ≤ 3.85 GBq group. The frequency of miscarriages was 17 % (group > 3.85 GBq) and 10 % (group ≤ 3.85 GBq) with 9 and 24 live births respectively. A causal relationship with the RIT has not been proven. Other possible causes could be an unstable thyroid hormone setting or pregnancy at an older age. Metallo et al. found no congenital malformations and no increased mortality in the first year [686].
In 111,459 Korean women aged 20-49 years after thyroidectomy for differentiated thyroid carcinoma, Kim et al. found no increased rate of miscarriage, preterm birth or congenital malformations when conception occurred 6 months after RIT [687].
After RIT, the avoidance of pregnancy by adequate contraceptive methods is therefore recommended for at least 6 months in patients of childbearing potential. A more recent meta-analysis by Zhang et al. analyzed 125,591 women with 13,811 pregnancies. It was found that postoperative RIT had no significant effect on the spontaneous abortion rate (OR = 1.05, P = 0.701), induced abortion (OR = 1.06, P = 0. 859), the rate of miscarriages (OR = 1.07, P = 0.098), the rate of premature births (OR = 1.02, P = 0.756), the rate of stillbirths (OR = 1.58, P = 0.364), or congenital malformations (OR = 1.00, P = 0.986). The cumulative treatment activity >3.7 GBq or <3.7 GBq had no significant effect on miscarriages (OR = 0.94, P = 0.252) or congenital malformations (OR = 1.05, P = 0.752). If the interval between the last RIT and the pregnancy > was 1 year, this group had a significantly lower risk of miscarriage than the group with an interval of < 1 year (OR = 0.60, p = 0.001) [200].
If a pregnancy or conception occurs within the above-mentioned waiting periods, this does not automatically constitute an indication for an abortion. Risk assessment counseling is recommended. Good hydration with frequent emptying of the bladder and avoidance of constipation reduce the radiation exposure of the gonads.
5.8.6.5 Cryopreservation/procreative leave
Cryopreservation of sperm can be offered if the expected cumulative gonadal dose exceeds 1 Gy, which is only exceeded in exceptional cases for total activities up to 12 GBq ¹³¹I. In men, contraception should be observed for 4 months after radioiodine therapy.
- Consensus
- Strong consensus (96%)
Aspects of cryopreservation are clinically relevant if family planning has not yet been completed. Reference should be made here to the corresponding S2k guideline "Fertility preservation in oncological diseases" (https://register.awmf.org/de/leitlinien/detail/015-082).
The estimated dose for the testicles is 85 mGy/3.7 GBq - an increase in gamete mutations is only expected above 1 Gy [688]. The occurrence of transient or permanent oligospermia or azoospermia is described as dependent on the cumulative treatment activity. The gonadal organ dose can be reduced by adequate hydration and regular, sufficient bladder and bowel emptying [689].
The risk of permanent fertility reduction after a single adjuvant RIT is very low for men [690], [60], [691]. Regular cryopreservation is therefore not considered necessary. A mostly transient oligospermia as well as a reduced percentage of morphologically normal spermatozoa can occur after a single administration of 3.7-5.5 GBq radioiodine, whereby normalization can be expected after 12-18 months [692], [693], [691]. Increased levels of follicle-stimulating hormone (FSH) in the blood have been reported. However, an increase in FSH can also be expected as a result of low-dose irradiation of the pituitary gland.
Permanent oligospermia to azoospermia have been reported from an activity of 13 GBq radioiodine, which is why some authors recommend cryopreservation of sperm from therapy activities of 12 GBq ¹³¹I [694]. Performing multiple cycles of RIT can lead to permanent impairment of gonadal function in men [695]. If high accumulated therapy activities (e.g. ≥ 11-15 GBq ¹³¹I or ≥ 2 high-dose radioiodine therapy) are to be expected, sperm cryopreservation can be considered for patients without completed family planning.
For men, a fertility waiting period of 4 months after RIT is recommended. This recommendation is based on the life cycle of the spermatozoa of 4 months.
A negative influence of radioiodine therapy on female fertility is not to be expected with adjuvant radioiodine therapy and earlier radioiodine therapy should not be seen as an obstacle to pregnancy.
Piek et al. [696] considered 26 publications in their meta-analysis and investigated the influence of radioiodine therapy on ovarian function and fertility in women with thyroid cancer. Irregularities in the menstrual cycle were found in 12 to 31% of patients in the first year of radioiodine therapy and thyroid hormone replacement therapy. 8 to 16% of patients had amenorrhea in the first year. The patients who had radioiodine therapy entered the menopause slightly earlier at 49.5 years than a comparison group without radioiodine therapy at 51 years. In four studies, the anti-Müllerian hormone was lower in patients who had radioiodine therapy than in comparison groups without radioiodine therapy. However, the meta-analysis did not show any restriction in becoming pregnant, i.e. no restriction in fertility. The result is associated with a very low quality of evidence.
Radioiodine therapy, especially adjuvant radioiodine therapy, is therefore not an obstacle to pregnancy.
Women in whom the interval between the last radioiodine therapy and pregnancy was >1 year had a significantly lower risk of miscarriage than women in whom the interval was <1 year (OR = 0.60, P = 0.000). [697]
5.8.6.6 Iodine restriction
A diet rich in iodine shall be avoided for approx. 14 days prior to radioiodine therapy. Any increased iodine intake (e.g. iodine-containing medication and food supplements, disinfectants, algae products) shall be avoided for at least 6 to 8 weeks.
- Consensus
- Strong consensus (96%)
High iodine intake shall be avoided before RIT, as this competitively reduces iodine uptake in metastases and residual tissue [698]. High iodine incorporation ("iodine contamination"), e.g. through iodine-containing X-ray contrast media, iodine-containing medication, and cutaneous contact with iodine, e.g. with iodine-containing disinfectants, prevent successful RIT, sometimes for a longer period of time. This also applies to external agents such as disinfectants or iodine-containing ointments (e.g. povidone-iodine [Betaisodona®]) for external application (also when used on other people or on animals), as iodine is easily absorbed through the skin. Just one drop of an iodine-containing solution on the skin can impair RIT.
Foods particularly rich in iodine are iodine-containing multivitamin or trace element combinations or seaweed. The duration of a low iodine diet prior to RIT is largely based on expert consensus based on clinical experience. Dietary iodine restriction (1-) 2 weeks prior to RIT appears to be advisable. High iodine exposure requires postponement of RIT for up to 4 months until normalization of urinary iodine excretion.
A study conducted by Pluijmen et al. on 120 patients showed that a low-iodine diet reduced 24-hour urinary excretion of iodine by 83%; at the same time, radioiodine uptake in thyroid remnants increased compared to controls. The effectiveness of RIT in terms of successful ablation was better in the low-iodine group in 65% compared to 48% of patients in the control group (p < 0.001) [699]. Sohn et al. also showed that high urinary iodine excretion (> 250 µg iodine / g creatinine) reduces the effectiveness of RIT [700]. Dobrenic et al. confirmed that a two-week low-iodine diet can significantly reduce urinary iodine excretion prior to RIT [701].
The short-term discontinuation of levothyroxine medication prior to thyrotrophin alpha administration, e.g. starting 5 days before the first thyrotrophin alpha injection, is another way of reducing iodine intake pre-therapeutically [702]; however, the effect is small. If iodine-containing X-ray contrast medium has been given, a period of 8 - 12 weeks before RIT is recommended. Lan et al. were able to show that X-ray contrast medium prior to RIT worsens the response rate, which is why these authors recommended a waiting period of 3-4 months [703]. Significantly longer time intervals of ≥ 12 months until RIT is performed may be necessary after discontinuation of amiodarone, if necessary measuring urinary iodine excretion [60], [704]. In these cases, it is recommended to determine the iodine excretion in the urine before the RIT.
However, an iodine allergy is not a contraindication for carrying out an RIT [705]. One GBq ¹³¹I corresponds to about 200 ng iodide and thus roughly the natural amount of iodine in 5g of bread.
5.8.6.7 Salivary gland protection
Lemon or (acidic) candies can be used to stimulate salivation with the aim of increasing radioiodine secretion; the evidence for measures to protect the salivary glands is limited.
- Consensus
- Strong consensus (96%)
Whether and when the stimulation of salivary flow (e.g. lemon juice, sour candies) is of benefit in reducing the radiation exposure of the salivary gland remains unclear. There is little evidence on the clinical benefit and optimal timing of the use of salivary gland protection. The available data do not allow a clear recommendation as to when the administration of lemon should be started [706]. If these measures are used, this should not be done immediately after administration of the therapeutic activity, as otherwise there may be an undesirable increase in blood flow and thus an increased accumulation of activity in the salivary glands at the time of the highest radioiodine concentration [707]. Other measures to minimize damage to the salivary glands, such as the infusion of amifostine, the administration of cholinergic substances or good hydration are also insufficiently proven in their benefit to make a recommendation for or against them. Such drug therapy is not generally used. The saliva empties significantly during meals (through chewing), so it may be advantageous to schedule the time of application on the day of admission sufficiently early before the midday meal [708].
5.8.6.8 Endogenous versus exogenous stimulation (hypothyroidism versus thyrotrophin alpha)
If the risk of recurrence is low, the variants of TSH stimulation (endogenous versus exogenous with thyrotropin alpha) for adjuvant radioiodine therapy shall be discussed with the patient and the procedure determined together with the patient.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- ⊕⊕⊕⊝
Successful ablation, follow-up 12 months
⊕⊕⊝⊝Quality of life, follow-up 12 months
⊕⊕⊕⊕Side effects
- Consensus
- Strong consensus (96%)
- References
- [709]
In high-risk patients, TSH secretion should be stimulated endogenously, provided there are no contraindications to hypothyroidism.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- ⊕⊕⊕⊝
Endogenous TSH stimulation
- Consensus
- Strong consensus (96%)
- References
- [709]
For radioiodine therapy after surgery, TSH stimulation is required to optimize iodine uptake into the residual thyroid tissue. This can be achieved either by hormone deprivation (endogenous) or by injection of thyrotropin alpha (recombinant TSH = rhTSH). Thyrotropin alpha is not approved for metastasis therapy, but aims to ablate residual thyroid tissue.
In the case of endogenous stimulation, the effectiveness of ablative radioiodine therapy and radioiodine therapy of metastases depends on the TSH level; a TSH > 30 mU/l is favorable. This TSH level is usually reached 2 - 3 weeks after thyroidectomy or 4 - 5 weeks after discontinuation of levothyroxine (T4) medication. In order to shorten the period of hormone abstinence, a bridging 1 to 2-week triiodothyronine (T3) medication can be given up to 2 weeks before radioiodine therapy after discontinuation of levothyroxine medication, although an improvement in quality of life through bridging triiodothyronine administration has not been proven [710].
Fu et al. published a meta-analysis of 7 randomized controlled trials and 1,325 patients [709]. The results compared thyroid hormone withdrawal versus thyrotropin alpha. The thyroid restablation rate was not significantly different between the two methods (OR 0.87, 95%CI 0.56-1.37, p=0.56). Significantly different were aspects of quality of life with a mean difference of 3.59, 95%CI 2.81-4.37, p < 0.00001) on a scale of 0 to 100 as well as adverse events during and after ablation (OR 0.57, 95% CI 0,44 to 0.73, P<0.00001) and radiation exposure of blood and bone marrow (mean difference -0.01, 95% CI -0.02 to -0.01, P<0.00001), the associated higher irradiation of tumor tissue could not be recorded for methodological reasons. In addition, no significant difference in the successful ablation rate was found between the low activity (1.11 GBq and 1.85 GBq) and the higher activity (3.7 GBq) of radioiodine using rhTSH (OR 0.85, 95% CI 0.49 to 1.47, P=0.56). There were no deaths and no serious adverse effects in DTC patients treated with either rhTSH or THW. Thyrotropin alpha is thus as effective as hormone deprivation in radioiodine ablation of thyroid remnants, with significant benefits in health-related quality of life, adverse effects during and after ablation, and reduced whole-body radiation exposure [709]. This justifies the preferred use of thyrotropin alpha in patients with a low risk of recurrence (recommendation [5.60]).
In the case of certain comorbidities such as cardiopulmonary diseases, diabetes mellitus, renal insufficiency, neurological and psychiatric diseases (e.g. manic-depressive illness or schizophrenia) and bilateral recurrent paresis (risk of glottic edema in the case of severe hypothyroidism), several weeks of hormone abstinence with the consequence of manifest hypothyroidism is not indicated. In these situations, thyrotrophin alpha is the stimulation method of choice. In patients with a hypothalamic/pituitary disorder in the thyroid hormone control circuit, treatment with thyrotrophin alpha is the only way to achieve sufficient TSH stimulation. The medication history is also important, as prolonged hypothyroidism increases (e.g. lithium) or decreases (e.g. anticoagulants) the effect of individual medications [711]. In a retrospective study, Gomes-Lima et al. showed that preparation with endogenous and exogenous TSH stimulation made no difference in PFS or OS even in high-risk patients with limited follow-up time.
In the publication by Fu et al. [709], special reference should be made to two prospective studies: HiLo with 438 patients [676] and ESTIMABL with 752 patients [712]. These prospective studies compared the efficiency of residual tissue elimination in terms of "ablative" therapy. The inclusion criteria varied between the studies and mainly included patients with pT1-T3 tumors, N0 or Nx. The definitions of successful ablation were not homogeneous. Distant metastases (M1) were regularly an exclusion criterion. Therefore, hormone deprivation is preferred for patients with a high risk of recurrence or for metastasis therapy, as a higher focal or tumor dose can be expected with hormone deprivation [713], [679]. The statement that lower and higher therapy activities bring the same success is also not homogeneous. In fact, the HiLo study in the thyrotrophin alpha group showed a 6 percentage points worse ablation success in the low-dose group (1.1 GBq ¹³¹I) compared to the group treated with 3.7 GBq ¹³¹I. Therefore, the selected therapy activity should be based on the risk of recurrence.
5.8.6.9 Laxatives
To reduce radiation exposure, a (mild) laxative should be used and the bladder emptied frequently in the first few days after application of the therapy activity.
- Consensus
- Strong consensus (100%)
Adequate fluid intake and regular emptying of the bladder reduce radiation exposure. Laxatives can be used to regulate the stool and also aim to reduce radiation exposure; in addition, the informative value of ¹³¹I whole-body scintigraphy is improved due to less non-specific intestinal accumulation. Drug intervention must be considered in relation to possible side effects. It is obvious that a shorter dwell time of the activity in the body and close to the gonads reduces the dose. Therefore, the indication for laxatives can be generous in terms of radiation protection. Lactulose syrup is suitable as a (mild) laxative (10-20 ml), possibly in combination with dimethicone (sab simplex). Alternatively, lecicarbon suppositories or sodium picosulphate (drops/suppositories/tablets) can be used. As far as the bladder is concerned, a good filling is already very helpful due to the self-shielding effect. Even more important than frequent emptying is therefore a good fluid intake, taking into account individual patient factors (e.g. cardiac or renal insufficiency).
5.8.7 Therapy activity in radioiodine therapy
For radioiodine therapy, the activity of ¹³¹I should be selected in a risk-adapted manner, so that the therapeutic success is achieved as far as possible through single-stage radioiodine therapy. If metastasis is known, higher therapy activities can be given.
Table 18: The table shows the range usually depending on the risk of the therapy activities used.
| Risk classification | Activity of ¹³¹I |
| Papillary microcarcinoma (PTC pT1a, PTMC) without risk factors | No RIT |
| Papillary microcarcinoma (PTMC) with risk factors | 1.0 - 4.0 GBq |
| PTC pT1b | 1.0 - 4.0 GBq (individual decision) |
| PTC pT2 | 1.0 - 4.0 GBq |
| PTC pT3 | 2.0 - 5.5 GBq |
| PTC pT4 | 3.5 - 7.5 GBq |
| PTC, aggressive histologic subtypes | 2.0 - 7.5 GBq |
| PTC Nx / N1 | 2.0 - 7.5 GBq (with N1 persistence up to 12 GBq) |
| PTC M1 | 5.5 - 12 GBq (or individually or dosimetry-controlled with a target dose of ≥ 100 Gy in the tumor, taking into account bone marrow and lung tolerances) |
| FTC, minimally invasive, without vascular invasion | No RIT |
| FTC, minimally invasive, with vascular invasion | 3.5 - 7.5 GBq |
| FTC, grossly invasive | 3.5 - 12 GBq (or individual or dosimetry-guided with a target dose of ≥ 100 Gy in the tumor, taking into account bone marrow and lung tolerances) |
Studies on radioiodine therapy usually focus on the ablation of residual thyroid tissue that remains after thyroidectomy, but which still produces thyroglobulin and thus makes thyroglobulin-based follow-up at least more difficult if it is left in place. In these studies, different therapeutic activities were compared in order to achieve a defined ablation success. A "low-dose" activity is usually defined as 1 GBq (27 mCi) or 2 GBq (54 mCi), while a "high-dose" activity is defined as 3.7 GBq (100 mCi) or an even higher radioiodine activity. The definition of ablation success varies between studies. It is usually defined as an unremarkable ¹³¹I whole-body scintigraphy 6 to 12 months after radioiodine therapy and a stimulated (rhTSH) thyroglobulin level below a certain threshold, which is sometimes below the functional assay sensitivity and sometimes below 1 or 2 ng/ml.
Ma et al. studied 278 evaluable Chinese PTC or FTC patients with stage T1 to T3, N0 or Nx or N1, M0 tumors, of which 155 patients had received 1.85 GBq (50 mCi) and 123 patients had received 3.7 GBq (100 mCi) [714]. Ablation success was defined by a thyroglobulin value of ≤ 2 ng/ml 6 or 9 months after radioiodine therapy. This was achieved by 87.1% in the "low dose" group and 89% in the "high dose" group; this was not statistically significantly different (p = 0.569). A second ablation was required by 27 patients (17.4%) in the low dose group and 17 patients (13.8%) in the high dose group. No recurrences occurred during the 2 to 3-year follow-up. Changes in blood count, liver or kidney function were seen in less than 4.1% of patients and were not significantly different between the groups. Side effects such as nausea, taste changes, or salivary gland dysfunction were not investigated in this study.
Qu et al. examined the effects between a "low-dose" group treated with 1.1 GBq (30 mCi) and a "high-dose" group that received 3.7 GBq (100 mCi) of radioiodine [715]. The patients had a differentiated thyroid carcinoma with a low or intermediate risk of recurrence T1 N0-1M0. In the low-dose group 53/66 patients (80%) and in the high-dose group 56/66 patients (85%) had an excellent response. The remaining patients had an intermediate (13/66 in the low-dose group and 7/66 in the high-dose group) or biochemically incomplete (0/66 in the low-dose group and 3/66 in the high-dose group) response. The differences were not significant (p = 0.087). Patients with lymph node metastases (N1b) had significantly worse ablation results. Side effects were higher in the high-dose group (39%) than in the low-dose group (18%).
In their study, Jin et al. chose staggered treatment activities of 1.1, 1.85, 3.7 and 5.5 GBq radioiodine depending on the radioiodine uptake (≤2%, 2-5%, 5-15%, > 15%) and the thyroglobulin level (≤ 2, 2-5, 5-10, > 10 ng/ml) [717]. 215 patients with differentiated thyroid carcinoma were treated; patients with distant metastases were excluded. In addition, there was a group of 62 patients with fixed therapy activity of 3.7 GBq radioiodine. The radioiodine uptake was measured after application of 0.185 MBq radioiodine. If the radioiodine uptake and the thyroglobulin value were not in the same category, the next higher therapy activity was applied. Successful radioiodine therapy was defined as a negative whole-body scintigraphy and a stimulated (rhTSH) thyroglobulin value below 1 ng/ml (TgAb negative) or only a negative whole-body scintigraphy with positive thyroglobulin antibodies at the earliest 6 months after radioiodine therapy. The success rate between the groups was not statistically significantly different between the groups (p = 0.543). In contrast, the rate of side effects was lower in patients treated according to radioiodine uptake and thyroglobulin levels. This was particularly true for xerostomia, with 9.2% in the group treated according to radioiodine uptake and thyroglobulin level versus 19% (p = 0.038) in the group treated with 3.7 GBq radioiodine.
Shengguang et al. published a meta-analysis of 14 randomized controlled trials. Three groups were compared according to treatment activity (1.1 GBq versus 1.85 GBq versus 3.7 GBq, corresponding to 30, 50, and 100 mCi) [716]. When comparing 1.1 with 1.85 GBq and 1.85 and 3.7 GBq radioiodine, there were no significant differences. The comparison of 1.1 with 3.7 GBq showed a 5% lower rate of successful residual tissue ablation. The analysis showed that 3.7 GBq (100 mCi) radioiodine is favored in Europe, especially when the extent of surgery was not a total thyroidectomy and residual thyroid tissue was still present after incomplete resection. The rate of side effects was not investigated.
These studies justify the recommendation [5.32] on the choice of treatment activity so that, depending on the extent of resection, an excellent response is achieved with a single radioiodine therapy if possible and a second ablation therapy is avoided. The studies ([714], [715], [717] and [716]) excluded metastatic patients and refer to the situation of "radioiodine ablation". For the success rate of residual tissue ablation therapy, there is an advantage for a higher activity with moderate quality of evidence, but also a margin for the choice of activity - side effects appear to be more frequent with higher activity with very low quality of evidence. Therefore, the recommendation leaves room for an individualized decision.
All studies investigate the ablation of healthy residual thyroid tissue. The success of treatment in terms of recurrence-free survival or overall survival is only marginally assessed at best.
Table Range & therapy risk reflects the necessary broad corridor to treat patients individually, especially if lymph node metastases or distant metastases are present. The main objectives of RIT are to achieve an excellent response, avoid recurrence and achieve very good long-term survival without reducing life expectancy compared to the normal population and, if possible, without impairing quality of life [718].
The available literature is heterogeneous in terms of patient population and treatment concepts. In some cases, only low-risk patients were included [719] but sometimes also T3 or stage III patients [720] and also patients with lymph node metastases [676]. The exclusion criterion was usually an M1 situation. The ablation criteria for success varied; sometimes an unremarkable sonographic examination of the neck, sometimes an unremarkable ¹³¹I whole-body scintigraphy, sometimes an unremarkable thyroglobulin value (< 1-2 ng/ml) or a combination of unremarkable imaging and thyroglobulin value were required. The timing of the ablation check also plays a role. A time interval of 6-12 months after the first RIT is usual.
In the ESTIMABL study (France), the residual tissue ablation success was 90% in the study arm with 1.1 GBq I-131 after thyrotrophin alpha and 92 to 94% in the three other study arms [721]. In the HiLo study (UK), residual tissue ablation was primarily successful in 84% of patients after 1.1 GBq ¹³¹I with thyrotrophin alpha; in the three other study arms, the success rates were 88 to 92%, which means a failure rate of 16% compared to 12% and 8% respectively [676].
No statements on the success of treatment with regard to progression-free long-term survival or overall survival can be found in these studies.
In a review, Andresen et al. compiled indications for RIT and a broad corridor of treatment activities. In high-risk patients, including those with positive surgical margins, gross extrathyroidal extension, lymph node involvement, subtotal thyroidectomy or > 5% uptake, higher-dose RIT offers better ablation rates and tumor control [722].
Jentzen et al. published that the lowest effective therapeutic activity for ablation of the thyroid remnant is around 2.2 GBq [723]. Verburg et al. reported poorer disease-specific survival (disease-free survival = DFS) after 15 years in the low-risk group 16.1% and in the high-risk group 44.4%) when using treatment activities ≤ 2.0 GBq I-131 [724]. Long-term data on recurrences are rather sparse: Kukulska et al. report an equivalence of results 5 years after RIT, but 22% of the patients treated with 1.1 GBq required a second RIT compared to 11% of the patients treated with 3.7 GBq [725]. The table summarizes typical risk-adapted therapy activities.
5.8.8 ¹³¹I-Whole-body scintigraphy / ¹³¹I-SPECT/CT
A whole-body scintigraphy, possibly supplemented by a SPECT/CT, shall be carried out for every radioiodine therapy.
- Consensus
- Consent (88%)
In addition to therapy monitoring, radiation protection legislation requires that a maximum of diagnostic information is obtained from a radiation application. Scintigraphic visualization of the therapy activity distribution is therefore mandatory. Scintigraphy using therapy activity enables highly sensitive localization and activity assessment of residual thyroid tissue and distant metastases. The detection of local lymph node metastases is also possible - with decreasing sensitivity with increasing proximity to the residual tissue.
Due to the high probability of lymphogenic metastasis, iodine-avid lymph node metastases are found more frequently after adjuvant RIT using modern nuclear medicine imaging, in particular SPECT/CT. Miller et al. investigated how frequently lymph node metastases could be found after thyroidectomy with ¹³¹I-SPECT/CT in the context of RIT. 146/352 patients at intermediate or high risk (41.5%) had lymph node metastases on diagnostic ¹³¹I scintigraphy [726]. Spanu et al. confirmed the higher number of iodine-avid lymph node metastases by SPECT/CT compared to planar ¹³¹I whole-body scintigraphy [727]. SPECT/CT therefore has a high diagnostic value for the detection and precise localization of iodine-avid metastases.
In a group of 320 thyroid cancer patients referred for postoperative RIT, Avram et al. showed that diagnostic imaging with ¹³¹I including SPECT/CT after thyroid hormone withdrawal (THW) visualized regional metastases in 35% and distant metastases in 8% of cases. TNM staging was altered by this imaging in 4% of younger and 25% of older patients [728]. Avram et al. reported that such information changes the risk classification in about 15% of patients and changes the clinical management in about 30% of patients [729]. This statement is confirmed by studies by Szujo et al. that SPECT/CT can provide a gain in diagnostic information compared to planar whole-body scintigraphy [730].
In another study by Avram et al., postoperative ¹³¹I imaging data and stimulated thyroglobulin levels provided information that changed the treatment of patients in 29% of cases compared to the original strategy based on surgical pathology information and clinical information alone [731]. Banerjee et al. reported that the use of ¹³¹I whole-body scintigraphy was associated with better disease-specific survival due to improved diagnostics [732].
SPECT/CT therefore aims to detect iodine-avid lymph node metastases that escape planar imaging due to superimposition effects. If this examination modality is not available, it should be examined whether iodine accumulations can be morphologically correlated post-therapeutically by using MRI, for example.
5.8.9 Response evaluation using ¹³¹I whole-body scintigraphy / ¹³¹I-SPECT/CT + stimulated thyroglobulin value
After radioiodine therapy, monitoring shall be carried out at 3 - 6 monthly intervals using sonography, determination of hsTg (highly sensitive Tg assay), TgAb and thyroid-specific hormones, initially for a period of 12 to 24 months.
- Consensus
- Strong consensus (95,7%)
In the case of TgAb positivity and an initially medium or high risk of recurrence, a ¹³¹I whole-body scintigraphy shall be performed after 6 - 12 months.
- Recommendation grade
- A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
- Level of evidence
- 2a
- Consensus
- Strong consensus (100%)
- References
- [733]
A ¹³¹I whole-body scintigraphy should be dispensed with if the initial RIT has already produced an excellent result and if hsTg values are undetectable over the course of time or if hsTg values are falling at a low level.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2a
- Consensus
- Strong consensus (100%)
- References
- [733]
The response evaluation of radioiodine therapy is carried out using ¹³¹I whole-body scintigraphy and stimulated tumor marker thyroglobulin. This allows classification into response classes with excellent, acceptable, biochemically incomplete and structurally incomplete response, which has consequences for further aftercare and therapy (see Chapter How should follow-up care be provided for proven differentiated and poorly differentiated thyroid cancer? and Chapter Terminology of treatment response and risk assessment for recurrence of DTC). In Germany, the need to check the success of treatment is a result of the general nuclear medicine treatment standard and is stipulated in the Radiation Protection Act and the Radiation Protection Directive. The quality assurance of nuclear medicine treatments requires that the data of all patients are reviewed by the treating physician with regard to their treatment outcome [535], [536], [734], [537]. Iodine-avid metastases can escape detection during initial radioiodine therapy if there is a strongly accumulating thyroid remnant that outshines weaker accumulating metastases ("stellate artifact"). These are then only detectable after elimination of the residual thyroid tissue in the subsequent ¹³¹I whole-body scintigraphy after rhTSH stimulation. An inconspicuous ¹³¹I whole-body scintigraphy and a stimulated thyroglobulin value below the functional assay sensitivity are a desirable therapeutic goal and document an excellent response [735].
Over the years, increasingly sensitive thyroglobulin assays have been developed. Therefore, Giovanella et al. [733] analyzed whether an inconspicuous basal (i.e. non-stimulated) thyroglobulin value makes a ¹³¹I whole-body scintigraphy unnecessary, because such a result of the thyroglobulin measurement suggests an inconspicuous ¹³¹I whole-body scintigraphy or makes the later occurrence of a relapse very unlikely. Giovanella et al. analyzed 10 retrospective studies with 1,796 DTC patients (1,542 PTC and 151 FTC patients), of which 8 retrospective studies with 1,568 DTC patients investigated the diagnostic significance of a non-stimulated thyroglobulin value under ongoing levothyroxine medication. The functional assay sensitivity of the assays used was between 0.03 and 0.1 µg/l. The methods used to rule out metastases and serve as the "gold standard" varied between studies and included sonography, chest X-ray, CT, MRI, PET, fine needle aspiration, sestamibi scintigraphy and iodine-131 whole-body scintigraphy. Accordingly, there was only a low positive predictive value of 21.3% (95% CI 11.9-30.7%). In contrast, there was a very good negative predictive value of 99.4% (95% CI 98.9-99.9%). Five studies made it possible to investigate the prognostic significance with regard to the occurrence of recurrences with median follow-up periods of 23 to 64 months. Here too, the negative predictive value was 99.4% (95%CI 98.8 - 100%). It should be emphasized that in 8 studies, only patients with negative thyroglobulin antibodies were included. If patients test positive for thyroglobulin antibodies, there is a risk of false negative thyroglobulin measurements. This justifies recommendation [5.65], that in TgAb-positive patients, ¹³¹I whole-body scintigraphy should continue to be used for response evaluation, and recommendation [5.66], that in patients with an initially medium or high risk of recurrence, ¹³¹I whole-body scintigraphy should not be dispensed with, because the studies predominantly examined patients with low tumor stages and the evidence for higher tumor stages is low. If, on the other hand, there is already an excellent therapeutic result after the initial radioiodine therapy or if a thyroglobulin value below the functional assay sensitivity (< 0.1 - 0.2 ng/ml) is found in patients at low risk of recurrence, ¹³¹I whole-body scintigraphy can be dispensed with [733]. It should be noted that the collectives examined in the individual studies were heterogeneous. In the two German publications [736] and [737], patients were included who had received one or two high-dose radioiodine therapies and subsequently had an unremarkable ¹³¹I whole-body scintigraphy, so it is not surprising if a negative ¹³¹I whole-body scintigraphy results in an unmeasurable thyroglobulin value after such initial therapy and follow-up care.
5.8.10 Side effects of radioiodine therapy
In general, RIT is a well-tolerated therapy with few side effects. A distinction is made between early side effects occurring soon after administration of the radioiodine and late long-term side effects, which occur with varying frequency in children and adults. The risk of side effects and their possible intensity depend, among other things, on the level of activity applied. The side effects described below primarily concern recurrence and metastasis therapies in which high cumulative therapy activities are used.
5.8.10.1 Early/acute side effects
Radiogenic gastritis
Radiogenic gastritis can occur transiently (for a few hours); the main symptom is nausea with a frequency of <5% to 60% [738], [739], [740]. In patients with a corresponding predisposition, gastroprotection should be considered before treatment; alternatively, symptom-oriented treatment is carried out if radiogenic gastritis occurs.
Radiogenic thyroiditis
Radiogenic thyroiditis is a transient, painful local swelling of the postoperative thyroid remnant/tumor remnant/metastases that usually lasts only a few hours. The reported frequency varies greatly between approx. 5-50% and is primarily dependent on the residual tissue mass after the surgery [741], [742]. This side effect is rare in thyroidectomies performed according to oncological aspects. Therapy is carried out with ice packs and, if necessary, with anti-inflammatory medication. Radiogenic thyroiditis is easily treatable.
Sialadenitis/later xerostomia
RIT causes irradiation of the salivary glands, which can lead to sialadenitis. This depends on the therapy activity and is reported in <5% of patients, sometimes with a frequency of 12.8% - 33% [743], [744], [745], [742], [746]. This side effect occurs more frequently primarily during activities above adjuvant therapy [747]. Clinically, there is pain and swelling in the area of the parotid gland, sometimes with transient changes in taste [747], [748], [718]. The symptoms are predominantly transient. However, persistent damage is also observed. In a complex dosimetric study, Jentzen et al. showed an average salivary gland radiation dose so low that deterministic damage is not to be expected with normal treatment activities. The study showed that chewing leads to a considerable excretion of activity and thus a reduction in dose [707]. Numerous medications have an effect on the salivary glands, so that such a cause should also be sought [749].
Xerophthalmia/later sicca syndrome
Lacrimal gland dysfunctions are reported with frequencies of <5%, sometimes with 4.1% - 22.1% [743], [741], [748]. Fard-Esfahani et al. showed a significant difference in the symptoms of a "burning sensation" and eye redness after RIT, the Schirmer test was significantly lower after RIT (p = 0.016). However, there was no correlation between the Schirmer test and the ¹³¹I activity administered [750], a result that casts doubt on causality with RIT. Irradiation of the lacrimal glands was reported to cause tearing ("epiphora") [748]. Since a sicca syndrome can also occur independently of RIT and a clear dependence on activity cannot be proven, a causal relationship cannot be clearly established.
Blood count changes
Grünwald et al. described blood count changes (Hb ≤ 9.0 g/dl in women / 10.5 g/dl in men, or erythrocytes ≤ 3.1 x 1012/l in women / 3.5 x 1012/l in men, leukocytes ≤ 2.5 x 109/l, thrombocytes ≤ 0.5 x 1011/l) in only 5/469 (1.1%) patients who were treated cumulatively with up to 18.5 GBq ¹³¹I. At higher therapy activities (18.5-37 GBq ¹³¹I), only 1/77 patients (1.3%) showed blood count changes. These changes were without clinical relevance [751].
Tumor/metastasis swelling
Rare individual cases of tumor/metastasis swelling have been described. Neurological symptoms as compression syndrome or possibly (also independent of RIT) as hemorrhage in spinal or cerebral metastases [752], [753], [754]. In the presence of metastases in critical locations, prophylactic glucocorticoid administration or additional local therapy should be considered.
5.8.10.2 Late/chronic side effects
Side effects that occur acutely can persist or occur late.
- Consensus
- Strong consensus (96%)
Chronic xerostomia/chronic sialadenitis
Chronic inflammation of the salivary glands can lead to a reduction in function, possibly with a change in taste and an increased risk of caries. The frequency of chronic xerostomia reported in the literature varies considerably between <5% with ranges of 5.4% - 72% [755], [745], [748]. Examination times and methods vary in the literature and are not very standardized [741], [744], [748]. Clement et al. reported symptomatic salivary gland dysfunction with a prevalence of 16-54%. Abnormal salivary gland scintigraphy findings were reported with a prevalence in the range of 37 - 72% [741]. However, the extent of dysfunction is difficult to determine due to differences in definition and the lack of a gold standard. There are clear differences between the results of a salivary gland scintigraphy and the patient's perceived symptoms. Jeong et al. showed a significant correlation between the salivary gland dysfunctions observed by scintigraphy and their symptoms. Nevertheless, in their study, patients classified as asymptomatic were also in the groups with moderate to severe decrease in uptake score (29% asymptomatic) and ejection fraction (60% asymptomatic) [756]. Klein-Hesselink et al. were able to demonstrate a decrease in saliva production after RIT in a group of 67 patients, 21% of patients reported frequent or constant xerostomia, although 7.5% of patients already had these complaints before RIT [757]. Solans et al. described xerostomia in 32.9% of patients in the first year after RIT, after 3 years in 15.2% of patients, 5.1% of patients developed severe xerostomia [758]. Hyer et al. reported chronic swelling and pain in the area of the salivary glands in 21.1% of patients; in 12% of patients, these symptoms did not develop until 3 months after treatment [745].
In a study by An et al., 29.7% of patients showed signs of sialadenitis in the late phase (median 336 days after treatment), 66% of these patients already showed these in the early phase (7 days post RIT) [755].
In a study by Rosario et al., 5.4% of patients reported symptoms of salivary gland hypofunction or inflammation after 12 months [748]. According to Clement et al., a correlation between the administered ¹³¹I activity and the salivary gland scintigraphy findings was found in all 6 studies examined; 3 out of 5 studies also showed a correlation in symptomatic salivary gland dysfunction [741].
Wu et al. found no unfavorable effects with regard to xerostomia in activities up to 5.5 GBq (150 mCi) ¹³¹I [759]. In the case of taste changes and xerostomia, it should be noted that there are a number of drug influences; statements on concomitant medication are often missing in the above-mentioned studies [749].
Chronic xerophthalmia/sicca syndrome
Chronic lacrimal gland dysfunction is rare, but is reported by some authors with frequencies of 4.1% - 22.1%. [743], [741], [748]. Solans et al. described xerophthalmia in 25.3% of patients in the first year after RIT with improvement over time. Keratoconjunctivitis sicca was still present in 7.6% of patients 3 years after RIT. Reductions in lacrimal gland function can be reversible [758]. Jonklaas et al. report a frequency of approx. 10% of nasolacrimal complaints [760]. This raises the question of a selection phenomenon, because side effects of this type or frequency have not been published for RIT in German-speaking countries and a convincing connection between applied activity and functional impairment cannot be proven.
Bone marrow depression with thrombocytopenia and neutropenia
Bone marrow depression with thrombocytopenia and neutropenia is relatively rare. The frequency depends on the cumulative activity. Grünwald et al. described that at very high therapy activities above 37 GBq ¹³¹I, platelet formation is impaired, pancytopenia was observed in 4 patients [751]. The bone marrow dose with potentially resulting complications is also influenced by renal function, which is why the creatinine value and renal function should be known in addition to the differential blood count before RIT. A significant decrease in leukocytes and thrombocytes was described within the first year after RIT by Molinaro et al. [761]. Prinsen et al. described transient decreases in leukocytes and platelets up to one year after RIT with normalization of values up to 5 years after RIT. 4.2% of patients developed thrombocytopenia, risk factors were older age, male gender and the cumulative dose, relevant (long-term) side effects were not found [762].
It should be noted that the studies were generally retrospective studies and the side effects were not objectified or quantified. There is also often a lack of information on treatment activity and further treatment such as percutaneous radiotherapy. The rate and intensity of side effects depends on the treatment activity. The side effects mentioned are primarily observed in high-dose therapy for targeted treatment of recurrence/metastases. If a study does not explicitly describe a dose dependency of the side effect, a causal relationship between RIT and the side effect described is not plausible.
5.8.10.3 Secondary malignancies after radioiodine therapy
A certain risk of secondary malignancies due to RIT can be assumed in principle. The risk of secondary malignancies depends on the cumulative dose and the age at exposure and could only be proven in large case series with cumulative activities above 5.5 GBq ¹³¹I. In patients with a low risk of recurrence, the radiation risk should be taken into account when weighing up the individual benefit/risk of RIT.
Radiation experts assume a linear risk model. This means that the risk of cancer induction is proportional to the radiation dose and there is no threshold. This linear model has been proven above about 100 mSv and there are no studies for lower doses. On this basis, a lifelong additional risk of secondary carcinoma is expected after radioiodine therapy, depending on age and actual exposure. In athyroid adults, the doses typically expected in risk-relevant organs are usually between 40 and 90 mGy per GBq ¹³¹I [765], but vary depending on body size and kidney function and can be higher, especially in older people. At these low radiation doses, a latency period of up to decades can be assumed.
Nappi et al. published a systematic review and meta-analysis on the risk of breast cancer due to radioiodine therapy [763]. 14 studies with a total of 200,247 patients with differentiated thyroid carcinoma were identified, of which 98,368 were treated with radioiodine and 101,879 without radioiodine. The relative risk with compared to without radioiodine therapy was 0.83 (95%CI 0.70 - 0.99) with a range of 0.45 - 2.55. Thus, no increased carcinoma risk was found for the particularly radiosensitive organ after radioiodine therapy.
Reinecke et al. analyzed the risk of secondary malignancies due to radioiodine therapy [764]. In 10 studies, the risk increase for secondary malignancies was 1.14 to 1.84 when comparing patients treated with radioiodine therapy with comparison collectives without radioiodine therapy, whereby in 5/7 studies, in which the 95% confidence interval was given, a value of 1.0 was included and only in 2/7 studies a value of 1 was exceeded (Silva-Vieira RR for SPM 1.84, 95% CI 1.02 - 3.31 and Molenaar SIR for SPM 1.30, 95% CI 1.12 - 1.51). However, most of the results were not statistically significant. It should be noted that these studies and the studies cited below are not limited to adjuvant radioiodine therapies, but also included high-dose therapies. In seven out of eight studies, the risk increased - as expected - with increasing cumulative treatment activity. The studies did not take into account whether the patients received percutaneous radiotherapy. Furthermore, a bias due to more intensive examinations after diagnosis of thyroid carcinoma is to be expected. This is always the case if the secondary carcinoma is diagnosed within the latency period for the development of a radiation-induced malignancy. Taking into account the low quality of the studies, the risk of secondary malignancies is therefore considered to be low at best and justifies the above recommendation.
Further, non-systematic studies show a low but statistically significant higher probability of secondary carcinoma with higher treatment activity. For example, Silva-Vieira et al. found a small but significant increase in the risk of secondary malignancies from a cumulative activity of 7.4 GBq ¹³¹I [766], Teng et al. from a cumulative activity of 5.6 GBq [767]. The rate of percutaneous irradiation is unknown.
Hematological diseases and the risk of leukemia are discussed in detail below, as a higher radiation risk is expected for these than for solid tumors. Molenaar et al. found a higher risk after RIT (RR: 1.30 [95% CI: 1.12-1.51]) based on 148,215 patient data from the SEER registry [768], [769]. These results are in line with the results of Rubino's working group, even if they are not statistically significant (RR: 2.5 [95% CI: 1.0-7.4]) [770]. The absolute number of hematologic diseases caused by RIT is given by Rubino et al. as 0.8 cases per GBq radioiodine and 100,000 person-years and is thus in the very low range. However, it is not known whether these patients also received percutaneous radiotherapy. With regard to a dose-response relationship, Seo et al. were able to demonstrate a significantly increased, but in absolute terms low risk only above 3.7 GBq ¹³¹I activity in 211,360 participants [771]. However, with a median follow-up of 2.4 years, these results should be viewed with caution, as a longer latency period is to be expected for secondary malignancies and the data are therefore likely to represent a screening bias.
Korean data on 211,360 patients examined the risk of leukemia after radioiodine therapy. No increased leukemia rate was observed in the group with activities up to 3.7 GBq ¹³¹I. However, an increased leukemia rate was seen in the group of patients who were treated with a higher activity and who were therefore in an advanced tumor stage. In this group, 1 in 2,000 patients developed leukemia. At 8 months, the latency phase until leukemia developed was so short [771] that a causal relationship with RIT can be virtually ruled out. Depending on the activity used and the follow-up period, there are studies that found no increased leukemia rate [772], [773], [774] and others that describe a slightly increased leukemia rate [770], [775]. Rubino et al. analyzed three large cohorts from Sweden, France and Italy and found 3 additional leukemias per 10,000 patients (0.03%, RR = 2.5) [770]. Sawka et al. reported a slightly increased leukemia rate with a relative risk of 2.5 as well [775].
The risk of secondary malignancies is considered slightly higher in children. Seo et al. reported on 18,617 children and young adults treated for differentiated thyroid carcinoma in South Korea [776]. During the 120,474 person-years of follow-up, a total of 124 cases of secondary malignancies occurred; 43 (0.5%) in the operated patients and 81 (0.8%) in the cohort additionally treated with RIT. The RIT cohort thus showed a slightly increased risk of secondary malignancies (adjusted HR 1.52 [95% confidence interval 1.03-2.24], p = 0.035).
5.8.10.4 Pulmonary fibrosis
In the case of disseminated lung metastasis, lung function tests should be performed when using high cumulative therapy activities due to the possible development of pulmonary fibrosis.
- Consensus
- Strong consensus (96%)
Radiation-induced pneumonitis and subsequent pulmonary fibrosis in radioiodine-positive pulmonary metastases occur rarely in patients with pulmonary metastasis and depend on the cumulative treatment activity and the extent of pulmonary metastasis (approx. 1%) [777], [778]. Diffuse pulmonary metastasis can be dose-limiting for radioiodine activity [779], [780], [781], [782]. Patients who develop pneumonitis should be monitored more intensively in order to be able to initiate therapeutic steps in good time in the event of progressive, potentially life-threatening symptoms, such as glucocorticoid therapy, e.g. high doses of 1 mg/kg body weight prednisolone daily for 2-4 weeks [783], [784]. The presence of pulmonary fibrosis can limit the implementation of further RIT cycles [785], [786].
5.8.10.5 Cardiovascular system
In a retrospective cohort study of 4,845 patients in Korea, Kim et al. found no negative effects of RIT (mean treatment activity 3.8 GBq ¹³¹I) with regard to the occurrence of ischemic or hemorrhagic apoplexy, coronary heart disease, or heart failure. 2,533 patients with thyroid carcinoma and RIT were compared with the remaining patients who did not receive RIT [787].
5.8.10.6 Side effects in children
The possible side effects of RIT do not differ in their main features between children and adults. Albano et al. reported on 302 treatment cycles in 105 children. The treatments were given in a metastatic situation with correspondingly high activity. Early side effects were reported in 35% of patients, mainly nausea in 29% and sialadenitis in 22% of patients. Transient blood count changes occurred in 6%. Late side effects were significantly less frequent in only 11% of patients, 2 patients showed sialadenitis, 4 patients permanent blood count changes, 5 patients each showed pulmonary fibrosis and fertility disorders (between 2 and 7%) [788].
Brown et al. reported in their work that there is a slightly increased risk of second malignancies after RIT for younger patients [789]. It remained unclear whether repeated therapies with higher cumulative activities occurred here. In a study by Hay's team, which only examined pediatric patients, a number of second malignancies and increased mortality between the ages of 30 and 50 were described, with 68% of deaths resulting from a second malignancy [467].
In an analysis of the SEER database, Marti et al. also showed an increased risk of second malignancies for pediatric patients and patients <25 years of age. Of the 1,571 children treated with radioiodine, 26 children (1.7%) were diagnosed with a secondary malignancy; this would have been statistically expected in 18 children compared to the healthy population as a whole. The increased risk of secondary malignancies was mainly due to the fact that 3 children developed salivary gland carcinoma, statistically only 0.9 children should have been affected [774]. Overall, it should be noted that few patients are reported to be affected by secondary malignancies.
Further studies express the suspicion that prepubertal testes react more sensitively to the effect of radiotherapy, which is why cryopreservation of sperm should be discussed individually in pubertal patients [790]. The risk of pulmonary fibrosis in pediatric patients with extensive lung metastases is more age-dependent than in adults, which is why pre-therapeutic dosimetry can be discussed in these cases [791]. Pasqual et al. reported a slightly increased risk of secondary malignancies in children treated with RIT, especially in a period of 20 years after RIT. This concerned uterine carcinomas
References
[340] Musholt, T. J., Bockisch, A., Clerici, T., Dotzenrath, C., Dralle, H., Goretzki, P. E., et.al. Aktualisierung der S2k-Leitlinie, 2018. 89(9): p. 699 - 709., https://doi.org/10.1007/s00104-018-0653-y
[341] Robbins, KT, Shaha, AR, Medina, JE, Califano, JA, Wolf, GT, Ferlito, A, et.al. Consensus statement on the classification and terminology of neck dissection., Arch Otolaryngol Head Neck Surg, 2008. 134 (5)(5): p. 536-8., https://pubmed.ncbi.nlm.nih.gov/18490577/
[342] Carty, SE, Cooper, DS, Doherty, GM, Duh, QY, Kloos, RT, Mandel, SJ, et.al. Consensus statement on the terminology and classification of central neck dissection for thyroid cancer., Thyroid, 2009. 19 (11)(11): p. 1153-8., https://pubmed.ncbi.nlm.nih.gov/19860578/
[343] Dralle, H, Damm, I, Scheumann, GF, Kotzerke, J, Kupsch, E, Geerlings, H, et.al. Compartment-oriented microdissection of regional lymph nodes in medullary thyroid carcinoma., Surg Today, 1994. 24 (2)(2): p. 112-21., https://pubmed.ncbi.nlm.nih.gov/8054788/
[344] Dralle, H., Lorenz, K., Machens, A., Chirurgie der Schilddrüsenkarzinome, 2009. 80(11): p. 1069 - 1084., https://doi.org/10.1007/s00104-009-1769-x
[345] Dralle, H, Machens, A, Lorenz, K, [Hereditary thyroid cancer]., Chirurg, 2008. 79 (11)(11): p. 1017-28., https://pubmed.ncbi.nlm.nih.gov/18818894/
[346] von Lanz, T., Wachsmuth, W., Praktische Anatomie, Hals, 1955. Volume 1 / 2:
[347] Földi, Michael;, Kubik, Stefan (Hrsg.), Lehrbuch LymphologieGustav Fischer Verlag, Für Mediziner und Physiotherapeuten, 1989.
[348] Shonka, DC, Ho, A, Chintakuntlawar, AV, Geiger, JL, Park, JC, Seetharamu, N, et.al. American Head and Neck Society Endocrine Surgery Section and International Thyroid Oncology Group consensus statement on mutational testing in thyroid cancer: Defining advanced thyroid cancer and its targeted treatment., Head Neck, 2022. 44 (6)(6): p. 1277-1300., https://pubmed.ncbi.nlm.nih.gov/35274388/
[349] Kelley, S, Beck, AC, Weigel, RJ, Howe, JR, Sugg, SL, Lal, G, Influence of endocrine multidisciplinary tumor board on patient management and treatment decision making., Am J Surg, 2022. 223 (1)(1): p. 76-80., https://pubmed.ncbi.nlm.nih.gov/34303521/
[350] El Saghir, NS, Keating, NL, Carlson, RW, Khoury, KE, Fallowfield, L, Tumor boards: optimizing the structure and improving efficiency of multidisciplinary management of patients with cancer worldwide., Am Soc Clin Oncol Educ Book, 2014. (): p. e461-6., https://pubmed.ncbi.nlm.nih.gov/24857140/
[351] Lamb, BW, Green, JS, Benn, J, Brown, KF, Vincent, CA, Sevdalis, N, Improving decision making in multidisciplinary tumor boards: prospective longitudinal evaluation of a multicomponent intervention for 1,421 patients., J Am Coll Surg, 2013. 217 (3)(3): p. 412-20., https://pubmed.ncbi.nlm.nih.gov/23891067/
[352] Miyauchi, A, Kudo, T, Ito, Y, Oda, H, Sasai, H, Higashiyama, T, et.al. Estimation of the lifetime probability of disease progression of papillary microcarcinoma of the thyroid during active surveillance., Surgery, 2018. 163 (1)(1): p. 48-52., https://pubmed.ncbi.nlm.nih.gov/29103582/
[353] Miyauchi, A, Chronology of Thyroid Cancer., World J Surg, 2023. 47 (2)(2): p. 288-295., https://pubmed.ncbi.nlm.nih.gov/36153411/
[354] Bibbins-Domingo, K, Grossman, DC, Curry, SJ, Barry, MJ, Davidson, KW, Doubeni, CA, et.al. Screening for Thyroid Cancer: US Preventive Services Task Force Recommendation Statement., JAMA, 2017. 317 (18)(18): p. 1882-1887., https://pubmed.ncbi.nlm.nih.gov/28492905/
[355] Robert-Koch-Institut, Krebs in Deutschland für 2017/2018, Zentrum für Krebsregisterdaten, 2018., https://www.krebsdaten.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/krebs_in_deutschland_inhalt.html?nn=2378942
[356] Christakis, I, Dimas, S, Kafetzis, ID, Roukounakis, N, Risk stratification of 282 differentiated thyroid cancers found incidentally in 1369 total thyroidectomies according to the 2015 ATA guidelines; implications for management and treatment., Ann R Coll Surg Engl, 2018. 100 (5)(5): p. 357-365., https://pubmed.ncbi.nlm.nih.gov/29484944/
[357] Miyauchi, A, Ito, Y, Oda, H, Insights into the Management of Papillary Microcarcinoma of the Thyroid., Thyroid, 2018. 28 (1)(1): p. 23-31., https://pubmed.ncbi.nlm.nih.gov/28629253/
[358] Ito, Y, Miyauchi, A, Oda, H, Low-risk papillary microcarcinoma of the thyroid: A review of active surveillance trials., Eur J Surg Oncol, 2018. 44 (3)(3): p. 307-315., https://pubmed.ncbi.nlm.nih.gov/28343733/
[359] Venkatesh, S, Pasternak, JD, Beninato, T, Drake, FT, Kluijfhout, WP, Liu, C, et.al. Cost-effectiveness of active surveillance versus hemithyroidectomy for micropapillary thyroid cancer., Surgery, 2017. 161 (1)(1): p. 116-126., https://pubmed.ncbi.nlm.nih.gov/27839930/
[360] Sugitani, I, Ito, Y, Takeuchi, D, Nakayama, H, Masaki, C, Shindo, H, et.al. Indications and Strategy for Active Surveillance of Adult Low-Risk Papillary Thyroid Microcarcinoma: Consensus Statements from the Japan Association of Endocrine Surgery Task Force on Management for Papillary Thyroid Microcarcinoma., Thyroid, 2021. 31 (2)(2): p. 183-192., https://pubmed.ncbi.nlm.nih.gov/33023426/
[361] Oh, HS, Ha, J, Kim, HI, Kim, TH, Kim, WG, Lim, DJ, et.al. Active Surveillance of Low-Risk Papillary Thyroid Microcarcinoma: A Multi-Center Cohort Study in Korea., Thyroid, 2018. 28 (12)(12): p. 1587-1594., https://pubmed.ncbi.nlm.nih.gov/30226447/
[362] Sugitani, I, Ito, Y, Miyauchi, A, Imai, T, Suzuki, S, Active Surveillance Versus Immediate Surgery: Questionnaire Survey on the Current Treatment Strategy for Adult Patients with Low-Risk Papillary Thyroid Microcarcinoma in Japan., Thyroid, 2019. 29 (11)(11): p. 1563-1571., https://pubmed.ncbi.nlm.nih.gov/31441377/
[363] Jeon, MJ, Kim, WG, Kwon, H, Kim, M, Park, S, Oh, HS, et.al. Clinical outcomes after delayed thyroid surgery in patients with papillary thyroid microcarcinoma., Eur J Endocrinol, 2017. 177 (1)(1): p. 25-31., https://pubmed.ncbi.nlm.nih.gov/28432268/
[364] Vuong, HG, Altibi, AMA, Duong, UNP, Hassell, L, Prognostic implication of BRAF and TERT promoter mutation combination in papillary thyroid carcinoma-A meta-analysis., Clin Endocrinol (Oxf), 2017. 87 (5)(5): p. 411-417., https://pubmed.ncbi.nlm.nih.gov/28666074/
[365] Ng, SC, Kuo, SF, Chen, ST, Hsueh, C, Huang, BY, Lin, JD, Therapeutic Outcomes of Patients with Multifocal Papillary Thyroid Microcarcinomas and Larger Tumors., Int J Endocrinol, 2017. 2017 (): p. 4208178., https://pubmed.ncbi.nlm.nih.gov/28642790/
[366] Chien, MN, Yang, PS, Lee, JJ, Wang, TY, Hsu, YC, Cheng, SP, Recurrence-associated genes in papillary thyroid cancer: An analysis of data from The Cancer Genome Atlas., Surgery, 2017. 161 (6)(6): p. 1642-1650., https://pubmed.ncbi.nlm.nih.gov/28237646/
[367] Song, JY, Sun, SR, Dong, F, Huang, T, Wu, B, Zhou, J, Predictive Value of BRAF, Curr Med Sci, 2018. 38 (5)(5): p. 785-797., https://pubmed.ncbi.nlm.nih.gov/30341513/
[368] Tong, M, Li, S, Li, Y, Li, Y, Feng, Y, Che, Y, Efficacy and safety of radiofrequency, microwave and laser ablation for treating papillary thyroid microcarcinoma: a systematic review and meta-analysis., Int J Hyperthermia, 2019. 36 (1)(1): p. 1278-1286., https://pubmed.ncbi.nlm.nih.gov/31826684/
[369] Chen, J, Cao, J, Qiu, F, Huang, P, The Efficacy and The Safety of Ultrasound-guided Ablation Therapy for Treating Papillary Thyroid Microcarcinoma., J Cancer, 2019. 10 (21)(21): p. 5272-5282., https://pubmed.ncbi.nlm.nih.gov/31602278/
[370] Chan, S, Karamali, K, Kolodziejczyk, A, Oikonomou, G, Watkinson, J, Paleri, V, et.al. Systematic Review of Recurrence Rate after Hemithyroidectomy for Low-Risk Well-Differentiated Thyroid Cancer., Eur Thyroid J, 2020. 9 (2)(2): p. 73-84., https://pubmed.ncbi.nlm.nih.gov/32257956/
[371] Sullivan, MC, Graham, PH, Alexander, EK, Ruan, DT, Nehs, MA, Gawande, AA, et.al. Prevalence of Contralateral Tumors in Patients with Follicular Variant of Papillary Thyroid Cancer., J Am Coll Surg, 2017. 224 (6)(6): p. 1021-1027., https://pubmed.ncbi.nlm.nih.gov/28017809/
[372] Joseph, KR, Edirimanne, S, Eslick, GD, Multifocality as a prognostic factor in thyroid cancer: A meta-analysis., Int J Surg, 2018. 50 (): p. 121-125., https://pubmed.ncbi.nlm.nih.gov/29337178/
[373] Kim, SK, Park, I, Woo, JW, Lee, JH, Choe, JH, Kim, JH, et.al. Total thyroidectomy versus lobectomy in conventional papillary thyroid microcarcinoma: Analysis of 8,676 patients at a single institution., Surgery, 2017. 161 (2)(2): p. 485-492., https://pubmed.ncbi.nlm.nih.gov/27593085/
[374] Liu, Z, Zhao, Q, Liu, C, Zeng, W, Ming, J, Chen, C, et.al. Is biopsy enough for papillary thyroid microcarcinoma?: An analysis of the SEER database 2004 to 2013 with propensity score matching., Medicine (Baltimore), 2018. 97 (31)(31): p. e11791., https://pubmed.ncbi.nlm.nih.gov/30075609/
[375] Adam, MA, Thomas, S, Hyslop, T, Scheri, RP, Roman, SA, Sosa, JA, Exploring the Relationship Between Patient Age and Cancer-Specific Survival in Papillary Thyroid Cancer: Rethinking Current Staging Systems., J Clin Oncol, 2016. 34 (36)(36): p. 4415-4420., https://pubmed.ncbi.nlm.nih.gov/27998233/
[376] Dal Maso, L, Tavilla, A, Pacini, F, Serraino, D, van Dijk, BAC, Chirlaque, MD, et.al. Survival of 86,690 patients with thyroid cancer: A population-based study in 29 European countries from EUROCARE-5., Eur J Cancer, 2017. 77 (): p. 140-152., https://pubmed.ncbi.nlm.nih.gov/28410490/
[377] Passler, C, Scheuba, C, Asari, R, Kaczirek, K, Kaserer, K, Niederle, B, Importance of tumour size in papillary and follicular thyroid cancer., Br J Surg, 2005. 92 (2)(2): p. 184-9., https://pubmed.ncbi.nlm.nih.gov/15685703/
[378] Noguchi, S, Yamashita, H, Uchino, S, Watanabe, S, Papillary microcarcinoma., World J Surg, 2008. 32 (5)(5): p. 747-53., https://pubmed.ncbi.nlm.nih.gov/18264828/
[379] Kwon, H, Jeon, MJ, Kim, WG, Park, S, Kim, M, Song, DE, et.al. A comparison of lobectomy and total thyroidectomy in patients with papillary thyroid microcarcinoma: a retrospective individual risk factor-matched cohort study., Eur J Endocrinol, 2017. 176 (4)(4): p. 371-378., https://pubmed.ncbi.nlm.nih.gov/28089996/
[380] Wu, ZG, Yan, XQ, Su, RS, Ma, ZS, Xie, BJ, Cao, FL, How Many Contralateral Carcinomas in Patients with Unilateral Papillary Thyroid Microcarcinoma are Preoperatively Misdiagnosed as Benign?, World J Surg, 2017. 41 (1)(1): p. 129-135., https://pubmed.ncbi.nlm.nih.gov/27541032/
[381] Ding, Y, Mao, Z, Ruan, J, Su, X, Li, L, Fahey, TJ, et.al. Nomogram-Based New Recurrence Predicting System in Early-Stage Papillary Thyroid Cancer., Int J Endocrinol, 2019. 2019 (): p. 1029092., https://pubmed.ncbi.nlm.nih.gov/31582973/
[382] Wang, F, Yu, X, Shen, X, Zhu, G, Huang, Y, Liu, R, et.al. The Prognostic Value of Tumor Multifocality in Clinical Outcomes of Papillary Thyroid Cancer., J Clin Endocrinol Metab, 2017. 102 (9)(9): p. 3241-3250., https://pubmed.ncbi.nlm.nih.gov/28582521/
[383] Dong, S, Xie, XJ, Xia, Q, Wu, YJ, Indicators of multifocality in papillary thyroid carcinoma concurrent with Hashimoto's thyroiditis., Am J Cancer Res, 2019. 9 (8)(8): p. 1786-1795., https://pubmed.ncbi.nlm.nih.gov/31497359/
[384] Kim, KJ, Kim, SG, Tan, J, Shen, X, Viola, D, Elisei, R, et.al. BRAF V600E status may facilitate decision-making on active surveillance of low-risk papillary thyroid microcarcinoma., Eur J Cancer, 2020. 124 (): p. 161-169., https://pubmed.ncbi.nlm.nih.gov/31790974/
[385] Hughes, DT, Rosen, JE, Evans, DB, Grubbs, E, Wang, TS, Solórzano, CC, Prophylactic Central Compartment Neck Dissection in Papillary Thyroid Cancer and Effect on Locoregional Recurrence., Ann Surg Oncol, 2018. 25 (9)(9): p. 2526-2534., https://pubmed.ncbi.nlm.nih.gov/29786126/
[386] Liu, LS, Liang, J, Li, JH, Liu, X, Jiang, L, Long, JX, et.al. The incidence and risk factors for central lymph node metastasis in cN0 papillary thyroid microcarcinoma: a meta-analysis., Eur Arch Otorhinolaryngol, 2017. 274 (3)(3): p. 1327-1338., https://pubmed.ncbi.nlm.nih.gov/27645473/
[387] Liu, W, Cheng, R, Su, Y, Diao, C, Qian, J, Zhang, J, et.al. Risk factors of central lymph node metastasis of papillary thyroid carcinoma: A single-center retrospective analysis of 3273 cases., Medicine (Baltimore), 2017. 96 (43)(43): p. e8365., https://pubmed.ncbi.nlm.nih.gov/29069024/
[388] Sun, W., Lan, X., Zhang, H., Dong, W., Wang, Z., He, L., et.al. Risk Factors for Central Lymph Node Metastasis in CN0 Papillary Thyroid Carcinoma: A Systematic Review and Meta-Analysis, PLoS One, 2015. 10(10): p. e0139021., https://pubmed.ncbi.nlm.nih.gov/26431346/
[389] Wang, Y, Guan, Q, Xiang, J, Nomogram for predicting central lymph node metastasis in papillary thyroid microcarcinoma: A retrospective cohort study of 8668 patients., Int J Surg, 2018. 55 (): p. 98-102., https://pubmed.ncbi.nlm.nih.gov/29803769/
[390] Xu, Y, Xu, L, Wang, J, Clinical predictors of lymph node metastasis and survival rate in papillary thyroid microcarcinoma: analysis of 3607 patients at a single institution., J Surg Res, 2018. 221 (): p. 128-134., https://pubmed.ncbi.nlm.nih.gov/29229118/
[391] Chen, BD, Zhang, Z, Wang, KK, Shang, MY, Zhao, SS, Ding, WB, et.al. A multivariable model of BRAF, Cancer Manag Res, 2019. 11 (): p. 7211-7217., https://pubmed.ncbi.nlm.nih.gov/31440100/
[392] Liu, Z., Wang, L., Yi, P., Wang, C. Y., Huang, T., Risk factors for central lymph node metastasis of patients with papillary thyroid microcarcinoma: a meta-analysis, Int J Clin Exp Pathol, 2014. 7(3): p. 932-7., https://pubmed.ncbi.nlm.nih.gov/24696711/
[393] Qu, N, Zhang, L, Ji, QH, Chen, JY, Zhu, YX, Cao, YM, et.al. Risk Factors for Central Compartment Lymph Node Metastasis in Papillary Thyroid Microcarcinoma: A Meta-Analysis., World J Surg, 2015. 39 (10)(10): p. 2459-70., https://pubmed.ncbi.nlm.nih.gov/26099728/
[394] Slijepcevic, N, Zivaljevic, V, Diklic, A, Jovanovic, M, Oluic, B, Paunovic, I, Risk factors associated with intrathyroid extension of thyroid microcarcinomas., Langenbecks Arch Surg, 2018. 403 (5)(5): p. 615-622., https://pubmed.ncbi.nlm.nih.gov/29770856/
[395] Wei, X, Wang, M, Wang, X, Zheng, X, Li, Y, Pan, Y, et.al. Prediction of cervical lymph node metastases in papillary thyroid microcarcinoma by sonographic features of the primary site., Cancer Biol Med, 2019. 16 (3)(3): p. 587-594., https://pubmed.ncbi.nlm.nih.gov/31565487/
[396] Feng, J, Gan, X, Shen, F, Cai, W, Xu, B, The role of two tumor foci for predicting central lymph node metastasis in papillary thyroid carcinoma: A meta-analysis., Int J Surg, 2018. 52 (): p. 166-170., https://pubmed.ncbi.nlm.nih.gov/29481991/
[397] Zheng, W, Wang, K, Wu, J, Wang, W, Shang, J, Multifocality is associated with central neck lymph node metastases in papillary thyroid microcarcinoma., Cancer Manag Res, 2018. 10 (): p. 1527-1533., https://pubmed.ncbi.nlm.nih.gov/29942154/
[398] Zhao, Q, Ming, J, Liu, C, Shi, L, Xu, X, Nie, X, et.al. Multifocality and total tumor diameter predict central neck lymph node metastases in papillary thyroid microcarcinoma., Ann Surg Oncol, 2013. 20 (3)(3): p. 746-52., https://pubmed.ncbi.nlm.nih.gov/22972508/
[399] Hu, JQ, Wen, D, Ma, B, Zhang, TT, Liao, T, Shi, X, et.al. The extent of lymph node yield in central neck dissection can be affected by preoperative and intraoperative assessment and alter the prognosis of papillary thyroid carcinoma., Cancer Med, 2020. 9 (3)(3): p. 1017-1024., https://pubmed.ncbi.nlm.nih.gov/31854077/
[400] Ito, Y, Miyauchi, A, Kudo, T, Kihara, M, Fukushima, M, Miya, A, The Effectiveness of Prophylactic Modified Neck Dissection for Reducing the Development of Lymph Node Recurrence of Papillary Thyroid Carcinoma., World J Surg, 2017. 41 (9)(9): p. 2283-2289., https://pubmed.ncbi.nlm.nih.gov/28429089/
[401] Qiu, Y, Fei, Y, Liu, J, Liu, C, He, X, Zhu, N, et.al. Prevalence, Risk Factors And Location Of Skip Metastasis In Papillary Thyroid Carcinoma: A Systematic Review And Meta-Analysis., Cancer Manag Res, 2019. 11 (): p. 8721-8730., https://pubmed.ncbi.nlm.nih.gov/31576174/
[402] Shan, CX, Zhang, W, Jiang, DZ, Zheng, XM, Liu, S, Qiu, M, Routine central neck dissection in differentiated thyroid carcinoma: a systematic review and meta-analysis., Laryngoscope, 2012. 122 (4)(4): p. 797-804., https://pubmed.ncbi.nlm.nih.gov/22294492/
[403] Song, E, Han, M, Oh, HS, Kim, WW, Jeon, MJ, Lee, YM, et.al. Lobectomy Is Feasible for 1-4 cm Papillary Thyroid Carcinomas: A 10-Year Propensity Score Matched-Pair Analysis on Recurrence., Thyroid, 2019. 29 (1)(1): p. 64-70., https://pubmed.ncbi.nlm.nih.gov/30375260/
[404] Vargas-Pinto, S, Romero Arenas, MA, Lobectomy Compared to Total Thyroidectomy for Low-Risk Papillary Thyroid Cancer: A Systematic Review., J Surg Res, 2019. 242 (): p. 244-251., https://pubmed.ncbi.nlm.nih.gov/31103828/
[405] Adam, MA, Pura, J, Goffredo, P, Dinan, MA, Hyslop, T, Reed, SD, et.al. Impact of extent of surgery on survival for papillary thyroid cancer patients younger than 45 years., J Clin Endocrinol Metab, 2015. 100 (1)(1): p. 115-21., https://pubmed.ncbi.nlm.nih.gov/25337927/
[406] Kim, MJ, Lee, MC, Lee, GH, Choi, HS, Cho, SW, Kim, SJ, et.al. Extent of surgery did not affect recurrence during 7-years follow-up in papillary thyroid cancer sized 1-4 cm: Preliminary results., Clin Endocrinol (Oxf), 2017. 87 (1)(1): p. 80-86., https://pubmed.ncbi.nlm.nih.gov/28338234/
[256] Cooper, DS, Doherty, GM, Haugen, BR, Kloos, RT, Lee, SL, Mandel, SJ, et.al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer., Thyroid, 2009. 19 (11)(11): p. 1167-214., https://pubmed.ncbi.nlm.nih.gov/19860577/
[60] Perros, P, Boelaert, K, Colley, S, Evans, C, Evans, RM, Gerrard Ba, G, et.al. Guidelines for the management of thyroid cancer., Clin Endocrinol (Oxf), 2014. 81 Suppl 1 (): p. 1-122., https://pubmed.ncbi.nlm.nih.gov/24989897/
[24] Haugen, BR, Alexander, EK, Bible, KC, Doherty, GM, Mandel, SJ, Nikiforov, YE, et.al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer., Thyroid, 2016. 26 (1)(1): p. 1-133., https://pubmed.ncbi.nlm.nih.gov/26462967/
[407] Machens, Andreas, Dralle, Henning, Prediction of Mediastinal Lymph Node Metastasis in Papillary Thyroid Cancer, 2009. 16(1): p. 171 - 176., https://doi.org/10.1245/s10434-008-0201-y
[408] Giordano, D, Valcavi, R, Thompson, GB, Pedroni, C, Renna, L, Gradoni, P, et.al. Complications of central neck dissection in patients with papillary thyroid carcinoma: results of a study on 1087 patients and review of the literature., Thyroid, 2012. 22 (9)(9): p. 911-7., https://pubmed.ncbi.nlm.nih.gov/22827494/
[409] Moo, TA, Umunna, B, Kato, M, Butriago, D, Kundel, A, Lee, JA, et.al. Ipsilateral versus bilateral central neck lymph node dissection in papillary thyroid carcinoma., Ann Surg, 2009. 250 (3)(3): p. 403-8., https://pubmed.ncbi.nlm.nih.gov/19661784/
[410] Sadowski, BM, Snyder, SK, Lairmore, TC, Routine bilateral central lymph node clearance for papillary thyroid cancer., Surgery, 2009. 146 (4)(4): p. 696-703; discussion 703-5., https://pubmed.ncbi.nlm.nih.gov/19789029/
[411] Yan, B, Hou, Y, Chen, D, He, J, Jiang, Y, Risk factors for contralateral central lymph node metastasis in unilateral cN0 papillary thyroid carcinoma: A meta-analysis., Int J Surg, 2018. 59 (): p. 90-98., https://pubmed.ncbi.nlm.nih.gov/30342280/
[412] Sun, W, Zheng, B, Wang, Z, Dong, W, Qin, Y, Zhang, H, Meta-analysis of risk factors for CCLNM in patients with unilateral cN0 PTC., Endocr Connect, 2020. 9 (5)(5): p. 387-395., https://pubmed.ncbi.nlm.nih.gov/32272445/
[413] Sanabria, A, Betancourt-Agüero, C, Sánchez-Delgado, JG, García-Lozano, C, Prophylactic Central Neck Lymph Node Dissection in Low-risk Thyroid Carcinoma Patients Does Not Decrease the Incidence of Locoregional Recurrence: A Meta-analysis of Randomized Trials., Ann Surg, 2022. 276 (1)(1): p. 66-73., https://pubmed.ncbi.nlm.nih.gov/35129470/
[414] Ji, YB, Lee, DW, Song, CM, Kim, KR, Park, CW, Tae, K, Accuracy of intraoperative determination of central node metastasis by the surgeon in papillary thyroid carcinoma., Otolaryngol Head Neck Surg, 2014. 150 (4)(4): p. 542-7., https://pubmed.ncbi.nlm.nih.gov/24429357/
[415] Lim, YC, Choi, EC, Yoon, YH, Koo, BS, Occult lymph node metastases in neck level V in papillary thyroid carcinoma., Surgery, 2010. 147 (2)(2): p. 241-5., https://pubmed.ncbi.nlm.nih.gov/19910012/
[258] Dralle, H, Musholt, TJ, Schabram, J, Steinmüller, T, Frilling, A, Simon, D, et.al. German Association of Endocrine Surgeons practice guideline for the surgical management of malignant thyroid tumors., Langenbecks Arch Surg, 2013. 398 (3)(3): p. 347-75., https://pubmed.ncbi.nlm.nih.gov/23456424/
[416] Madenci, AL, Caragacianu, D, Boeckmann, JO, Stack, BC, Shin, JJ, Lateral neck dissection for well-differentiated thyroid carcinoma: a systematic review., Laryngoscope, 2014. 124 (7)(7): p. 1724-34., https://pubmed.ncbi.nlm.nih.gov/24390830/
[417] Ito, Y, Miyauchi, A, Lateral and mediastinal lymph node dissection in differentiated thyroid carcinoma: indications, benefits, and risks., World J Surg, 2007. 31 (5)(5): p. 905-15., https://pubmed.ncbi.nlm.nih.gov/17219265/
[418] Machens, A, Hauptmann, S, Dralle, H, Lymph node dissection in the lateral neck for completion in central node-positive papillary thyroid cancer., Surgery, 2009. 145 (2)(2): p. 176-81., https://pubmed.ncbi.nlm.nih.gov/19167972/
[419] Chung, YS, Kim, JY, Bae, JS, Song, BJ, Kim, JS, Jeon, HM, et.al. Lateral lymph node metastasis in papillary thyroid carcinoma: results of therapeutic lymph node dissection., Thyroid, 2009. 19 (3)(3): p. 241-6., https://pubmed.ncbi.nlm.nih.gov/19265495/
[420] Cooper, DS, Tufano, RP, Prophylactic central neck dissection in differentiated thyroid cancer: a procedure in search of an indication., Thyroid, 2012. 22 (4)(4): p. 341-3., https://pubmed.ncbi.nlm.nih.gov/22458971/
[421] Dralle, H, Lorenz, K, Schabram, P, Musholt, TJ, Dotzenrath, C, Goretzki, PE, et.al. [Intraoperative neuromonitoring in thyroid surgery. Recommendations of the Surgical Working Group for Endocrinology]., Chirurg, 2013. 84 (12)(12): p. 1049-56., https://pubmed.ncbi.nlm.nih.gov/24337220/
[422] Ito, Y, Tomoda, C, Uruno, T, Takamura, Y, Miya, A, Kobayashi, K, et.al. Ultrasonographically and anatomopathologically detectable node metastases in the lateral compartment as indicators of worse relapse-free survival in patients with papillary thyroid carcinoma., World J Surg, 2005. 29 (7)(7): p. 917-20., https://pubmed.ncbi.nlm.nih.gov/15951927/
[423] Ito, Y, Higashiyama, T, Takamura, Y, Miya, A, Kobayashi, K, Matsuzuka, F, et.al. Risk factors for recurrence to the lymph node in papillary thyroid carcinoma patients without preoperatively detectable lateral node metastasis: validity of prophylactic modified radical neck dissection., World J Surg, 2007. 31 (11)(11): p. 2085-91., https://pubmed.ncbi.nlm.nih.gov/17885787/
[424] Caron, NR, Tan, YY, Ogilvie, JB, Triponez, F, Reiff, ES, Kebebew, E, et.al. Selective modified radical neck dissection for papillary thyroid cancer-is level I, II and V dissection always necessary?, World J Surg, 2006. 30 (5)(5): p. 833-40., https://pubmed.ncbi.nlm.nih.gov/16555024/
[425] van Wilgen, CP, Dijkstra, PU, van der Laan, BF, Plukker, JT, Roodenburg, JL, Shoulder complaints after nerve sparing neck dissections., Int J Oral Maxillofac Surg, 2004. 33 (3)(3): p. 253-7., https://pubmed.ncbi.nlm.nih.gov/15287308/
[426] Kupferman, ME, Patterson, DM, Mandel, SJ, LiVolsi, V, Weber, RS, Safety of modified radical neck dissection for differentiated thyroid carcinoma., Laryngoscope, 2004. 114 (3)(3): p. 403-6., https://pubmed.ncbi.nlm.nih.gov/15091209/
[427] Roh, JL, Kim, DH, Park, CI, Prospective identification of chyle leakage in patients undergoing lateral neck dissection for metastatic thyroid cancer., Ann Surg Oncol, 2008. 15 (2)(2): p. 424-9., https://pubmed.ncbi.nlm.nih.gov/17999116/
[428] Lorenz, K, Abuazab, M, Sekulla, C, Nguyen-Thanh, P, Brauckhoff, M, Dralle, H, Management of lymph fistulas in thyroid surgery., Langenbecks Arch Surg, 2010. 395 (7)(7): p. 911-7., https://pubmed.ncbi.nlm.nih.gov/20652586/
[429] McGarvey, AC, Chiarelli, PE, Osmotherly, PG, Hoffman, GR, Physiotherapy for accessory nerve shoulder dysfunction following neck dissection surgery: a literature review., Head Neck, 2011. 33 (2)(2): p. 274-80., https://pubmed.ncbi.nlm.nih.gov/20222043/
[430] Attard, A, Paladino, NC, Lo Monte, AI, Falco, N, Melfa, G, Rotolo, G, et.al. Skip metastases to lateral cervical lymph nodes in differentiated thyroid cancer: a systematic review., BMC Surg, 2019. 18 (Suppl 1)(Suppl 1): p. 112., https://pubmed.ncbi.nlm.nih.gov/31074393/
[431] Wada, N, Masudo, K, Nakayama, H, Suganuma, N, Matsuzu, K, Hirakawa, S, et.al. Clinical outcomes in older or younger patients with papillary thyroid carcinoma: impact of lymphadenopathy and patient age., Eur J Surg Oncol, 2008. 34 (2)(2): p. 202-7., https://pubmed.ncbi.nlm.nih.gov/18023321/
[432] Xiao, GZ, Gao, L, Central lymph node metastasis: is it a reliable indicator of lateral node involvement in papillary thyroid carcinoma?, World J Surg, 2010. 34 (2)(2): p. 237-41., https://pubmed.ncbi.nlm.nih.gov/20041247/
[433] Park, JH, Lee, YS, Kim, BW, Chang, HS, Park, CS, Skip lateral neck node metastases in papillary thyroid carcinoma., World J Surg, 2012. 36 (4)(4): p. 743-7., https://pubmed.ncbi.nlm.nih.gov/22354485/
[434] Xiang, D, Xie, L, Xu, Y, Li, Z, Hong, Y, Wang, P, Papillary thyroid microcarcinomas located at the middle part of the middle third of the thyroid gland correlates with the presence of neck metastasis., Surgery, 2015. 157 (3)(3): p. 526-33., https://pubmed.ncbi.nlm.nih.gov/25433730/
[435] Zhao, H, Huang, T, Li, H, Risk factors for skip metastasis and lateral lymph node metastasis of papillary thyroid cancer., Surgery, 2019. 166 (1)(1): p. 55-60., https://pubmed.ncbi.nlm.nih.gov/30876667/
[436] Zhang, C, Li, Y, Li, J, Chen, X, Total thyroidectomy versus lobectomy for papillary thyroid cancer: A systematic review and meta-analysis., Medicine (Baltimore), 2020. 99 (6)(6): p. e19073., https://pubmed.ncbi.nlm.nih.gov/32028431/
[437] Zhan, X, Xue, S, Yin, Y, Chen, G, [Related factors on skip metastasis of neck lymph node in papillary thyroid carcinoma]., Zhonghua Wai Ke Za Zhi, 2017. 55 (8)(8): p. 599-602., https://pubmed.ncbi.nlm.nih.gov/28789510/
[438] Kayser, C., Tittelbach-Helmrich, Dietlind, Meyer, Sebastian, Thomusch, Oliver, Indikation und Ausmaß der zervikalen Lymphadenektomie beim differenzierten Schilddrüsenkarzinom, 2010/08/01. 135:
[439] Moritani, S, Impact of superior mediastinal metastasis on the prognosis of papillary thyroid carcinoma., Endocr J, 2016. 63 (4)(4): p. 349-57., https://pubmed.ncbi.nlm.nih.gov/26765269/
[440] Gartland, RM, Lubitz, CC, Impact of Extent of Surgery on Tumor Recurrence and Survival for Papillary Thyroid Cancer Patients., Ann Surg Oncol, 2018. 25 (9)(9): p. 2520-2525., https://pubmed.ncbi.nlm.nih.gov/29855833/
[441] Bilimoria, KY, Bentrem, DJ, Ko, CY, Stewart, AK, Winchester, DP, Talamonti, MS, et.al. Extent of surgery affects survival for papillary thyroid cancer., Ann Surg, 2007. 246 (3)(3): p. 375-81; discussion 381-4., https://pubmed.ncbi.nlm.nih.gov/17717441/
[442] Rajjoub, SR, Yan, H, Calcatera, NA, Kuchta, K, Wang, CE, Lutfi, W, et.al. Thyroid lobectomy is not sufficient for T2 papillary thyroid cancers., Surgery, 2018. 163 (5)(5): p. 1134-1143., https://pubmed.ncbi.nlm.nih.gov/29426618/
[443] Macedo, FI, Mittal, VK, Total thyroidectomy versus lobectomy as initial operation for small unilateral papillary thyroid carcinoma: A meta-analysis., Surg Oncol, 2015. 24 (2)(2): p. 117-22., https://pubmed.ncbi.nlm.nih.gov/25956302/
[196] Kim, SY, Lee, HS, Moon, J, Kim, EK, Moon, HJ, Yoon, JH, et.al. Fine-needle aspiration versus core needle biopsy for diagnosis of thyroid malignancy and neoplasm: a matched cohort study., Eur Radiol, 2017. 27 (2)(2): p. 801-811., https://pubmed.ncbi.nlm.nih.gov/27260342/
[270] Harries, V, Wang, LY, McGill, M, Xu, B, Tuttle, RM, Wong, RJ, et.al. Should multifocality be an indication for completion thyroidectomy in papillary thyroid carcinoma?, Surgery, 2020. 167 (1)(1): p. 10-17., https://pubmed.ncbi.nlm.nih.gov/31515125/
[444] Glockzin, G, Hornung, M, Kienle, K, Thelen, K, Boin, M, Schreyer, AG, et.al. Completion thyroidectomy: effect of timing on clinical complications and oncologic outcome in patients with differentiated thyroid cancer., World J Surg, 2012. 36 (5)(5): p. 1168-73., https://pubmed.ncbi.nlm.nih.gov/22366982/
[445] Sosa, JA, Bowman, HM, Tielsch, JM, Powe, NR, Gordon, TA, Udelsman, R, The importance of surgeon experience for clinical and economic outcomes from thyroidectomy., Ann Surg, 1998. 228 (3)(3): p. 320-30., https://pubmed.ncbi.nlm.nih.gov/9742915/
[446] Sosa, JA, Mehta, PJ, Wang, TS, Boudourakis, L, Roman, SA, A population-based study of outcomes from thyroidectomy in aging Americans: at what cost?, J Am Coll Surg, 2008. 206 (6)(6): p. 1097-105., https://pubmed.ncbi.nlm.nih.gov/18501806/
[447] Papaleontiou, M, Gauger, PG, Haymart, MR, REFERRAL OF OLDER THYROID CANCER PATIENTS TO A HIGH-VOLUME SURGEON: RESULTS OF A MULTIDISCIPLINARY PHYSICIAN SURVEY., Endocr Pract, 2017. 23 (7)(7): p. 808-815., https://pubmed.ncbi.nlm.nih.gov/28534681/
[448] Youngwirth, LM, Adam, MA, Scheri, RP, Roman, SA, Sosa, JA, Patients Treated at Low-Volume Centers have Higher Rates of Incomplete Resection and Compromised Outcomes: Analysis of 31,129 Patients with Papillary Thyroid Cancer., Ann Surg Oncol, 2016. 23 (2)(2): p. 403-9., https://pubmed.ncbi.nlm.nih.gov/26416710/
[449] Kim, MJ, Chung, WY, Yonsei Experience of 5000 Gasless Transaxillary Robotic Thyroidectomies: Reply., World J Surg, 2018. 42 (7)(7): p. 2281-2282., https://pubmed.ncbi.nlm.nih.gov/29362890/
[450] Lorenz, K, Raffaeli, M, Barczyński, M, Lorente-Poch, L, Sancho, J, Volume, outcomes, and quality standards in thyroid surgery: an evidence-based analysis-European Society of Endocrine Surgeons (ESES) positional statement., Langenbecks Arch Surg, 2020. 405 (4)(4): p. 401-425., https://pubmed.ncbi.nlm.nih.gov/32524467/
[451] Piazza, C, Del Bon, F, Barbieri, D, Grazioli, P, Paderno, A, Perotti, P, et.al. Tracheal and Crico-Tracheal Resection and Anastomosis for Malignancies Involving the Thyroid Gland and the Airway., Ann Otol Rhinol Laryngol, 2016. 125 (2)(2): p. 97-104., https://pubmed.ncbi.nlm.nih.gov/26296930/
[452] Kim, H, Jung, HJ, Lee, SY, Kwon, TK, Kim, KH, Sung, MW, et.al. Prognostic factors of locally invasive well-differentiated thyroid carcinoma involving the trachea., Eur Arch Otorhinolaryngol, 2016. 273 (7)(7): p. 1919-26., https://pubmed.ncbi.nlm.nih.gov/26198285/
[453] Nixon, IJ, Simo, R, Newbold, K, Rinaldo, A, Suarez, C, Kowalski, LP, et.al. Management of Invasive Differentiated Thyroid Cancer., Thyroid, 2016. 26 (9)(9): p. 1156-66., https://pubmed.ncbi.nlm.nih.gov/27480110/
[454] Ito, Y, Tomoda, C, Uruno, T, Takamura, Y, Miya, A, Kobayashi, K, et.al. Prognostic significance of extrathyroid extension of papillary thyroid carcinoma: massive but not minimal extension affects the relapse-free survival., World J Surg, 2006. 30 (5)(5): p. 780-6., https://pubmed.ncbi.nlm.nih.gov/16411013/
[455] Mercante, G, Frasoldati, A, Pedroni, C, Formisano, D, Renna, L, Piana, S, et.al. Prognostic factors affecting neck lymph node recurrence and distant metastasis in papillary microcarcinoma of the thyroid: results of a study in 445 patients., Thyroid, 2009. 19 (7)(7): p. 707-16., https://pubmed.ncbi.nlm.nih.gov/19348581/
[456] Rivera, M, Ricarte-Filho, J, Tuttle, RM, Ganly, I, Shaha, A, Knauf, J, et.al. Molecular, morphologic, and outcome analysis of thyroid carcinomas according to degree of extrathyroid extension., Thyroid, 2010. 20 (10)(10): p. 1085-93., https://pubmed.ncbi.nlm.nih.gov/20860430/
[457] Fukushima, M, Ito, Y, Hirokawa, M, Miya, A, Shimizu, K, Miyauchi, A, Prognostic impact of extrathyroid extension and clinical lymph node metastasis in papillary thyroid carcinoma depend on carcinoma size., World J Surg, 2010. 34 (12)(12): p. 3007-14., https://pubmed.ncbi.nlm.nih.gov/20824274/
[458] Brauckhoff, M, Meinicke, A, Bilkenroth, U, Lorenz, K, Brauckhoff, K, Gimm, O, et.al. Long-term results and functional outcome after cervical evisceration in patients with thyroid cancer., Surgery, 2006. 140 (6)(6): p. 953-9., https://pubmed.ncbi.nlm.nih.gov/17188144/
[459] Brauckhoff, M., Dralle, H., Zervikoviszerale Resektionen beim organüberschreitenden Schilddrüsenkarzinom, 2009. 80(2): p. 88 - 98., https://doi.org/10.1007/s00104-008-1610-y
[460] Musholt, TJ, Musholt, PB, Behrend, M, Raab, R, Scheumann, GF, Klempnauer, J, Invasive differentiated thyroid carcinoma: tracheal resection and reconstruction procedures in the hands of the endocrine surgeon., Surgery, 1999. 126 (6)(6): p. 1078-87; discussion 1087-8., https://pubmed.ncbi.nlm.nih.gov/10598191/
[461] Brauckhoff, M, Machens, A, Thanh, PN, Lorenz, K, Schmeil, A, Stratmann, M, et.al. Impact of extent of resection for thyroid cancer invading the aerodigestive tract on surgical morbidity, local recurrence, and cancer-specific survival., Surgery, 2010. 148 (6)(6): p. 1257-66., https://pubmed.ncbi.nlm.nih.gov/21134559/
[462] Hotomi, M, Sugitani, I, Toda, K, Kawabata, K, Fujimoto, Y, A novel definition of extrathyroidal invasion for patients with papillary thyroid carcinoma for predicting prognosis., World J Surg, 2012. 36 (6)(6): p. 1231-40., https://pubmed.ncbi.nlm.nih.gov/22402972/
[463] Pawelczak, M, David, R, Franklin, B, Kessler, M, Lam, L, Shah, B, Outcomes of children and adolescents with well-differentiated thyroid carcinoma and pulmonary metastases following ¹³¹I treatment: a systematic review., Thyroid, 2010. 20 (10)(10): p. 1095-101., https://pubmed.ncbi.nlm.nih.gov/20860418/
[464] Francis, GL, Waguespack, SG, Bauer, AJ, Angelos, P, Benvenga, S, Cerutti, JM, et.al. Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer., Thyroid, 2015. 25 (7)(7): p. 716-59., https://pubmed.ncbi.nlm.nih.gov/25900731/
[465] Baumgarten, H, Jenks, CM, Isaza, A, Bhatti, T, Mostoufi-Moab, S, Kazahaya, K, et.al. Bilateral papillary thyroid cancer in children: Risk factors and frequency of postoperative diagnosis., J Pediatr Surg, 2020. 55 (6)(6): p. 1117-1122., https://pubmed.ncbi.nlm.nih.gov/32171533/
[466] Chen, J, Huang, N, Ji, Q, Wang, Y, Zhu, Y, Li, D, Multifocal papillary thyroid cancer in children and adolescents: 12-year experience in a single center., Gland Surg, 2019. 8 (5)(5): p. 507-515., https://pubmed.ncbi.nlm.nih.gov/31741881/
[467] Hay, I. D., Gonzalez-Losada, T., Reinalda, M. S., Honetschlager, J. A., Richards, M. L., Thompson, G. B., Long-term outcome in 215 children and adolescents with papillary thyroid cancer treated during 1940 through 2008, World J Surg, 2010. 34(6): p. 1192-202., https://pubmed.ncbi.nlm.nih.gov/20087589/
[468] Balachandar, S, La Quaglia, M, Tuttle, RM, Heller, G, Ghossein, RA, Sklar, CA, Pediatric Differentiated Thyroid Carcinoma of Follicular Cell Origin: Prognostic Significance of Histologic Subtypes., Thyroid, 2016. 26 (2)(2): p. 219-26., https://pubmed.ncbi.nlm.nih.gov/26854950/
[469] Onder, S, Ozturk Sari, S, Yegen, G, Sormaz, IC, Yilmaz, I, Poyrazoglu, S, et.al. Classic Architecture with Multicentricity and Local Recurrence, and Absence of TERT Promoter Mutations are Correlates of BRAF (V600E) Harboring Pediatric Papillary Thyroid Carcinomas., Endocr Pathol, 2016. 27 (2)(2): p. 153-61., https://pubmed.ncbi.nlm.nih.gov/26951110/
[470] Vassilopoulou-Sellin, R, Goepfert, H, Raney, B, Schultz, PN, Differentiated thyroid cancer in children and adolescents: clinical outcome and mortality after long-term follow-up., Head Neck, 1998. 20 (6)(6): p. 549-55., https://pubmed.ncbi.nlm.nih.gov/9702543/
[471] Al-Qurayshi, Z, Hauch, A, Srivastav, S, Aslam, R, Friedlander, P, Kandil, E, A National Perspective of the Risk, Presentation, and Outcomes of Pediatric Thyroid Cancer., JAMA Otolaryngol Head Neck Surg, 2016. 142 (5)(5): p. 472-8., https://pubmed.ncbi.nlm.nih.gov/27031884/
[472] Leboulleux, S, Baudin, E, Hartl, DW, Travagli, JP, Schlumberger, M, Follicular cell-derived thyroid cancer in children., Horm Res, 2005. 63 (3)(3): p. 145-51., https://pubmed.ncbi.nlm.nih.gov/15802922/
[473] Machens, A, Lorenz, K, Nguyen Thanh, P, Brauckhoff, M, Dralle, H, Papillary thyroid cancer in children and adolescents does not differ in growth pattern and metastatic behavior., J Pediatr, 2010. 157 (4)(4): p. 648-52., https://pubmed.ncbi.nlm.nih.gov/20553841/
[474] Machens, A, Elwerr, M, Thanh, PN, Lorenz, K, Schneider, R, Dralle, H, Impact of central node dissection on postoperative morbidity in pediatric patients with suspected or proven thyroid cancer., Surgery, 2016. 160 (2)(2): p. 484-92., https://pubmed.ncbi.nlm.nih.gov/27117577/
[475] Farahati, J, Reiners, C, Demidchik, EP, Is the UICC/AJCC classification of primary tumor in childhood thyroid carcinoma valid?, J Nucl Med, 1999. 40 (12)(12): p. 2125., https://pubmed.ncbi.nlm.nih.gov/10616895/
[476] Dralle, H, [Thyroid gland surgery: risk factor surgeon]., Chirurg, 2012. 83 (3)(3): p. 280-1., https://pubmed.ncbi.nlm.nih.gov/22349789/
[477] Hundahl, SA, Cady, B, Cunningham, MP, Mazzaferri, E, McKee, RF, Rosai, J, et.al. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the united states during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study., Cancer, 2000. 89 (1)(1): p. 202-17., https://pubmed.ncbi.nlm.nih.gov/10897019/
[478] DeLellis, RA., , Lloyd, RV.,, Heitz, PU.,, Eng, C., WHO Classification of tumors., in Pathology and Genetics of Tumors of Endocrine Organs., 2004, IARC Press: Lyon. p. 49 - 133.
[274] Tuttle, RM, Haugen, B, Perrier, ND, Updated American Joint Committee on Cancer/Tumor-Node-Metastasis Staging System for Differentiated and Anaplastic Thyroid Cancer (Eighth Edition): What Changed and Why?, Thyroid, 2017. 27 (6)(6): p. 751-756., https://pubmed.ncbi.nlm.nih.gov/28463585/
[172] Lloyd, Ricardo V., Osamura, Robert Y., Klöppel, Günter, Rosai, Juan, World Health Organization, International Agency for Research on Cancer, WHO classification of tumours of endocrine organsInternational Agency for Research on Cancer (IARC), World Health Organization classification of tumours, 2017.
[253] Baloch, ZW, Asa, SL, Barletta, JA, Ghossein, RA, Juhlin, CC, Jung, CK, et.al. Overview of the 2022 WHO Classification of Thyroid Neoplasms., Endocr Pathol, 2022. 33 (1)(1): p. 27-63., https://pubmed.ncbi.nlm.nih.gov/35288841/
[479] Clerici, T, Kolb, W, Beutner, U, Bareck, E, Dotzenrath, C, Kull, C, et.al. Diagnosis and treatment of small follicular thyroid carcinomas., Br J Surg, 2010. 97 (6)(6): p. 839-44., https://pubmed.ncbi.nlm.nih.gov/20473996/
[480] Asari, R, Koperek, O, Scheuba, C, Riss, P, Kaserer, K, Hoffmann, M, et.al. Follicular thyroid carcinoma in an iodine-replete endemic goiter region: a prospectively collected, retrospectively analyzed clinical trial., Ann Surg, 2009. 249 (6)(6): p. 1023-31., https://pubmed.ncbi.nlm.nih.gov/19474675/
[481] O'Neill, C. J., Vaughan, L., Learoyd, D. L., Sidhu, S. B., Delbridge, L. W., Sywak, M. S., Management of follicular thyroid carcinoma should be individualised based on degree of capsular and vascular invasion, Eur J Surg Oncol, 2011. 37(2): p. 181-5.
[482] Schmid, KW, Sheu, SY, Görges, R, Ensinger, C, Tötsch, M, [Thyroid tumors]., Pathologe, 2003. 24 (5)(5): p. 357-72., https://pubmed.ncbi.nlm.nih.gov/12961024/
[483] LiVolsi, Virginia A, Papillary thyroid carcinoma: an update, 2011. 24(2): p. S1 - S9., https://doi.org/10.1038/modpathol.2010.129
[484] Udelsman, R, Westra, WH, Donovan, PI, Sohn, TA, Cameron, JL, Randomized prospective evaluation of frozen-section analysis for follicular neoplasms of the thyroid., Ann Surg, 2001. 233 (5)(5): p. 716-22., https://pubmed.ncbi.nlm.nih.gov/11323510/
[485] Miller, MC, Rubin, CJ, Cunnane, M, Bibbo, M, Miller, JL, Keane, WM, et.al. Intraoperative pathologic examination: cost effectiveness and clinical value in patients with cytologic diagnosis of cellular follicular thyroid lesion., Thyroid, 2007. 17 (6)(6): p. 557-65., https://pubmed.ncbi.nlm.nih.gov/17614777/
[486] Basolo, F, Torregrossa, L, Giannini, R, Miccoli, M, Lupi, C, Sensi, E, et.al. Correlation between the BRAF V600E mutation and tumor invasiveness in papillary thyroid carcinomas smaller than 20 millimeters: analysis of 1060 cases., J Clin Endocrinol Metab, 2010. 95 (9)(9): p. 4197-205., https://pubmed.ncbi.nlm.nih.gov/20631031/
[487] Lin, JD, Chao, TC, Hsueh, C, Clinical characteristics of poorly differentiated thyroid carcinomas compared with those of classical papillary thyroid carcinomas., Clin Endocrinol (Oxf), 2007. 66 (2)(2): p. 224-8., https://pubmed.ncbi.nlm.nih.gov/17223992/
[488] Baloch, Z, LiVolsi, VA, Jain, P, Jain, R, Aljada, I, Mandel, S, et.al. Role of repeat fine-needle aspiration biopsy (FNAB) in the management of thyroid nodules., Diagn Cytopathol, 2003. 29 (4)(4): p. 203-6., https://pubmed.ncbi.nlm.nih.gov/14506672/
[489] O'Neill, CJ, Bullock, M, Chou, A, Sidhu, SB, Delbridge, LW, Robinson, BG, et.al. BRAF(V600E) mutation is associated with an increased risk of nodal recurrence requiring reoperative surgery in patients with papillary thyroid cancer., Surgery, 2010. 148 (6)(6): p. 1139-45; discussion 1145-6., https://pubmed.ncbi.nlm.nih.gov/21134544/
[490] Dionigi, G, Kraimps, JL, Schmid, KW, Hermann, M, Sheu-Grabellus, SY, De Wailly, P, et.al. Minimally invasive follicular thyroid cancer (MIFTC)--a consensus report of the European Society of Endocrine Surgeons (ESES)., Langenbecks Arch Surg, 2014. 399 (2)(2): p. 165-84., https://pubmed.ncbi.nlm.nih.gov/24233345/
[491] Huang, CC, Hsueh, C, Liu, FH, Chao, TC, Lin, JD, Diagnostic and therapeutic strategies for minimally and widely invasive follicular thyroid carcinomas., Surg Oncol, 2011. 20 (1)(1): p. 1-6., https://pubmed.ncbi.nlm.nih.gov/19596568/
[492] Sugino, K, Ito, K, Nagahama, M, Kitagawa, W, Shibuya, H, Ohkuwa, K, et.al. Prognosis and prognostic factors for distant metastases and tumor mortality in follicular thyroid carcinoma., Thyroid, 2011. 21 (7)(7): p. 751-7., https://pubmed.ncbi.nlm.nih.gov/21615311/
[318] Staubitz, JI, Elmrich, I, Musholt, PB, Cámara, RJA, Watzka, F, Dralle, H, et.al. Targeted use of intraoperative frozen-section analysis lowers the frequency of completion thyroidectomy., BJS Open, 2021. 5 (2)(2):, https://pubmed.ncbi.nlm.nih.gov/33851986/
[493] British Thyroid Association, Guidelines for the management of thyroid cancer., 2007., http://www.british-thyroid-association.org
[494] Pacini, F, Schlumberger, M, Dralle, H, Elisei, R, Smit, JW, Wiersinga, W, European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium., Eur J Endocrinol, 2006. 154 (6)(6): p. 787-803., https://pubmed.ncbi.nlm.nih.gov/16728537/
[495] Dutch Association of comprehensive cancer centres thyroid cancer, National evidence-based guideline., 2007. Version 1.0.:, http://www.oncoline.nl
[496] Luster, M, Clarke, SE, Dietlein, M, Lassmann, M, Lind, P, Oyen, WJ, et.al. Guidelines for radioiodine therapy of differentiated thyroid cancer., Eur J Nucl Med Mol Imaging, 2008. 35 (10)(10): p. 1941-59., https://pubmed.ncbi.nlm.nih.gov/18670773/
[497] Dietlein, M, Dressler, J, Eschner, W, Grünwald, F, Lassmann, M, Leisner, B, et.al. [Procedure guidelines for radioiodine therapy of differentiated thyroid cancer (version 3)]., Nuklearmedizin, 2007. 46 (5)(5): p. 213-9., https://pubmed.ncbi.nlm.nih.gov/17938757/
[498] Takami, H, Ito, Y, Okamoto, T, Yoshida, A, Therapeutic strategy for differentiated thyroid carcinoma in Japan based on a newly established guideline managed by Japanese Society of Thyroid Surgeons and Japanese Association of Endocrine Surgeons., World J Surg, 2011. 35 (1)(1): p. 111-21., https://pubmed.ncbi.nlm.nih.gov/21042913/
[499] Dralle, H, Lorenz, K, Machens, A, [Surgery of thyroid carcinoma]., Chirurg, 2009. 80 (11)(11): p. 1069-82; quiz 1083., https://pubmed.ncbi.nlm.nih.gov/19902289/
[500] Reiners, C, Hänscheid, H, Luster, M, Lassmann, M, Verburg, FA, Radioiodine for remnant ablation and therapy of metastatic disease., Nat Rev Endocrinol, 2011. 7 (10)(10): p. 589-95., https://pubmed.ncbi.nlm.nih.gov/21826102/
[501] Machens, A, Holzhausen, HJ, Lautenschläger, C, Thanh, PN, Dralle, H, Enhancement of lymph node metastasis and distant metastasis of thyroid carcinoma., Cancer, 2003. 98 (4)(4): p. 712-9., https://pubmed.ncbi.nlm.nih.gov/12910514/
[502] Carling, T, Udelsman, R, Follicular neoplasms of the thyroid: what to recommend., Thyroid, 2005. 15 (6)(6): p. 583-7., https://pubmed.ncbi.nlm.nih.gov/16029125/
[503] Besic, N, Hocevar, M, Zgajnar, J, Petric, R, Pilko, G, Aggressiveness of therapy and prognosis of patients with Hürthle cell papillary thyroid carcinoma., Thyroid, 2006. 16 (1)(1): p. 67-72., https://pubmed.ncbi.nlm.nih.gov/16487016/
[504] Montone, KT, Baloch, ZW, LiVolsi, VA, The thyroid Hürthle (oncocytic) cell and its associated pathologic conditions: a surgical pathology and cytopathology review., Arch Pathol Lab Med, 2008. 132 (8)(8): p. 1241-50., https://pubmed.ncbi.nlm.nih.gov/18684023/
[505] Guerrero, MA, Suh, I, Vriens, MR, Shen, WT, Gosnell, J, Kebebew, E, et.al. Age and tumor size predicts lymph node involvement in Hürthle Cell Carcinoma., J Cancer, 2010. 1 (): p. 23-6., https://pubmed.ncbi.nlm.nih.gov/20842220/
[506] Lopez-Penabad, L, Chiu, AC, Hoff, AO, Schultz, P, Gaztambide, S, Ordoñez, NG, et.al. Prognostic factors in patients with Hürthle cell neoplasms of the thyroid., Cancer, 2003. 97 (5)(5): p. 1186-94., https://pubmed.ncbi.nlm.nih.gov/12599224/
[507] Carcangiu, ML, Hürthle cell carcinoma: clinic-pathological and biological aspects., Tumori, 2003. 89 (5)(5): p. 529-32., https://pubmed.ncbi.nlm.nih.gov/14870778/
[508] Kushchayeva, Y, Duh, QY, Kebebew, E, Clark, OH, Prognostic indications for Hürthle cell cancer., World J Surg, 2004. 28 (12)(12): p. 1266-70., https://pubmed.ncbi.nlm.nih.gov/15517492/
[509] Sanders, EM, LiVolsi, VA, Brierley, J, Shin, J, Randolph, GW, An evidence-based review of poorly differentiated thyroid cancer., World J Surg, 2007. 31 (5)(5): p. 934-45., https://pubmed.ncbi.nlm.nih.gov/17431717/
[510] Chambers, AJ., , Pasieka, JL., Poorly differentiated and undifferentiated thyroid cancern, in In: Endocrine Surgery, 2009, Springer: London. p. 121 - 136.
[511] Walczyk, A, Kopczyński, J, Gąsior-Perczak, D, Pałyga, I, Kowalik, A, Chrapek, M, et.al. Poorly differentiated thyroid cancer in the context of the revised 2015 American Thyroid Association Guidelines and the Updated American Joint Committee on Cancer/Tumor-Node-Metastasis Staging System (eighth edition)., Clin Endocrinol (Oxf), 2019. 91 (2)(2): p. 331-339., https://pubmed.ncbi.nlm.nih.gov/30525210/
[512] Patel, KN, Shaha, AR, Poorly differentiated thyroid cancer., Curr Opin Otolaryngol Head Neck Surg, 2014. 22 (2)(2): p. 121-6., https://pubmed.ncbi.nlm.nih.gov/24492853/
[513] Ibrahimpasic, T., Ghossein, R., Shah, J. P., Ganly, I., Poorly Differentiated Carcinoma of the Thyroid Gland: Current Status and Future Prospects, Thyroid, 2019. 29(3): p. 311-321., https://pubmed.ncbi.nlm.nih.gov/30747050/
[514] Hescot, S, Al Ghuzlan, A, Henry, T, Sheikh-Alard, H, Lamartina, L, Borget, I, et.al. Prognostic of recurrence and survival in poorly differentiated thyroid cancer., Endocr Relat Cancer, 2022. 29 (11)(11): p. 625-634., https://pubmed.ncbi.nlm.nih.gov/36040800/
[515] Volante, M, Landolfi, S, Chiusa, L, Palestini, N, Motta, M, Codegone, A, et.al. Poorly differentiated carcinomas of the thyroid with trabecular, insular, and solid patterns: a clinicopathologic study of 183 patients., Cancer, 2004. 100 (5)(5): p. 950-7., https://pubmed.ncbi.nlm.nih.gov/14983490/
[516] Akaishi, J, Kondo, T, Sugino, K, Ogimi, Y, Masaki, C, Hames, KY, et.al. Prognostic Impact of the Turin Criteria in Poorly Differentiated Thyroid Carcinoma., World J Surg, 2019. 43 (9)(9): p. 2235-2244., https://pubmed.ncbi.nlm.nih.gov/31098668/
[252] Lloyd, R. V.; Osamura, R.Y.; Klöppel, G.; Rosai, J., WHO classification of tumours of enndocrine organs, World Health Organization Classification of Tumours, International Agency for Research on Cancer (IARC), 2017.
[261] Volante, M, Collini, P, Nikiforov, YE, Sakamoto, A, Kakudo, K, Katoh, R, et.al. Poorly differentiated thyroid carcinoma: the Turin proposal for the use of uniform diagnostic criteria and an algorithmic diagnostic approach., Am J Surg Pathol, 2007. 31 (8)(8): p. 1256-64., https://pubmed.ncbi.nlm.nih.gov/17667551/
[517] Volante, M, Papotti, M, Poorly differentiated thyroid carcinoma: 5 years after the 2004 WHO classification of endocrine tumours., Endocr Pathol, 2010. 21 (1)(1): p. 1-6., https://pubmed.ncbi.nlm.nih.gov/19960273/
[518] Hiltzik, D., Carlson, D. L., Tuttle, R. M., Chuai, S., Ishill, N., Shaha, A., et.al. Poorly differentiated thyroid carcinomas defined on the basis of mitosis and necrosis: a clinicopathologic study of 58 patients, Cancer, 2006. 106(6): p. 1286-95., https://pubmed.ncbi.nlm.nih.gov/16470605/
[519] Wong, KS, Lorch, JH, Alexander, EK, Marqusee, E, Cho, NL, Nehs, MA, et.al. Prognostic Significance of Extent of Invasion in Poorly Differentiated Thyroid Carcinoma., Thyroid, 2019. 29 (9)(9): p. 1255-1261., https://pubmed.ncbi.nlm.nih.gov/31397224/
[520] Lam, KY, Lo, CY, Chan, KW, Wan, KY, Insular and anaplastic carcinoma of the thyroid: a 45-year comparative study at a single institution and a review of the significance of p53 and p21., Ann Surg, 2000. 231 (3)(3): p. 329-38., https://pubmed.ncbi.nlm.nih.gov/10714625/
[521] Dettmer, M, Schmitt, A, Steinert, H, Haldemann, A, Meili, A, Moch, H, et.al. Poorly differentiated thyroid carcinomas: how much poorly differentiated is needed?, Am J Surg Pathol, 2011. 35 (12)(12): p. 1866-72., https://pubmed.ncbi.nlm.nih.gov/21989341/
[522] Chao, T. C., Lin, J. D., Chen, M. F., Insular carcinoma: infrequent subtype of thyroid cancer with aggressive clinical course, World J Surg, 2004. 28(4): p. 393-6., https://pubmed.ncbi.nlm.nih.gov/14994145/
[523] Patel, KN, Shaha, AR, Poorly differentiated and anaplastic thyroid cancer., Cancer Control, 2006. 13 (2)(2): p. 119-28., https://pubmed.ncbi.nlm.nih.gov/16735986/
[524] Jung, TS, Kim, TY, Kim, KW, Oh, YL, Park, DJ, Cho, BY, et.al. Clinical features and prognostic factors for survival in patients with poorly differentiated thyroid carcinoma and comparison to the patients with the aggressive variants of papillary thyroid carcinoma., Endocr J, 2007. 54 (2)(2): p. 265-74., https://pubmed.ncbi.nlm.nih.gov/17379963/
[145] Patel, A, Shostrom, V, Treude, K, Lydiatt, W, Smith, R, Goldner, W, Serum Thyroglobulin: Preoperative Levels and Factors Affecting Postoperative Optimal Timing following Total Thyroidectomy., Int J Endocrinol, 2019. 2019 (): p. 1384651., https://pubmed.ncbi.nlm.nih.gov/30915112/
[525] Walczyk, A, Kopczyński, J, Gąsior-Perczak, D, Pałyga, I, Kowalik, A, Chrapek, M, et.al. Histopathology and immunohistochemistry as prognostic factors for poorly differentiated thyroid cancer in a series of Polish patients., PLoS One, 2020. 15 (2)(2): p. e0229264., https://pubmed.ncbi.nlm.nih.gov/32092093/
[526] de la Fouchardière, C, Decaussin-Petrucci, M, Berthiller, J, Descotes, F, Lopez, J, Lifante, JC, et.al. Predictive factors of outcome in poorly differentiated thyroid carcinomas., Eur J Cancer, 2018. 92 (): p. 40-47., https://pubmed.ncbi.nlm.nih.gov/29413688/
[527] Ho, AS, Luu, M, Barrios, L, Chen, I, Melany, M, Ali, N, et.al. Incidence and Mortality Risk Spectrum Across Aggressive Variants of Papillary Thyroid Carcinoma., JAMA Oncol, 2020. 6 (5)(5): p. 706-713., https://pubmed.ncbi.nlm.nih.gov/32134428/
[528] Dralle, H, Sekulla, C, Haerting, J, Timmermann, W, Neumann, HJ, Kruse, E, et.al. Risk factors of paralysis and functional outcome after recurrent laryngeal nerve monitoring in thyroid surgery., Surgery, 2004. 136 (6)(6): p. 1310-22., https://pubmed.ncbi.nlm.nih.gov/15657592/
[529] Maneck, M, Dotzenrath, C, Dralle, H, Fahlenbrach, C, Paschke, R, Steinmüller, T, et.al. [Complications after thyroid gland operations in Germany : A routine data analysis of 66,902 AOK patients]., Chirurg, 2017. 88 (1)(1): p. 50-57., https://pubmed.ncbi.nlm.nih.gov/27510155/
[530] Adam, MA, Thomas, S, Youngwirth, L, Hyslop, T, Reed, SD, Scheri, RP, et.al. Is There a Minimum Number of Thyroidectomies a Surgeon Should Perform to Optimize Patient Outcomes?, Ann Surg, 2017. 265 (2)(2): p. 402-407., https://pubmed.ncbi.nlm.nih.gov/28059969/
[531] Godballe, C, Madsen, AR, Sørensen, CH, Schytte, S, Trolle, W, Helweg-Larsen, J, et.al. Risk factors for recurrent nerve palsy after thyroid surgery: a national study of patients treated at Danish departments of ENT Head and Neck Surgery., Eur Arch Otorhinolaryngol, 2014. 271 (8)(8): p. 2267-76., https://pubmed.ncbi.nlm.nih.gov/24132654/
[532] Hauch, A, Al-Qurayshi, Z, Friedlander, P, Kandil, E, Association of socioeconomic status, race, and ethnicity with outcomes of patients undergoing thyroid surgery., JAMA Otolaryngol Head Neck Surg, 2014. 140 (12)(12): p. 1173-83., https://pubmed.ncbi.nlm.nih.gov/25187970/
[533] Maneck, M, Dotzenrath, C, Dralle, H, Fahlenbrach, C, Steinmüller, T, Simon, D, et.al. [Case volume and complications after thyroid gland surgery in Germany: an analysis of routine data from 48,387 AOK patients]., Chirurg, 2021. 92 (1)(1): p. 40-48., https://pubmed.ncbi.nlm.nih.gov/32430544/
[534] Cirocchi, R, Arezzo, A, D'Andrea, V, Abraha, I, Popivanov, GI, Avenia, N, et.al. Intraoperative neuromonitoring versus visual nerve identification for prevention of recurrent laryngeal nerve injury in adults undergoing thyroid surgery., Cochrane Database Syst Rev, 2019. 1 (1)(1): p. CD012483., https://pubmed.ncbi.nlm.nih.gov/30659577/
[535] Justiz, Bundesministerium der, Gesetz zum Schutz vor der schädlichen Wirkung ionisierender Strahlung (Strahlenschutzgesetz - StrlSchG). Strahlenschutzgesetz vom 27. Juni 2017 (BGBl. I S. 1966), das zuletzt durch die Bekanntmachung vom 3. Januar 2022 (BGBl. I S. 15) geändert worden ist, 2017.
[536] Justiz, Bundesministerium der, Verordnung zur weiteren Modernisierung des Strahlenschutzrechts, 2018.
[537] Strahlenschutzkommission, Therapeutische Verfahren in der Nuklearmedizin, 2022.
[538] Eilsberger, F., Kreissl, M. C., Luster, M., Pfestroff, A., [Therapy concepts for thyroid carcinoma], Nuklearmedizin, 2022. 61(3): p. 223-230., https://pubmed.ncbi.nlm.nih.gov/34644802/
[539] Krajewska, J., Jarzab, M., Kukulska, A., Czarniecka, A., Roskosz, J., Puch, Z., et.al. Postoperative Radioiodine Treatment within 9 Months from Diagnosis Significantly Reduces the Risk of Relapse in Low-Risk Differentiated Thyroid Carcinoma, Nucl Med Mol Imaging, 2019. 53(5): p. 320-327.
[540] Yu, F., Li, X., Ji, Y., Tan, J., Zhang, G., Wang, P., et.al. Delayed Initial Radioiodine Adjuvant Therapy Does Affect Biochemical Response in Intermediate- to High-Risk Differentiated Thyroid Cancer, Front Endocrinol (Lausanne), 2021. 12: p. 743310., https://pubmed.ncbi.nlm.nih.gov/34858329/
[541] Schmid, K. W., Synoracki, S., Dralle, H., Wittekind, C., [Proposal for an extended pTNM classification of thyroid carcinoma : Commentary on deficits of the 8th edition of the TNM classification (German version)], Pathologe, 2018. 39(1): p. 49-56.
[542] Schmid, K. W., Synoracki, S., Dralle, H., Wittekind, C., Proposal for an extended pTNM classification of thyroid carcinoma, Der Pathologe, 2019. 40(1): p. 18-24., https://doi.org/10.1007/s00292-018-0418-x
[543] Tuttle, RM, Tala, H, Shah, J, Leboeuf, R, Ghossein, R, Gonen, M, et.al. Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system., Thyroid, 2010. 20 (12)(12): p. 1341-9., https://pubmed.ncbi.nlm.nih.gov/21034228/
[544] Castagna, MG, Maino, F, Cipri, C, Belardini, V, Theodoropoulou, A, Cevenini, G, et.al. Delayed risk stratification, to include the response to initial treatment (surgery and radioiodine ablation), has better outcome predictivity in differentiated thyroid cancer patients., Eur J Endocrinol, 2011. 165 (3)(3): p. 441-6., https://pubmed.ncbi.nlm.nih.gov/21750043/
[545] Vaisman, F, Momesso, D, Bulzico, DA, Pessoa, CH, Dias, F, Corbo, R, et.al. Spontaneous remission in thyroid cancer patients after biochemical incomplete response to initial therapy., Clin Endocrinol (Oxf), 2012. 77 (1)(1): p. 132-8., https://pubmed.ncbi.nlm.nih.gov/22248037/
[546] Pitoia, F, Bueno, F, Urciuoli, C, Abelleira, E, Cross, G, Tuttle, RM, Outcomes of patients with differentiated thyroid cancer risk-stratified according to the American thyroid association and Latin American thyroid society risk of recurrence classification systems., Thyroid, 2013. 23 (11)(11): p. 1401-7., https://pubmed.ncbi.nlm.nih.gov/23517313/
[547] Li, J., Liang, J., Zhao, T., Lin, Y., Noninferior response in BRAF(V600E) mutant nonmetastatic papillary thyroid carcinoma to radioiodine therapy, Eur J Nucl Med Mol Imaging, 2016. 43(6): p. 1034-9.
[548] Orosco, RK, Hussain, T, Noel, JE, Chang, DC, Dosiou, C, Mittra, E, et.al. Radioactive iodine in differentiated thyroid cancer: a national database perspective., Endocr Relat Cancer, 2019. 26 (10)(10): p. 795-802., https://pubmed.ncbi.nlm.nih.gov/31443087/
[549] Brierley, J. D., Panzarella, T., Tsang, R. W., Gospodarowicz, M. K., O'Sullivan, B., A comparison of different staging systems predictability of patient outcome. Thyroid carcinoma as an example, Cancer, 1997. 79(12): p. 2414-23., https://pubmed.ncbi.nlm.nih.gov/9191532/
[550] Tanase, K., Thies, E. D., Mäder, U., Reiners, C., Verburg, F. A., The TNM system (version 7) is the most accurate staging system for the prediction of loss of life expectancy in differentiated thyroid cancer, Clin Endocrinol (Oxf), 2016. 84(2): p. 284-291.
[551] Nixon, I. J., Wang, L. Y., Migliacci, J. C., Eskander, A., Campbell, M. J., Aniss, A., et.al. An International Multi-Institutional Validation of Age 55 Years as a Cutoff for Risk Stratification in the AJCC/UICC Staging System for Well-Differentiated Thyroid Cancer, Thyroid, 2016. 26(3): p. 373-80., https://pubmed.ncbi.nlm.nih.gov/26914539/
[552] Tuttle, R. M., Ahuja, S., Avram, A. M., Bernet, V. J., Bourguet, P., Daniels, G. H., et.al. Controversies, Consensus, and Collaboration in the Use of (131)I Therapy in Differentiated Thyroid Cancer: A Joint Statement from the American Thyroid Association, the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the European Thyroid Association, Thyroid, 2019. 29(4): p. 461-470.
[553] Orosco, R. K., Hussain, T., Brumund, K. T., Oh, D. K., Chang, D. C., Bouvet, M., Analysis of age and disease status as predictors of thyroid cancer-specific mortality using the Surveillance, Epidemiology, and End Results database, Thyroid, 2015. 25(1): p. 125-32., https://pubmed.ncbi.nlm.nih.gov/25369076/
[554] van Velsen, E. F. S., Visser, W. E., Stegenga, M. T., Mäder, U., Reiners, C., van Kemenade, F. J., et.al. Finding the Optimal Age Cutoff for the UICC/AJCC TNM Staging System in Patients with Papillary or Follicular Thyroid Cancer, Thyroid, 2021. 31(7): p. 1041-1049., https://pubmed.ncbi.nlm.nih.gov/33487121/
[555] Luster, M., Aktolun, C., Amendoeira, I., Barczyński, M., Bible, K. C., Duntas, L. H., et.al. European Perspective on 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: Proceedings of an Interactive International Symposium, Thyroid, 2019. 29(1): p. 7-26.
[556] Verburg, F. A., Flux, G., Giovanella, L., van Nostrand, D., Muylle, K., Luster, M., Differentiated thyroid cancer patients potentially benefitting from postoperative I-131 therapy: a review of the literature of the past decade, Eur J Nucl Med Mol Imaging, 2020. 47(1): p. 78-83.
[557] (IARC), International Agency for Research on Cancer, Cancer incidence in five continents XI:
[558] Pontius, L. N., Youngwirth, L. M., Thomas, S. M., Scheri, R. P., Roman, S. A., Sosa, J. A., Lymphovascular invasion is associated with survival for papillary thyroid cancer, Endocr Relat Cancer, 2016. 23(7): p. 555-62.
[559] Zhu, G.; Deng, Y.; Pan, L.; Ouyang, W.; Feng, H.; Wu, J.; Chen, P.; Wang, J.; Chen, Y.; Luo, J., Clinical significance of the BRAF V600E mutation in PTC and its effect on radioiodine therapy, Endocrine Connections, 2019. 8: p. 754-763., https://pubmed.ncbi.nlm.nih.gov/31071680/
[560] Schmidt, M., Bartenstein, P., Bucerius, J., Dietlein, M., Drzezga, A., Herrmann, K., et.al. Individualized treatment of differentiated thyroid cancer: The value of surgery in combination with radioiodine imaging and therapy - A German position paper from Surgery and Nuclear Medicine, Nuklearmedizin, 2022. 61(2): p. 87-96.
[561] Sawka, A. M., Thephamongkhol, K., Brouwers, M., Thabane, L., Browman, G., Gerstein, H. C., Clinical review 170: A systematic review and metaanalysis of the effectiveness of radioactive iodine remnant ablation for well-differentiated thyroid cancer, J Clin Endocrinol Metab, 2004. 89(8): p. 3668-76.
[562] Sawka, A. M., Brierley, J. D., Tsang, R. W., Thabane, L., Rotstein, L., Gafni, A., et.al. An updated systematic review and commentary examining the effectiveness of radioactive iodine remnant ablation in well-differentiated thyroid cancer, Endocrinol Metab Clin North Am, 2008. 37(2): p. 457-80, x.
[563] Sun, Y., Gong, J., Guo, B., Shang, J., Cheng, Y., Xu, H., Association of adjuvant radioactive iodine therapy with survival in node-positive papillary thyroid cancer, Oral Oncology, 2018. 87: p. 152-157., https://pubmed.ncbi.nlm.nih.gov/30527231/
[564] Jonklaas, J., Sarlis, N. J., Litofsky, D., Ain, K. B., Bigos, S. T., Brierley, J. D., et.al. Outcomes of patients with differentiated thyroid carcinoma following initial therapy, Thyroid, 2006. 16(12): p. 1229-42., https://pubmed.ncbi.nlm.nih.gov/17199433/
[565] Carhill, A. A., Litofsky, D. R., Ross, D. S., Jonklaas, J., Cooper, D. S., Brierley, J. D., et.al. Long-Term Outcomes Following Therapy in Differentiated Thyroid Carcinoma: NTCTCS Registry Analysis 1987-2012, J Clin Endocrinol Metab, 2015. 100(9): p. 3270-9., https://pubmed.ncbi.nlm.nih.gov/26171797/
[566] Yang, Z., Flores, J., Katz, S., Nathan, C. A., Mehta, V., Comparison of Survival Outcomes Following Postsurgical Radioactive Iodine Versus External Beam Radiation in Stage IV Differentiated Thyroid Carcinoma, Thyroid, 2017. 27(7): p. 944-952., https://pubmed.ncbi.nlm.nih.gov/28446057/
[567] Ruel, E., Thomas, S., Perkins, J. M., Roman, S. A., Sosa, J. A., The Impact of Pathologically Positive Lymph Nodes in the Clinically Negative Neck: An Analysis of 39,301 Patients with Papillary Thyroid Cancer, Annals of Surgical Oncology, 2017. 24(7): p. 1935-1942., https://pubmed.ncbi.nlm.nih.gov/28127652/
[568] Tang, J., Kong, D., Cui, Q., Wang, K., Zhang, D., Liao, X., et.al. The role of radioactive iodine therapy in papillary thyroid cancer: an observational study based on SEER, OncoTargets and therapy, 2018. 11: p. 3551-3560., https://pubmed.ncbi.nlm.nih.gov/29950860/
[569] Verburg, F. A., Mäder, U., Tanase, K., Thies, E. D., Diessl, S., Buck, A. K., et.al. Life expectancy is reduced in differentiated thyroid cancer patients ≥ 45 years old with extensive local tumor invasion, lateral lymph node, or distant metastases at diagnosis and normal in all other DTC patients, J Clin Endocrinol Metab, 2013. 98(1): p. 172-80.
[570] Adam, M. A., Pura, J., Gu, L., Dinan, M. A., Tyler, D. S., Reed, S. D., et.al. Extent of surgery for papillary thyroid cancer is not associated with survival: an analysis of 61,775 patients, Ann Surg, 2014. 260(4): p. 601-5; discussion 605-7., https://www.ncbi.nlm.nih.gov/pubmed/25203876
[571] Ruel, E., Thomas, S., Dinan, M., Perkins, J. M., Roman, S. A., Sosa, J. A., Adjuvant radioactive iodine therapy is associated with improved survival for patients with intermediate-risk papillary thyroid cancer, Journal of Clinical Endocrinology & Metabolism, 2015. 100(4): p. 1529-36., https://pubmed.ncbi.nlm.nih.gov/25642591/
[572] Liu, X.; Fan, Y.; Liu, Y.; He, X.; Zheng, X.; Tan, J. Jia, Q.; Meng Z., The impact of radioactive iodine treatmenton survival among papillary thyroid cancer patients according to the 7th and 8th editions of the AJCC/TNM staging system: a SEER-based study, Updates in Surgery, 2020. 72: p. 871-884.
[573] MacKinney, EC, Kuchta, KM, Winchester, DJ, Khokar, AM, Holoubek, SA, Moo-Young, TA, et.al. Overall survival is improved with total thyroidectomy and radiation for male patients and patients older than 55 with T2N0M0 Stage 1 classic papillary thyroid cancer., Surgery, 2022. 171 (1)(1): p. 197-202., https://pubmed.ncbi.nlm.nih.gov/34666913/
[574] Zhao, M.; Shi, X.; Zhang, J.; Deng, S.; Zhou, Y.; Wen, R.; Lu, Y.; Zhang, B., Radioactive Iodine Ablation Can Reduce the Structural Recurrence Rate of Intermediate-Risk Papillary Thyroid Microcarcinoma: A Meta-Analysis, Computational and Mathematical Methods in Medicine, 2022. Volume 2022 | Article ID 8028846:
[575] Sutton, W, Canner, JK, Segev, DL, Zeiger, MA, Mathur, A, Treatment Variation in Older Adults With Differentiated Thyroid Cancer., J Surg Res, 2020. 254 (): p. 154-164., https://pubmed.ncbi.nlm.nih.gov/32445931/
[576] Harach, H. R., Franssila, K. O., Wasenius, VM, Occult papillary carcinoma of the thyroid. A "normal" finding in Finland. A systematic autopsy study., Cancer, 1985. 56: p. 531-538., https://pubmed.ncbi.nlm.nih.gov/2408737/
[577] Hu, G., Zhu, W., Yang, W., Wang, H., Shen, L., Zhang, H., The Effectiveness of Radioactive Iodine Remnant Ablation for Papillary Thyroid Microcarcinoma: A Systematic Review and Meta-analysis, World Journal of Surgery, 2016. 40(1): p. 100-9., https://pubmed.ncbi.nlm.nih.gov/26578322/
[578] Baudin, E., Travagli, J. P., Ropers, J., Mancusi, F., Bruno-Bossio, G., Caillou, B., et.al. Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience, Cancer, 1998. 83(3): p. 553-9., https://pubmed.ncbi.nlm.nih.gov/9690549/
[579] Pillai, S., Gopalan, V., Smith, R. A., Lam, A. K., Diffuse sclerosing variant of papillary thyroid carcinoma--an update of its clinicopathological features and molecular biology, Crit Rev Oncol Hematol, 2015. 94(1): p. 64-73.
[580] Elisei, R., Viola, D., Torregrossa, L., Giannini, R., Romei, C., Ugolini, C., et.al. The BRAF(V600E) mutation is an independent, poor prognostic factor for the outcome of patients with low-risk intrathyroid papillary thyroid carcinoma: single-institution results from a large cohort study, J Clin Endocrinol Metab, 2012. 97(12): p. 4390-8., https://pubmed.ncbi.nlm.nih.gov/23066120/
[581] Machens, A., Holzhausen, H. J., Dralle, H., The prognostic value of primary tumor size in papillary and follicular thyroid carcinoma, Cancer, 2005. 103(11): p. 2269-73.
[582] Malandrino, P., Pellegriti, G., Attard, M., Violi, M. A., Giordano, C., Sciacca, L., et.al. Papillary thyroid microcarcinomas: a comparative study of the characteristics and risk factors at presentation in two cancer registries, J Clin Endocrinol Metab, 2013. 98(4): p. 1427-34.
[583] Mehanna, H., Al-Maqbili, T., Carter, B., Martin, E., Campain, N., Watkinson, J., et.al. Differences in the recurrence and mortality outcomes rates of incidental and nonincidental papillary thyroid microcarcinoma: a systematic review and meta-analysis of 21 329 person-years of follow-up, J Clin Endocrinol Metab, 2014. 99(8): p. 2834-43.
[584] Shattuck, T. M., Westra, W. H., Ladenson, P. W., Arnold, A., Independent clonal origins of distinct tumor foci in multifocal papillary thyroid carcinoma, N Engl J Med, 2005. 352(23): p. 2406-12.
[585] Genpeng, L., Jianyong, L., Jiaying, Y., Ke, J., Zhihui, L., Rixiang, G., et.al. Independent predictors and lymph node metastasis characteristics of multifocal papillary thyroid cancer, Medicine, 2018. 97(5): p. e9619., https://pubmed.ncbi.nlm.nih.gov/29384841/
[586] Leboulleux, S., Bournaud, C., Chougnet, C. N., Zerdoud, S., Al Ghuzlan, A., Catargi, B., et.al. Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer, N Engl J Med, 2022. 386(10): p. 923-932.
[587] Kwon, H, Jeon, MJ, Kim, WG, Park, S, Kim, M, Kim, TY, et.al. Lack of Efficacy of Radioiodine Remnant Ablation for Papillary Thyroid Microcarcinoma: Verification Using Inverse Probability of Treatment Weighting., Ann Surg Oncol, 2017. 24 (9)(9): p. 2596-2602., https://pubmed.ncbi.nlm.nih.gov/28600731/
[588] Al-Qahtani, KH, Al Asiri, M, Tunio, MA, Aljohani, NJ, Bayoumi, Y, Fatani, H, et.al. Adjuvant Radioactive iodine 131 ablation in papillary microcarcinoma of thyroid: Saudi Arabian experience [corrected]., J Otolaryngol Head Neck Surg, 2015. 44 (): p. 51., https://pubmed.ncbi.nlm.nih.gov/26621255/
[589] Goran, M., Markovic, I., Buta, M., Gavrilovic, D., Cvetkovic, A., Santrac, N., et.al. The influence of papillary thyroid microcarcinomas size on the occurrence of lymph node metastases, J buon, 2019. 24(5): p. 2120-2126., https://pubmed.ncbi.nlm.nih.gov/31786884/
[590] Gao, X., Zhang, X., Zhang, Y., Hua, W., Maimaiti, Y., Gao, Z., Is papillary thyroid microcarcinoma an indolent tumor?: A retrospective study on 280 cases treated with radioiodine, Medicine (Baltimore), 2016. 95(40): p. e5067., https://pubmed.ncbi.nlm.nih.gov/27749574/
[591] Gong, Y., Li, G., Lei, J., You, J., Jiang, K., Li, Z., et.al. A favorable tumor size to define papillary thyroid microcarcinoma: an analysis of 1176 consecutive cases, Cancer Manag Res, 2018. 10: p. 899-906., https://pubmed.ncbi.nlm.nih.gov/29740219/
[592] Al-Qurayshi, Z., Nilubol, N., Tufano, R. P., Kandil, E., Wolf in Sheep's Clothing: Papillary Thyroid Microcarcinoma in the US, J Am Coll Surg, 2020. 230(4): p. 484-491., https://www.ncbi.nlm.nih.gov/pubmed/32220437
[593] Huang, Y., Yin, Y., Zhou, W., Risk Factors for Central and Lateral Lymph Node Metastases in Patients With Papillary Thyroid Micro-Carcinoma: Retrospective Analysis on 484 Cases, Front Endocrinol (Lausanne), 2021. 12: p. 640565., https://pubmed.ncbi.nlm.nih.gov/33746905/
[594] Tuncel, M., Vrachimis, A., Campenni, A., de Keizer, B., Verburg, F. A., Kreissl, M. C., et.al. To give or not to give? A critical appraisal of a clinical trial on radioiodine treatment, Eur J Nucl Med Mol Imaging, 2022. 49(10): p. 3316-3319.
[595] Zhao, H, Gong, Y, Radioactive iodine in low- to intermediate-risk papillary thyroid cancer., Front Endocrinol (Lausanne), 2022. 13 (): p. 960682., https://pubmed.ncbi.nlm.nih.gov/36034423/
[596] Schmidt, M., Görges, R., Drzezga, A., Dietlein, M., A Matter of Controversy: Is Radioiodine Therapy Favorable in Differentiated Thyroid Carcinoma?, J Nucl Med, 2018. 59(8): p. 1195-1201.
[597] Wang, J. B., Sun, Y. Y., Shi, L. H., Xie, L., Predictive factors for non-small-volume central lymph node metastases (more than 5 or ≥ 2 mm) in clinically node-negative papillary thyroid carcinoma, Medicine (Baltimore), 2019. 98(1): p. e14028., https://pubmed.ncbi.nlm.nih.gov/30608456/
[598] Lei, J., Zhong, J., Jiang, K., Li, Z., Gong, R., Zhu, J., Skip lateral lymph node metastasis leaping over the central neck compartment in papillary thyroid carcinoma, Oncotarget, 2017. 8(16): p. 27022-27033.
[599] Nie, X., Tan, Z., Ge, M., Skip metastasis in papillary thyroid carcinoma is difficult to predict in clinical practice, BMC Cancer, 2017. 17(1): p. 702.
[600] Alzahrani, A. S., Xing, M., Impact of lymph node metastases identified on central neck dissection (CND) on the recurrence of papillary thyroid cancer: potential role of BRAFV600E mutation in defining CND, Endocr Relat Cancer, 2013. 20(1): p. 13-22., https://www.ncbi.nlm.nih.gov/pubmed/23132792
[601] Pereira, JA, Jimeno, J, Miquel, J, Iglesias, M, Munné, A, Sancho, JJ, et.al. Nodal yield, morbidity, and recurrence after central neck dissection for papillary thyroid carcinoma., Surgery, 2005. 138 (6)(6): p. 1095-100, discussion 1100-1., https://pubmed.ncbi.nlm.nih.gov/16360396/
[602] Wang, L. Y., Ganly, I., Nodal metastases in thyroid cancer: prognostic implications and management, Future Oncol, 2016. 12(7): p. 981-94., https://pubmed.ncbi.nlm.nih.gov/26948758/
[603] Robinson, T. J., Thomas, S., Dinan, M. A., Roman, S., Sosa, J. A., Hyslop, T., How Many Lymph Nodes Are Enough? Assessing the Adequacy of Lymph Node Yield for Papillary Thyroid Cancer, J Clin Oncol, 2016. 34(28): p. 3434-9.
[604] Randolph, G. W., Duh, Q. Y., Heller, K. S., LiVolsi, V. A., Mandel, S. J., Steward, D. L., et.al. The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension, Thyroid, 2012. 22(11): p. 1144-52.
[605] Randolph, GW, Duh, QY, Heller, KS, LiVolsi, VA, Mandel, SJ, Steward, DL, et.al. The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension., Thyroid, 2012. 22 (11)(11): p. 1144-52., https://pubmed.ncbi.nlm.nih.gov/23083442/
[606] Eustatia-Rutten, C. F., Corssmit, E. P., Biermasz, N. R., Pereira, A. M., Romijn, J. A., Smit, J. W., Survival and death causes in differentiated thyroid carcinoma, J Clin Endocrinol Metab, 2006. 91(1): p. 313-9., https://pubmed.ncbi.nlm.nih.gov/16263822/
[607] Holoubek, SA, MacKinney, EC, Khokar, AM, Kuchta, KM, Winchester, DJ, Prinz, RA, et.al. Radioactive iodine does not improve overall survival for patients with aggressive variants of papillary thyroid carcinoma less than 2 cm., Surgery, 2022. 171 (1)(1): p. 203-211., https://pubmed.ncbi.nlm.nih.gov/34384604/
[608] Gonzalez-Gonzalez, R., Bologna-Molina, R., Carreon-Burciaga, R. G., Gómezpalacio-Gastelum, M., Molina-Frechero, N., Salazar-Rodríguez, S., Papillary thyroid carcinoma: differential diagnosis and prognostic values of its different variants: review of the literature, ISRN Oncol, 2011. 2011: p. 915925., https://pubmed.ncbi.nlm.nih.gov/22432054/
[609] Jiang, C., Cheng, T., Zheng, X., Hong, S., Liu, S., Liu, J., et.al. Clinical behaviors of rare variants of papillary thyroid carcinoma are associated with survival: a population-level analysis, Cancer Manag Res, 2018. 10: p. 465-472., https://pubmed.ncbi.nlm.nih.gov/29563836/
[610] Lam, A. K., Saremi, N., Cribriform-morular variant of papillary thyroid carcinoma: a distinctive type of thyroid cancer, Endocr Relat Cancer, 2017. 24(4): p. R109-r121.
[611] Ito, Y., Miyauchi, A., Ishikawa, H., Hirokawa, M., Kudo, T., Tomoda, C., et.al. Our experience of treatment of cribriform morular variant of papillary thyroid carcinoma; difference in clinicopathological features of FAP-associated and sporadic patients, Endocr J, 2011. 58(8): p. 685-9., https://pubmed.ncbi.nlm.nih.gov/21670544/
[612] Yu, X. M., Schneider, D. F., Leverson, G., Chen, H., Sippel, R. S., Follicular variant of papillary thyroid carcinoma is a unique clinical entity: a population-based study of 10,740 cases, Thyroid, 2013. 23(10): p. 1263-8., https://pubmed.ncbi.nlm.nih.gov/23477346/
[613] Koo, J. S., Hong, S., Park, C. S., Diffuse sclerosing variant is a major subtype of papillary thyroid carcinoma in the young, Thyroid, 2009. 19(11): p. 1225-31.
[614] Fukushima, M., Ito, Y., Hirokawa, M., Akasu, H., Shimizu, K., Miyauchi, A., Clinicopathologic characteristics and prognosis of diffuse sclerosing variant of papillary thyroid carcinoma in Japan: an 18-year experience at a single institution, World J Surg, 2009. 33(5): p. 958-62., https://pubmed.ncbi.nlm.nih.gov/19198928/
[615] Regalbuto, C., Malandrino, P., Tumminia, A., Le Moli, R., Vigneri, R., Pezzino, V., A diffuse sclerosing variant of papillary thyroid carcinoma: clinical and pathologic features and outcomes of 34 consecutive cases, Thyroid, 2011. 21(4): p. 383-9.
[616] Coca-Pelaz, A., Shah, J. P., Hernandez-Prera, J. C., Ghossein, R. A., Rodrigo, J. P., Hartl, D. M., et.al. Papillary Thyroid Cancer-Aggressive Variants and Impact on Management: A Narrative Review, Adv Ther, 2020. 37(7): p. 3112-3128., https://pubmed.ncbi.nlm.nih.gov/32488657/
[617] Nikiforov, Y. E., Erickson, L. A., Nikiforova, M. N., Caudill, C. M., Lloyd, R. V., Solid variant of papillary thyroid carcinoma: incidence, clinical-pathologic characteristics, molecular analysis, and biologic behavior, Am J Surg Pathol, 2001. 25(12): p. 1478-84.
[618] Nikiforov, Y., Gnepp, D. R., Fagin, J. A., Thyroid lesions in children and adolescents after the Chernobyl disaster: implications for the study of radiation tumorigenesis, J Clin Endocrinol Metab, 1996. 81(1): p. 9-14.
[619] Reiners, C., Biko, J., Haenscheid, H., Hebestreit, H., Kirinjuk, S., Baranowski, O., et.al. Twenty-five years after Chernobyl: outcome of radioiodine treatment in children and adolescents with very high-risk radiation-induced differentiated thyroid carcinoma, J Clin Endocrinol Metab, 2013. 98(7): p. 3039-48.
[620] Vuong, H. G., Odate, T., Duong, U. N. P., Mochizuki, K., Nakazawa, T., Katoh, R., et.al. Prognostic importance of solid variant papillary thyroid carcinoma: A systematic review and meta-analysis, Head Neck, 2018. 40(7): p. 1588-1597.
[621] Ohashi, R., Kawahara, K., Namimatsu, S., Igarashi, T., Sakatani, T., Sugitani, I., et.al. Clinicopathological significance of a solid component in papillary thyroid carcinoma, Histopathology, 2017. 70(5): p. 775-781.
[622] Chang, H., Kim, S. M., Chun, K. W., Kim, B. W., Lee, Y. S., Chang, H. S., et.al. Clinicopathologic features of solid variant papillary thyroid cancer, ANZ J Surg, 2014. 84(5): p. 380-2., https://pubmed.ncbi.nlm.nih.gov/23826897/
[623] Cartwright, S., Fingeret, A., Contemporary evaluation and management of tall cell variant of papillary thyroid carcinoma, Curr Opin Endocrinol Diabetes Obes, 2020. 27(5): p. 351-357., https://pubmed.ncbi.nlm.nih.gov/32701516/
[624] Kazaure, H. S., Roman, S. A., Sosa, J. A., Aggressive variants of papillary thyroid cancer: incidence, characteristics and predictors of survival among 43,738 patients, Ann Surg Oncol, 2012. 19(6): p. 1874-80.
[625] Leung, A. K., Chow, S. M., Law, S. C., Clinical features and outcome of the tall cell variant of papillary thyroid carcinoma, Laryngoscope, 2008. 118(1): p. 32-8.
[626] Longheu, A., Canu, G. L., Cappellacci, F., Erdas, E., Medas, F., Calò, P. G., Tall Cell Variant versus Conventional Papillary Thyroid Carcinoma: A Retrospective Analysis in 351 Consecutive Patients, J Clin Med, 2020. 10(1):
[627] Xu, J., Zhang, Y., Liu, J., Qiu, S., Wang, M., A population-based study of the three major variants of papillary thyroid carcinoma, J Int Med Res, 2021. 49(2): p. 300060520984618., https://pubmed.ncbi.nlm.nih.gov/33535844/
[628] Michels, J. J., Jacques, M., Henry-Amar, M., Bardet, S., Prevalence and prognostic significance of tall cell variant of papillary thyroid carcinoma, Hum Pathol, 2007. 38(2): p. 212-9.
[629] Holoubek, S. A., Yan, H., Khokar, A. H., Kuchta, K. M., Winchester, D. J., Prinz, R. A., et.al. Aggressive variants of papillary thyroid microcarcinoma are associated with high-risk features, but not decreased survival, Surgery, 2020. 167(1): p. 19-27., https://pubmed.ncbi.nlm.nih.gov/31627846/
[630] Limberg, J., Ullmann, T. M., Stefanova, D., Buicko, J. L., Finnerty, B. M., Zarnegar, R., et.al. Does Aggressive Variant Histology Without Invasive Features Predict Overall Survival in Papillary Thyroid Cancer?: A National Cancer Database Analysis, Ann Surg, 2021. 274(3): p. e276-e281.
[631] Regalbuto, C., Malandrino, P., Frasca, F., Pellegriti, G., Le Moli, R., Vigneri, R., et.al. The tall cell variant of papillary thyroid carcinoma: clinical and pathological features and outcomes, J Endocrinol Invest, 2013. 36(4): p. 249-54.
[632] Wei, S., Gao, M., Zhao, C., Pan, Y., Li, H., Li, J., et.al. Low expression of sodium iodide symporter expression in aggressive variants of papillary thyroid carcinoma, Int J Clin Oncol, 2014. 19(5): p. 800-4.
[633] Silver, C. E., Owen, R. P., Rodrigo, J. P., Rinaldo, A., Devaney, K. O., Ferlito, A., Aggressive variants of papillary thyroid carcinoma, Head Neck, 2011. 33(7): p. 1052-9.
[634] Wong, K. S., Higgins, S. E., Marqusee, E., Nehs, M. A., Angell, T., Barletta, J. A., Tall Cell Variant of Papillary Thyroid Carcinoma: Impact of Change in WHO Definition and Molecular Analysis, Endocr Pathol, 2019. 30(1): p. 43-48.
[635] Chen, J. H., Faquin, W. C., Lloyd, R. V., Nosé, V., Clinicopathological and molecular characterization of nine cases of columnar cell variant of papillary thyroid carcinoma, Mod Pathol, 2011. 24(5): p. 739-49., https://pubmed.ncbi.nlm.nih.gov/21358618/
[636] Nath, M. C., Erickson, L. A., Aggressive Variants of Papillary Thyroid Carcinoma: Hobnail, Tall Cell, Columnar, and Solid, Adv Anat Pathol, 2018. 25(3): p. 172-179.
[637] Song, E., Jeon, M. J., Oh, H. S., Han, M., Lee, Y. M., Kim, T. Y., et.al. Do aggressive variants of papillary thyroid carcinoma have worse clinical outcome than classic papillary thyroid carcinoma?, Eur J Endocrinol, 2018. 179(3): p. 135-142.
[638] Wang, S., Xiong, Y., Zhao, Q., Song, H., Yi, P., Liu, C., Columnar cell papillary thyroid carcinoma prognosis: findings from the SEER database using propensity score matching analysis, Am J Transl Res, 2019. 11(9): p. 6262-6270., https://pubmed.ncbi.nlm.nih.gov/31632592/
[639] Wenig, B. M., Thompson, L. D., Adair, C. F., Shmookler, B., Heffess, C. S., Thyroid papillary carcinoma of columnar cell type: a clinicopathologic study of 16 cases, Cancer, 1998. 82(4): p. 740-53.
[640] Asioli, S., Erickson, L. A., Sebo, T. J., Zhang, J., Jin, L., Thompson, G. B., et.al. Papillary thyroid carcinoma with prominent hobnail features: a new aggressive variant of moderately differentiated papillary carcinoma. A clinicopathologic, immunohistochemical, and molecular study of eight cases, Am J Surg Pathol, 2010. 34(1): p. 44-52., https://pubmed.ncbi.nlm.nih.gov/19956062/
[641] Mohapatra, D., Naik, S., Das, P., Agrawala, S., Metastatic hobnail variant of papillary thyroid carcinoma: A diagnostic challenge in cell block preparation, Indian J Pathol Microbiol, 2021. 64(2): p. 358-361.
[642] Asioli, S., Erickson, L. A., Righi, A., Lloyd, R. V., Papillary thyroid carcinoma with hobnail features: histopathologic criteria to predict aggressive behavior, Hum Pathol, 2013. 44(3): p. 320-8., https://pubmed.ncbi.nlm.nih.gov/23036367/
[643] Lubitz, C. C., Economopoulos, K. P., Pawlak, A. C., Lynch, K., Dias-Santagata, D., Faquin, W. C., et.al. Hobnail variant of papillary thyroid carcinoma: an institutional case series and molecular profile, Thyroid, 2014. 24(6): p. 958-65.
[644] Donaldson, L. B., Yan, F., Morgan, P. F., Kaczmar, J. M., Fernandes, J. K., Nguyen, S. A., et.al. Hobnail variant of papillary thyroid carcinoma: a systematic review and meta-analysis, Endocrine, 2021. 72(1): p. 27-39., https://pubmed.ncbi.nlm.nih.gov/33025563/
[645] Morandi, L.; Righi, A.; Maletta, F.; Rucci, P.; Pagni, F.; Gallo, M.; Rossi, S.; Caporali, L.; Sapino, A.; Lloyd, R.; Asioli, S., Somatic mutation profiling of hobnail variant of papillary thyroid carcinoma., Endocrine-related Cancer, 2017. 24: p. 107-117.
[646] Gross, M., Eliashar, R., Ben-Yaakov, A., Weinberger, J. M., Maly, B., Clinicopathologic features and outcome of the oncocytic variant of papillary thyroid carcinoma, Ann Otol Rhinol Laryngol, 2009. 118(5): p. 374-81., https://pubmed.ncbi.nlm.nih.gov/19548388/
[647] Herrera, M. F., Hay, I. D., Wu, P. S., Goellner, J. R., Ryan, J. J., Ebersold, J. R., et.al. Hürthle cell (oxyphilic) papillary thyroid carcinoma: a variant with more aggressive biologic behavior, World J Surg, 1992. 16(4): p. 669-74; discussion 774-5., https://pubmed.ncbi.nlm.nih.gov/1413835/
[648] Hong, J. H., Yi, H. S., Yi, S., Kim, H. W., Lee, J., Kim, K. S., Implications of oncocytic change in papillary thyroid cancer, Clin Endocrinol (Oxf), 2016. 85(5): p. 797-804., https://pubmed.ncbi.nlm.nih.gov/27234487/
[649] Carr, A. A., Yen, T. W. F., Ortiz, D. I., Hunt, B. C., Fareau, G., Massey, B. L., et.al. Patients with Oncocytic Variant Papillary Thyroid Carcinoma Have a Similar Prognosis to Matched Classical Papillary Thyroid Carcinoma Controls, Thyroid, 2018. 28(11): p. 1462-1467., https://pubmed.ncbi.nlm.nih.gov/30215297/
[650] Liu, C., Zhao, Q., Zeng, W., Chen, C., Ming, J., Wang, S., et.al. Do patients with oxyphilic cell papillary thyroid carcinoma have a poor prognosis? Analysis of the surveillance, epidemiology, and end results database 2004-2013 with propensity score matching, Oncotarget, 2017. 8(44): p. 77075-77085., https://pubmed.ncbi.nlm.nih.gov/29100371/
[651] Wenter, V., Jellinek, A., Unterrainer, M., Ahmaddy, F., Lehner, S., Albert, N. L., et.al. Long-term outcome of rare oncocytic papillary (Hürthle cell) thyroid carcinoma following (adjuvant) initial radioiodine therapy, Eur J Nucl Med Mol Imaging, 2019. 46(12): p. 2526-2535.
[652] Goffredo, P., Sosa, J. A., Roman, S. A., Differentiated thyroid cancer presenting with distant metastases: a population analysis over two decades, World Journal of Surgery, 2013. 37(7): p. 1599-605., https://pubmed.ncbi.nlm.nih.gov/23525600/
[653] Beckner, M. E., Heffess, C. S., Oertel, J. E., Oxyphilic papillary thyroid carcinomas, Am J Clin Pathol, 1995. 103(3): p. 280-7., https://pubmed.ncbi.nlm.nih.gov/7872249/
[654] Cipriani, N. A., Nagar, S., Kaplan, S. P., White, M. G., Antic, T., Sadow, P. M., et.al. Follicular Thyroid Carcinoma: How Have Histologic Diagnoses Changed in the Last Half-Century and What Are the Prognostic Implications?, Thyroid, 2015. 25(11): p. 1209-16., https://pubmed.ncbi.nlm.nih.gov/26440366/
[655] Yamazaki, H., Katoh, R., Sugino, K., Matsuzu, K., Masaki, C., Akaishi, J., et.al. Encapsulated Angioinvasive Follicular Thyroid Carcinoma: Prognostic Impact of the Extent of Vascular Invasion, Ann Surg Oncol, 2022., https://pubmed.ncbi.nlm.nih.gov/35169976/
[259] Goffredo, P., Cheung, K., Roman, S. A., Sosa, J. A., Can minimally invasive follicular thyroid cancer be approached as a benign lesion?: a population-level analysis of survival among 1,200 patients, Ann Surg Oncol, 2013. 20(3): p. 767-72., https://pubmed.ncbi.nlm.nih.gov/23111705/
[656] Ito, Y., Hirokawa, M., Masuoka, H., Yabuta, T., Kihara, M., Higashiyama, T., et.al. Prognostic factors of minimally invasive follicular thyroid carcinoma: extensive vascular invasion significantly affects patient prognosis, Endocr J, 2013. 60(5): p. 637-42., https://pubmed.ncbi.nlm.nih.gov/23327839/
[657] D'Avanzo, A., Treseler, P., Ituarte, P. H., Wong, M., Streja, L., Greenspan, F. S., et.al. Follicular thyroid carcinoma: histology and prognosis, Cancer, 2004. 100(6): p. 1123-9., https://pubmed.ncbi.nlm.nih.gov/15022277/
[658] Peth, S., Hummel, R., Schreckenberger, M., Schad, A., Raabe, R., Weber, T., [Is there an indication for thyroidectomy in cases of minimally invasive follicular thyroid carcinoma?], Chirurg, 2022. 93(5): p. 509-512.
[659] Wu, M. H., Lee, Y. Y., Lu, Y. L., Lin, S. F., Risk Factors and Prognosis for Metastatic Follicular Thyroid Cancer, Front Endocrinol (Lausanne), 2022. 13: p. 791826., https://pubmed.ncbi.nlm.nih.gov/35299967/
[660] Janovitz, T., Barletta, J. A., Clinically Relevant Prognostic Parameters in Differentiated Thyroid Carcinoma, Endocr Pathol, 2018. 29(4): p. 357-364., https://pubmed.ncbi.nlm.nih.gov/30238434/
[661] Vogrin, A., Besic, H., Besic, N., Music, M. M., Recurrence rate in regional lymph nodes in 737 patients with follicular or Hürthle cell neoplasms, Radiol Oncol, 2016. 50(3): p. 269-73.
[662] Oluic, B., Paunovic, I., Loncar, Z., Djukic, V., Diklic, A., Jovanovic, M., et.al. Survival and prognostic factors for survival, cancer specific survival and disease free interval in 239 patients with Hurthle cell carcinoma: a single center experience, BMC Cancer, 2017. 17(1): p. 371.
[663] Hundahl, S. A., Fleming, I. D., Fremgen, A. M., Menck, H. R., A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see commetns], Cancer, 1998. 83(12): p. 2638-48., https://pubmed.ncbi.nlm.nih.gov/9874472/
[664] Haigh, P. I., Urbach, D. R., The treatment and prognosis of Hürthle cell follicular thyroid carcinoma compared with its non-Hürthle cell counterpart, Surgery, 2005. 138(6): p. 1152-7; discussion 1157-8., https://pubmed.ncbi.nlm.nih.gov/16360403/
[665] Sugino, K., Kameyama, K., Ito, K., Nagahama, M., Kitagawa, W., Shibuya, H., et.al. Does Hürthle cell carcinoma of the thyroid have a poorer prognosis than ordinary follicular thyroid carcinoma?, Ann Surg Oncol, 2013. 20(9): p. 2944-50.
[666] Lopez-Penabad, L., Chiu, A. C., Hoff, A. O., Schultz, P., Gaztambide, S., Ordoñez, N. G., et.al. Prognostic factors in patients with Hürthle cell neoplasms of the thyroid, Cancer, 2003. 97(5): p. 1186-94.
[667] Jillard, C. L., Youngwirth, L., Scheri, R. P., Roman, S., Sosa, J. A., Radioactive Iodine Treatment Is Associated with Improved Survival for Patients with Hürthle Cell Carcinoma, Thyroid, 2016. 26(7): p. 959-64., https://pubmed.ncbi.nlm.nih.gov/27150319/
[668] Xu, L., Zou, Q., Jiao, J., Zhang, Y., Postoperative radioiodine therapy impact on survival in poorly differentiated thyroid carcinoma: a population-based study, Nucl Med Commun, 2022. 43(2): p. 145-151., https://pubmed.ncbi.nlm.nih.gov/34711774/
[669] Ibrahimpasic, T., Ghossein, R., Carlson, D. L., Nixon, I., Palmer, F. L., Shaha, A. R., et.al. Outcomes in patients with poorly differentiated thyroid carcinoma, J Clin Endocrinol Metab, 2014. 99(4): p. 1245-52., https://pubmed.ncbi.nlm.nih.gov/24512493/
[670] Park, E. K., Chung, J. K., Lim, I. H., Park, D. J., Lee, D. S., Lee, M. C., et.al. Recurrent/metastatic thyroid carcinomas false negative for serum thyroglobulin but positive by posttherapy I-131 whole body scans, Eur J Nucl Med Mol Imaging, 2009. 36(2): p. 172-9.
[671] Robenshtok, E., Grewal, R. K., Fish, S., Sabra, M., Tuttle, R. M., A low postoperative nonstimulated serum thyroglobulin level does not exclude the presence of radioactive iodine avid metastatic foci in intermediate-risk differentiated thyroid cancer patients, Thyroid, 2013. 23(4): p. 436-42.
[672] Prabhu, M., Samson, S., Reddy, A., Venkataramanarao, S. H., Chandrasekhar, N. H., Pillai, V., et.al. Role of Preablative Stimulated Thyroglobulin in Prediction of Nodal and Distant Metastasis on Iodine Whole-Body Scan, Indian J Nucl Med, 2018. 33(2): p. 93-98.
[673] Giovanella, L., Suriano, S., Ceriani, L., Verburg, F. A., Undetectable thyroglobulin in patients with differentiated thyroid carcinoma and residual radioiodine uptake on a postablation whole-body scan, Clin Nucl Med, 2011. 36(2): p. 109-12., https://pubmed.ncbi.nlm.nih.gov/21220971/
[674] Matrone, A., Gambale, C., Piaggi, P., Viola, D., Giani, C., Agate, L., et.al. Postoperative Thyroglobulin and Neck Ultrasound in the Risk Restratification and Decision to Perform 131I Ablation, J Clin Endocrinol Metab, 2017. 102(3): p. 893-902.
[675] Campennì, A., Giovanella, L., Pignata, S. A., Vento, A., Alibrandi, A., Sturiale, L., et.al. Undetectable or low (<1 ng/ml) postsurgical thyroglobulin values do not rule out metastases in early stage differentiated thyroid cancer patients, Oncotarget, 2018. 9(25): p. 17491-17500., https://pubmed.ncbi.nlm.nih.gov/29707123/
[676] Mallick, U., Harmer, C., Yap, B., Wadsley, J., Clarke, S., Moss, L., et.al. Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer, New England journal of medicine, 2012. 366(18): p. 1674‐1685., https://www.cochranelibrary.com/central/doi/10.1002/central/CN-00814146/full, https://www.nejm.org/doi/pdf/10.1056/NEJMoa1109589?articleTools=true
[677] Maxon, H. R., Thomas, S. R., Hertzberg, V. S., Kereiakes, J. G., Chen, I. W., Sperling, M. I., et.al. Relation between effective radiation dose and outcome of radioiodine therapy for thyroid cancer, N Engl J Med, 1983. 309(16): p. 937-41.
[678] Flux, G. D., Haq, M., Chittenden, S. J., Buckley, S., Hindorf, C., Newbold, K., et.al. A dose-effect correlation for radioiodine ablation in differentiated thyroid cancer, Eur J Nucl Med Mol Imaging, 2010. 37(2): p. 270-5., https://pubmed.ncbi.nlm.nih.gov/19760413/
[679] Jentzen, W., Verschure, F., van Zon, A., van de Kolk, R., Wierts, R., Schmitz, J., et.al. 124I PET Assessment of Response of Bone Metastases to Initial Radioiodine Treatment of Differentiated Thyroid Cancer, J Nucl Med, 2016. 57(10): p. 1499-1504., https://pubmed.ncbi.nlm.nih.gov/27199362/
[680] Klubo-Gwiezdzinska, J., Van Nostrand, D., Atkins, F., Burman, K., Jonklaas, J., Mete, M., et.al. Efficacy of dosimetric versus empiric prescribed activity of 131I for therapy of differentiated thyroid cancer, J Clin Endocrinol Metab, 2011. 96(10): p. 3217-25.
[681] Hänscheid, H., Canzi, C., Eschner, W., Flux, G., Luster, M., Strigari, L., et.al. EANM Dosimetry Committee series on standard operational procedures for pre-therapeutic dosimetry II. Dosimetry prior to radioiodine therapy of benign thyroid diseases, Eur J Nucl Med Mol Imaging, 2013. 40(7): p. 1126-34., https://pubmed.ncbi.nlm.nih.gov/23576099/
[682] Pacini, F., Brianzoni, E., Durante, C., Elisei, R., Ferdeghini, M., Fugazzola, L., et.al. Recommendations for post-surgical thyroid ablation in differentiated thyroid cancer: a 2015 position statement of the Italian Society of Endocrinology, J Endocrinol Invest, 2016. 39(3): p. 341-7.
[683] Robinson, P. S., Barker, P., Campbell, A., Henson, P., Surveyor, I., Young, P. R., Iodine-131 in breast milk following therapy for thyroid carcinoma, J Nucl Med, 1994. 35(11): p. 1797-801.
[684] National Research Council, Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2The National Academies Press, 2006., https://nap.nationalacademies.org/catalog/11340/health-risks-from-exposure-to-low-levels-of-ionizing-radiation
[685] Schlumberger, M., De Vathaire, F., Ceccarelli, C., Delisle, M. J., Francese, C., Couette, J. E., et.al. Exposure to radioactive iodine-131 for scintigraphy or therapy does not preclude pregnancy in thyroid cancer patients, J Nucl Med, 1996. 37(4): p. 606-12.
[686] Metallo, M., Groza, L., Brunaud, L., Klein, M., Weryha, G., Feigerlova, E., Long-Term Quality of Life and Pregnancy Outcomes of Differentiated Thyroid Cancer Survivors Treated by Total Thyroidectomy and I(131) during Adolescence and Young Adulthood, Int J Endocrinol, 2016. 2016: p. 7586482.
[687] Kim, H. O., Lee, K., Lee, S. M., Seo, G. H., Association Between Pregnancy Outcomes and Radioactive Iodine Treatment After Thyroidectomy Among Women With Thyroid Cancer, JAMA Intern Med, 2020. 180(1): p. 54-61.
[200] Zhang, X, Zhang, X, Du, W, Dai, L, Luo, R, Fang, Q, et.al. Fine Needle Biopsy Versus Core Needle Biopsy Combined With/Without Thyroglobulin or BRAF 600E Mutation Assessment for Detecting Cervical Nodal Metastasis of Papillary Thyroid Carcinoma., Front Endocrinol (Lausanne), 2021. 12 (): p. 663720., https://pubmed.ncbi.nlm.nih.gov/33912138/
[688] Howell, R. W., Wessels, B. W., Loevinger, R., Watson, E. E., Bolch, W. E., Brill, A. B., et.al. The MIRD perspective 1999. Medical Internal Radiation Dose Committee, J Nucl Med, 1999. 40(1): p. 3s-10s., https://pubmed.ncbi.nlm.nih.gov/9935082/
[689] Mazzaferri, E. L., Gonadal damage from 131I therapy for thyroid cancer, Clin Endocrinol (Oxf), 2002. 57(3): p. 313-4.
[690] Pacini, F., Gasperi, M., Fugazzola, L., Ceccarelli, C., Lippi, F., Centoni, R., et.al. Testicular function in patients with differentiated thyroid carcinoma treated with radioiodine, J Nucl Med, 1994. 35(9): p. 1418-22.
[691] Wichers, M., Benz, E., Palmedo, H., Biersack, H. J., Grünwald, F., Klingmüller, D., Testicular function after radioiodine therapy for thyroid carcinoma, Eur J Nucl Med, 2000. 27(5): p. 503-7.
[692] Hyer, S., Vini, L., O'Connell, M., Pratt, B., Harmer, C., Testicular dose and fertility in men following I(131) therapy for thyroid cancer, Clin Endocrinol (Oxf), 2002. 56(6): p. 755-8., https://pubmed.ncbi.nlm.nih.gov/12072044/
[693] Sarkar, S. D., Beierwaltes, W. H., Gill, S. P., Cowley, B. J., Subsequent fertility and birth histories of children and adolescents treated with 131I for thyroid cancer, J Nucl Med, 1976. 17(6): p. 460-4.
[694] Rosário, P. W., Barroso, A. L., Rezende, L. L., Padrão, E. L., Borges, M. A., Guimarães, V. C., et.al. Testicular function after radioiodine therapy in patients with thyroid cancer, Thyroid, 2006. 16(7): p. 667-70.
[695] Canale, D., Ceccarelli, C., Caglieresi, C., Moscatelli, A., Gavioli, S., Santini, P., et.al. Effects of radioiodine treatment for differentiated thyroid cancer on testis function, Clin Endocrinol (Oxf), 2015. 82(2): p. 295-9., https://pubmed.ncbi.nlm.nih.gov/25138547/
[696] Piek, MW, Postma, EL, van Leeuwaarde, R, de Boer, JP, Bos, AME, Lok, C, et.al. The Effect of Radioactive Iodine Therapy on Ovarian Function and Fertility in Female Thyroid Cancer Patients: A Systematic Review and Meta-Analysis., Thyroid, 2021. 31 (4)(4): p. 658-668., https://pubmed.ncbi.nlm.nih.gov/33012254/
[697] Zhang, L, Huang, Y, Zheng, Y, Cai, L, Wen, J, Chen, G, The effect of I-131 therapy on pregnancy outcomes after thyroidectomy in patients with differentiated thyroid carcinoma: a meta-analysis., Endocrine, 2021. 73 (2)(2): p. 301-307., https://pubmed.ncbi.nlm.nih.gov/34009542/
[698] Sawka, A. M., Ibrahim-Zada, I., Galacgac, P., Tsang, R. W., Brierley, J. D., Ezzat, S., et.al. Dietary iodine restriction in preparation for radioactive iodine treatment or scanning in well-differentiated thyroid cancer: a systematic review, Thyroid, 2010. 20(10): p. 1129-38.
[699] Pluijmen, M. J., Eustatia-Rutten, C., Goslings, B. M., Stokkel, M. P., Arias, A. M., Diamant, M., et.al. Effects of low-iodide diet on postsurgical radioiodide ablation therapy in patients with differentiated thyroid carcinoma, Clin Endocrinol (Oxf), 2003. 58(4): p. 428-35.
[700] Sohn, S. Y., Choi, J. Y., Jang, H. W., Kim, H. J., Jin, S. M., Kim, S. W., et.al. Association between excessive urinary iodine excretion and failure of radioactive iodine thyroid ablation in patients with papillary thyroid cancer, Thyroid, 2013. 23(6): p. 741-7.
[701] Dobrenic, M., Huic, D., Zuvic, M., Grosev, D., Petrovic, R., Samardzic, T., Usefulness of low iodine diet in managing patients with differentiated thyroid cancer - initial results, Radiol Oncol, 2011. 45(3): p. 189-95., https://pubmed.ncbi.nlm.nih.gov/22933955/
[702] Barbaro, D., Boni, G., Meucci, G., Simi, U., Lapi, P., Orsini, P., et.al. Radioiodine treatment with 30 mCi after recombinant human thyrotropin stimulation in thyroid cancer: effectiveness for postsurgical remnants ablation and possible role of iodine content in L-thyroxine in the outcome of ablation, J Clin Endocrinol Metab, 2003. 88(9): p. 4110-5., https://pubmed.ncbi.nlm.nih.gov/12970272/
[703] Lan, W., Renjie, W., Qichang, W., Feiyue, T., Qingjie, M., Bin, J., Preoperative Use of Intravenous Contrast Media Is Associated With Decreased Excellent Response Rates in Intermediate-Risk DTC Patients Who Subsequently Receive Total Thyroidectomy and Low-Dose RAI Therapy, Front Oncol, 2020. 10: p. 1297.
[704] Petrulea, M. S., Lencu, C., Piciu, D., Lisencu, C. I., Georgescu, C. E., Challenges of thyroid cancer management in amiodarone-treated patients: a case report, Clujul Med, 2015. 88(4): p. 550-4.
[705] Puchalski, A. R., Chopra, I. J., Radioiodine treatment of differentiated thyroid cancer despite history of 'iodine allergy', Endocrinol Diabetes Metab Case Rep, 2014. 2014: p. 130084.
[706] Nakada, K., Ishibashi, T., Takei, T., Hirata, K., Shinohara, K., Katoh, S., et.al. Does lemon candy decrease salivary gland damage after radioiodine therapy for thyroid cancer?, J Nucl Med, 2005. 46(2): p. 261-6.
[707] Jentzen, W., Hobbs, R. F., Stahl, A., Knust, J., Sgouros, G., Bockisch, A., Pre-therapeutic (124)I PET(/CT) dosimetry confirms low average absorbed doses per administered (131)I activity to the salivary glands in radioiodine therapy of differentiated thyroid cancer, Eur J Nucl Med Mol Imaging, 2010. 37(5): p. 884-95., https://pubmed.ncbi.nlm.nih.gov/20069293/
[708] Jentzen, W., Balschuweit, D., Schmitz, J., Freudenberg, L., Eising, E., Hilbel, T., et.al. The influence of saliva flow stimulation on the absorbed radiation dose to the salivary glands during radioiodine therapy of thyroid cancer using 124I PET(/CT) imaging, Eur J Nucl Med Mol Imaging, 2010. 37(12): p. 2298-306., https://pubmed.ncbi.nlm.nih.gov/20625723/
[709] Fu, H., Ma, C., Tang, L., Wu, F., Liu, B., Wang, H., Recombinant human thyrotropin versus thyroid hormone withdrawal in radioiodine remnant ablation for differentiated thyroid cancer: a meta-analysis, The Quarterly Journal of Nuclear Medicine & Molecular Imaging, 2015. 59(1): p. 121-8., https://pubmed.ncbi.nlm.nih.gov/24844252/
[710] Verburg, FA, Stokkel, MP, Düren, C, Verkooijen, RB, Mäder, U, van Isselt, JW, et.al. No survival difference after successful (131)I ablation between patients with initially low-risk and high-risk differentiated thyroid cancer., Eur J Nucl Med Mol Imaging, 2010. 37 (2)(2): p. 276-83., https://pubmed.ncbi.nlm.nih.gov/20091165/
[711] Gomes-Lima, CJ, Chittimoju, S, Wehbeh, L, Dia, S, Pagadala, P, Al-Jundi, M, et.al. Metastatic Differentiated Thyroid Cancer Survival Is Unaffected by Mode of Preparation for , J Endocr Soc, 2022. 6 (5)(5): p. bvac032., https://pubmed.ncbi.nlm.nih.gov/35356009/
[712] Schlumberger, M., Catargi, B., Borget, I., Deandreis, D., Zerdoud, S., Bridji, B., et.al. Strategies of radioiodine ablation in patients with low-risk thyroid cancer, N Engl J Med, 2012. 366(18): p. 1663-73.
[713] Jentzen, W, Hoppenbrouwers, J, van Leeuwen, P, van der Velden, D, van de Kolk, R, Poeppel, TD, et.al. Assessment of lesion response in the initial radioiodine treatment of differentiated thyroid cancer using 124I PET imaging., J Nucl Med, 2014. 55 (11)(11): p. 1759-65., https://pubmed.ncbi.nlm.nih.gov/25332440/
[714] Ma, C, Feng, F, Wang, S, Fu, H, Wu, S, Ye, Z, et.al. Chinese Data of Efficacy of Low- and High-Dose Iodine-131 for the Ablation of Thyroid Remnant., Thyroid, 2017. 27 (6)(6): p. 832-837., https://pubmed.ncbi.nlm.nih.gov/28401794/
[715] Qu, Y, Huang, R, Li, L, Low- and high-dose radioiodine therapy for low-/intermediate-risk differentiated thyroid cancer: a preliminary clinical trial., Ann Nucl Med, 2017. 31 (1)(1): p. 71-83., https://pubmed.ncbi.nlm.nih.gov/27757803/
[716] Shengguang, Y, Ji-Eun, C, Lijuan, HL, I-131 for Remnant Ablation in Differentiated Thyroid Cancer After Thyroidectomy: A Meta-Analysis of Randomized Controlled Evidence., Med Sci Monit, 2016. 22 (): p. 2439-50., https://pubmed.ncbi.nlm.nih.gov/27406262/
[717] Jin, Y, Ruan, M, Cheng, L, Fu, H, Liu, M, Sheng, S, et.al. Radioiodine Uptake and Thyroglobulin-Guided Radioiodine Remnant Ablation in Patients with Differentiated Thyroid Cancer: A Prospective, Randomized, Open-Label, Controlled Trial., Thyroid, 2019. 29 (1)(1): p. 101-110., https://pubmed.ncbi.nlm.nih.gov/30560716/
[718] Vrachimis, A., Riemann, B., Gerss, J., Maier, T., Schober, O., Peace of mind for patients with differentiated thyroid cancer?, Nuklearmedizin, 2013. 52(4): p. 115-20.
[719] Abdulrezzak, U., Tutus, A., Isik, I., Kurt, Y., Kula, M., Quantitative comparison of low dose and standard dose radioiodine therapy effectiveness in patients with low risk differentiated thyroid cancer, Q J Nucl Med Mol Imaging, 2017. 61(3): p. 314-322., https://www.ncbi.nlm.nih.gov/pubmed/25600659
[720] Elrasad, S. A. A., Abdelhafeez, Y., Husseini, M. A., Amin, R. A. A., Elrefaei, S., Thyroid remnant ablation of differentiated thyroid carcinoma: a comparison of ablation success with high and low doses of radioiodine (I-131), European journal of nuclear medicine and molecular imaging., 2015. 42(1 SUPPL. 1): p. S328., https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01136120/full, https://link.springer.com/content/pdf/10.1007%2Fs00259-015-3198-z.pdf
[721] Schlumberger, M, Leboulleux, S, Catargi, B, Deandreis, D, Zerdoud, S, Bardet, S, et.al. Outcome after ablation in patients with low-risk thyroid cancer (ESTIMABL1): 5-year follow-up results of a randomised, phase 3, equivalence trial., Lancet Diabetes Endocrinol, 2018. 6 (8)(8): p. 618-626., https://pubmed.ncbi.nlm.nih.gov/29807824/
[722] Andresen, N. S., Buatti, J. M., Tewfik, H. H., Pagedar, N. A., Anderson, C. M., Watkins, J. M., Radioiodine Ablation following Thyroidectomy for Differentiated Thyroid Cancer: Literature Review of Utility, Dose, and Toxicity, Eur Thyroid J, 2017. 6(4): p. 187-196., https://pubmed.ncbi.nlm.nih.gov/28868259/
[723] Jentzen, W., Moldovan, A. S., Ruhlmann, M., Görges, R., Bockisch, A., Rosenbaum-Krumme, S., Lowest effective 131I activity for thyroid remnant ablation of differentiated thyroid cancer patients. Dosimetry-based model for estimation, Nuklearmedizin, 2015. 54(3): p. 137-43., https://pubmed.ncbi.nlm.nih.gov/25987357/
[724] Verburg, F. A., Mäder, U., Reiners, C., Hänscheid, H., Long-term survival in differentiated thyroid cancer is worse after low-activity initial post-surgical 131I therapy in both high- and low-risk patients, J Clin Endocrinol Metab, 2014. 99(12): p. 4487-96.
[725] Kukulska, A., Krajewska, J., Gawkowska-Suwinska, M., Puch, Z., Paliczka-Cieslik, E., Roskosz, J., et.al. Radioiodine thyroid remnant ablation in patients with differentiated thyroid carcinoma (DTC): prospective comparison of long-term outcomes of treatment with 30, 60 and 100 mCi, Thyroid research, 2010. 3(1): p. 9., https://pubmed.ncbi.nlm.nih.gov/21040579/
[726] Miller, J. E., Al-Attar, N. C., Brown, O. H., Shaughness, G. G., Rosculet, N. P., Avram, A. M., et.al. Location and Causation of Residual Lymph Node Metastasis After Surgical Treatment of Regionally Advanced Differentiated Thyroid Cancer, Thyroid, 2018. 28(5): p. 593-600.
[727] Spanu, A., Nuvoli, S., Marongiu, A., Gelo, I., Mele, L., Piras, B., et.al. Neck lymph node metastasis detection in patients with differentiated thyroid carcinoma (DTC) in long-term follow-up: a (131)I-SPECT/CT study, BMC Cancer, 2020. 20(1): p. 239.
[728] Avram, A. M., Fig, L. M., Frey, K. A., Gross, M. D., Wong, K. K., Preablation 131-I scans with SPECT/CT in postoperative thyroid cancer patients: what is the impact on staging?, J Clin Endocrinol Metab, 2013. 98(3): p. 1163-71., https://pubmed.ncbi.nlm.nih.gov/23430789/
[729] Avram, A. M., Dewaraja, Y. K., Thyroid Cancer Radiotheragnostics: the case for activity adjusted (131)I therapy, Clin Transl Imaging, 2018. 6(5): p. 335-346., https://pubmed.ncbi.nlm.nih.gov/30911535/
[730] Szujo, S., Sira, L., Bajnok, L., Bodis, B., Gyory, F., Nemes, O., et.al. The impact of post-radioiodine therapy SPECT/CT on early risk stratification in differentiated thyroid cancer; a bi-institutional study, Oncotarget, 2017. 8(45): p. 79825-79834.
[731] Avram, Anca M., Zukotynski, Katherine, Nadel, Helen Ruth, Giovanella, Luca, Management of Differentiated Thyroid Cancer: The Standard of Care, Journal of Nuclear Medicine, 2022. 63(2): p. 189-195., https://jnm.snmjournals.org/content/jnumed/63/2/189.full.pdf
[732] Banerjee, M., Wiebel, J. L., Guo, C., Gay, B., Haymart, M. R., Use of imaging tests after primary treatment of thyroid cancer in the United States: population based retrospective cohort study evaluating death and recurrence, Bmj, 2016. 354: p. i3839., https://pubmed.ncbi.nlm.nih.gov/27443325/
[733] Giovanella, L, Castellana, M, Trimboli, P, Unstimulated high-sensitive thyroglobulin is a powerful prognostic predictor in patients with thyroid cancer., Clin Chem Lab Med, 2019. 58 (1)(1): p. 130-137., https://pubmed.ncbi.nlm.nih.gov/31444962/
[734] Bundesministerium für Umwelt, Naturschutz, nukleare Sicherheit und Verbraucherschutz, Richtlinie zur Strahlenschutzverordnung, 2011.
[735] Verburg, F. A., Stokkel, M. P., Düren, C., Verkooijen, R. B., Mäder, U., van Isselt, J. W., et.al. No survival difference after successful (131)I ablation between patients with initially low-risk and high-risk differentiated thyroid cancer, Eur J Nucl Med Mol Imaging, 2010. 37(2): p. 276-83.
[736] Görges, R, Brandt-Mainz, K, Freudenberg, L, Frilling, A, Grimm, W, Bockisch, A, [Continously increasing sensitivity in thyroid cancer aftercare in the course of three generations of thyroglobulin IMAs]., Nuklearmedizin, 2003. 42 (4)(4): p. 157-66., https://pubmed.ncbi.nlm.nih.gov/12937694/
[737] Zöphel, K, Wunderlich, G, Smith, BR, Serum thyroglobulin measurements with a high sensitivity enzyme-linked immunosorbent assay: is there a clinical benefit in patients with differentiated thyroid carcinoma?, Thyroid, 2003. 13 (9)(9): p. 861-5., https://pubmed.ncbi.nlm.nih.gov/14588100/
[738] Kita, T., Yokoyama, K., Higuchi, T., Kinuya, S., Taki, J., Nakajima, K., et.al. Multifactorial analysis on the short-term side effects occurring within 96 hours after radioiodine-131 therapy for differentiated thyroid carcinoma, Ann Nucl Med, 2004. 18(4): p. 345-9.
[739] Pashnehsaz, M., Takavar, A., Izadyar, S., Zakariaee, S. S., Mahmoudi, M., Paydar, R., et.al. Gastrointestinal Side Effects of the Radioiodine Therapy for the Patients with Differentiated Thyroid Carcinoma Two Days after Prescription, World J Nucl Med, 2016. 15(3): p. 173-8.
[740] Van Nostrand, D., Neutze, J., Atkins, F., Side effects of "rational dose" iodine-131 therapy for metastatic well-differentiated thyroid carcinoma, J Nucl Med, 1986. 27(10): p. 1519-27.
[741] Clement, S. C., Peeters, R. P., Ronckers, C. M., Links, T. P., van den Heuvel-Eibrink, M. M., Nieveen van Dijkum, E. J., et.al. Intermediate and long-term adverse effects of radioiodine therapy for differentiated thyroid carcinoma--a systematic review, Cancer Treat Rev, 2015. 41(10): p. 925-34., https://pubmed.ncbi.nlm.nih.gov/26421813/
[742] Lu, L., Shan, F., Li, W., Lu, H., Short-Term Side Effects after Radioiodine Treatment in Patients with Differentiated Thyroid Cancer, Biomed Res Int, 2016. 2016: p. 4376720.
[743] Alexander, C., Bader, J. B., Schaefer, A., Finke, C., Kirsch, C. M., Intermediate and long-term side effects of high-dose radioiodine therapy for thyroid carcinoma, J Nucl Med, 1998. 39(9): p. 1551-4., https://www.ncbi.nlm.nih.gov/pubmed/9744341
[744] Mendoza, A., Shaffer, B., Karakla, D., Mason, M. E., Elkins, D., Goffman, T. E., Quality of life with well-differentiated thyroid cancer: treatment toxicities and their reduction, Thyroid, 2004. 14(2): p. 133-40.
[745] Hyer, S., Kong, A., Pratt, B., Harmer, C., Salivary gland toxicity after radioiodine therapy for thyroid cancer, Clin Oncol (R Coll Radiol), 2007. 19(1): p. 83-6., https://pubmed.ncbi.nlm.nih.gov/17305259/
[746] Adramerinas, M, Andreadis, D, Vahtsevanos, K, Poulopoulos, A, Pazaitou-Panayiotou, K, Sialadenitis as a complication of radioiodine therapy in patients with thyroid cancer: where do we stand?, Hormones (Athens), 2021. 20 (4)(4): p. 669-678., https://pubmed.ncbi.nlm.nih.gov/34143403/
[747] Rosário, P. W., Maia, F. F., Barroso, A., Padrão, E. L., Rezende, L., Purisch, S., [Sialoadenitis following ablative therapy with high doses of radioiodine for treatment of differentiated thyroid cancer], Arq Bras Endocrinol Metabol, 2004. 48(2): p. 310-4.
[748] Rosario, P. W., Calsolari, M. R., Salivary and lacrimal gland dysfunction after remnant ablation with radioactive iodine in patients with differentiated thyroid carcinoma prepared with recombinant human thyrotropin, Thyroid, 2013. 23(5): p. 617-9.
[749] Dietlein, M., Drzezga, A., [Taste dysfunction (dysgeusia) and radioiodine therapy of thyroid cancer - be aware of side effects by antidepressants and sedatives. Vorschädigung durch Antidepressiva und Sedativa beachten], Nuklearmedizin, 2017. 56(4): p. 125-131., https://pubmed.ncbi.nlm.nih.gov/28715040/
[750] Fard-Esfahani, A., Mirshekarpour, H., Fallahi, B., Eftekhari, M., Saghari, M., Beiki, D., et.al. The effect of high-dose radioiodine treatment on lacrimal gland function in patients with differentiated thyroid carcinoma, Clin Nucl Med, 2007. 32(9): p. 696-9., https://pubmed.ncbi.nlm.nih.gov/17710021/
[751] Grünwald, F., Schomburg, A., Menzel, C., Steinecker, S., Späth, G., Bockisch, A., et.al. [Changes in the blood picture after radioiodine therapy of thyroid cancer], Med Klin (Munich), 1994. 89(10): p. 522-8., https://pubmed.ncbi.nlm.nih.gov/7808352/
[752] Datz, F. L., Cerebral edema following iodine-131 therapy for thyroid carcinoma metastatic to the brain, J Nucl Med, 1986. 27(5): p. 637-40., https://pubmed.ncbi.nlm.nih.gov/3712081/
[753] Holmquest, D. L., Lake, P., Sudden hemorrhage in metastatic thyroid carcinoma of the brain during treatment with iodine-131, J Nucl Med, 1976. 17(4): p. 307-9., https://pubmed.ncbi.nlm.nih.gov/3632/
[754] Orita, Y., Sugitani, I., Matsuura, M., Ushijima, M., Tsukahara, K., Fujimoto, Y., et.al. Prognostic factors and the therapeutic strategy for patients with bone metastasis from differentiated thyroid carcinoma, Surgery, 2010. 147(3): p. 424-31.
[755] An, Y. S., Yoon, J. K., Lee, S. J., Song, H. S., Yoon, S. H., Jo, K. S., Symptomatic late-onset sialadenitis after radioiodine therapy in thyroid cancer, Ann Nucl Med, 2013. 27(4): p. 386-91., https://www.ncbi.nlm.nih.gov/pubmed/23389626
[756] Jeong, SY, Kim, HW, Lee, SW, Ahn, BC, Lee, J, Salivary gland function 5 years after radioactive iodine ablation in patients with differentiated thyroid cancer: direct comparison of pre- and postablation scintigraphies and their relation to xerostomia symptoms., Thyroid, 2013. 23 (5)(5): p. 609-16., https://pubmed.ncbi.nlm.nih.gov/23153322/
[757] Klein Hesselink, E. N., Brouwers, A. H., de Jong, J. R., van der Horst-Schrivers, A. N., Coppes, R. P., Lefrandt, J. D., et.al. Effects of Radioiodine Treatment on Salivary Gland Function in Patients with Differentiated Thyroid Carcinoma: A Prospective Study, J Nucl Med, 2016. 57(11): p. 1685-1691.
[758] Solans, R., Bosch, J. A., Galofré, P., Porta, F., Roselló, J., Selva-O'Callagan, A., et.al. Salivary and lacrimal gland dysfunction (sicca syndrome) after radioiodine therapy, J Nucl Med, 2001. 42(5): p. 738-43.
[759] Wu, J. Q., Feng, H. J., Ouyang, W., Sun, Y. G., Chen, P., Wang, J., et.al. Systematic evaluation of salivary gland damage following I-131 therapy in differentiated thyroid cancer patients by quantitative scintigraphy and clinical follow-up, Nucl Med Commun, 2015. 36(8): p. 819-26., https://pubmed.ncbi.nlm.nih.gov/25932534/
[760] Jonklaas, J., Nasal symptoms after radioiodine therapy: a rarely described side effect with similar frequency to lacrimal dysfunction, Thyroid, 2014. 24(12): p. 1806-14., https://pubmed.ncbi.nlm.nih.gov/25090584/
[761] Molinaro, E., Leboeuf, R., Shue, B., Martorella, A. J., Fleisher, M., Larson, S., et.al. Mild decreases in white blood cell and platelet counts are present one year after radioactive iodine remnant ablation, Thyroid, 2009. 19(10): p. 1035-41.
[762] Prinsen, H. T., Klein Hesselink, E. N., Brouwers, A. H., Plukker, J. T., Sluiter, W. J., van der Horst-Schrivers, A. N., et.al. Bone Marrow Function After (131)I Therapy in Patients With Differentiated Thyroid Carcinoma, J Clin Endocrinol Metab, 2015. 100(10): p. 3911-7.
[763] Nappi, C, Klain, M, Cantoni, V, Green, R, Piscopo, L, Volpe, F, et.al. Risk of primary breast cancer in patients with differentiated thyroid cancer undergoing radioactive iodine therapy: a systematic review and meta-analysis., Eur J Nucl Med Mol Imaging, 2022. 49 (5)(5): p. 1630-1639., https://pubmed.ncbi.nlm.nih.gov/34820683/
[764] Reinecke, MJ, Ahlers, G, Burchert, A, Eilsberger, F, Flux, GD, Marlowe, RJ, et.al. Second primary malignancies induced by radioactive iodine treatment of differentiated thyroid carcinoma - a critical review and evaluation of the existing evidence., Eur J Nucl Med Mol Imaging, 2022. 49 (9)(9): p. 3247-3256., https://pubmed.ncbi.nlm.nih.gov/35320386/
[765] Mattsson, S, Johansson, L, Leide Svegborn, S, Liniecki, J, Noßke, D, Riklund, KÅ, et.al. Radiation Dose to Patients from Radiopharmaceuticals: a Compendium of Current Information Related to Frequently Used Substances., Ann ICRP, 2015. 44 (2 Suppl)(2 Suppl): p. 7-321., https://pubmed.ncbi.nlm.nih.gov/26069086/
[766] Silva-Vieira, M., Carrilho Vaz, S., Esteves, S., Ferreira, T. C., Limbert, E., Salgado, L., et.al. Second Primary Cancer in Patients with Differentiated Thyroid Cancer: Does Radioiodine Play a Role?, Thyroid, 2017. 27(8): p. 1068-1076.
[767] Teng, C. J., Hu, Y. W., Chen, S. C., Yeh, C. M., Chiang, H. L., Chen, T. J., et.al. Use of Radioactive Iodine for Thyroid Cancer and Risk of Second Primary Malignancy: A Nationwide Population-Based Study, J Natl Cancer Inst, 2016. 108(2):
[768] Molenaar, R. J., Pleyer, C., Radivoyevitch, T., Sidana, S., Godley, A., Advani, A. S., et.al. Risk of developing chronic myeloid neoplasms in well-differentiated thyroid cancer patients treated with radioactive iodine, Leukemia, 2018. 32(4): p. 952-959., https://pubmed.ncbi.nlm.nih.gov/29104287/
[769] Molenaar, R. J., Sidana, S., Radivoyevitch, T., Advani, A. S., Gerds, A. T., Carraway, H. E., et.al. Risk of Hematologic Malignancies After Radioiodine Treatment of Well-Differentiated Thyroid Cancer, Journal of Clinical Oncology, 2018. 36(18): p. 1831-1839., https://pubmed.ncbi.nlm.nih.gov/29252123/
[770] Rubino, C., de Vathaire, F., Dottorini, M. E., Hall, P., Schvartz, C., Couette, J. E., et.al. Second primary malignancies in thyroid cancer patients, Br J Cancer, 2003. 89(9): p. 1638-44.
[771] Seo, G. H., Cho, Y. Y., Chung, J. H., Kim, S. W., Increased Risk of Leukemia After Radioactive Iodine Therapy in Patients with Thyroid Cancer: A Nationwide, Population-Based Study in Korea, Thyroid, 2015. 25(8): p. 927-34.
[772] Bhattacharyya, N., Chien, W., Risk of second primary malignancy after radioactive iodine treatment for differentiated thyroid carcinoma, Ann Otol Rhinol Laryngol, 2006. 115(8): p. 607-10., https://pubmed.ncbi.nlm.nih.gov/16944659/
[773] Hall, P., Holm, L. E., Lundell, G., Bjelkengren, G., Larsson, L. G., Lindberg, S., et.al. Cancer risks in thyroid cancer patients, Br J Cancer, 1991. 64(1): p. 159-63., https://pubmed.ncbi.nlm.nih.gov/1854616/
[774] Marti, J. L., Jain, K. S., Morris, L. G., Increased risk of second primary malignancy in pediatric and young adult patients treated with radioactive iodine for differentiated thyroid cancer, Thyroid, 2015. 25(6): p. 681-7., https://pubmed.ncbi.nlm.nih.gov/25851829/
[775] Sawka, A. M., Thabane, L., Parlea, L., Ibrahim-Zada, I., Tsang, R. W., Brierley, J. D., et.al. Second primary malignancy risk after radioactive iodine treatment for thyroid cancer: a systematic review and meta-analysis, Thyroid, 2009. 19(5): p. 451-7.
[776] Seo, GH, Kong, KA, Kim, BS, Kang, SY, Moon, BS, Yoon, HJ, et.al. Radioactive Iodine Treatment for Children and Young Adults with Thyroid Cancer in South Korea: A Population-based Study., J Clin Endocrinol Metab, 2021. 106 (7)(7): p. e2580-e2588., https://pubmed.ncbi.nlm.nih.gov/33755732/
[777] Rall, J. E., Alpers, J. B., Lewallen, C. G., Sonenberg, M., Berman, M., Rawson, R. W., Radiation pneumonitis and fibrosis: a complication of radioiodine treatment of pulmonary metastases from cancer of the thyroid, J Clin Endocrinol Metab, 1957. 17(11): p. 1263-76.
[778] Dietlein, M., Drzezga, A., [Ablative Radioiodtherapie bei niedrigem und intermediarem Rezidivrisiko. Hohere Uberlebensrate beim Schilddrusenkarzinom], Nuclear-Medizin, 2016. 55(3): p. 71-6., https://pubmed.ncbi.nlm.nih.gov/27350003/
[779] Benua, R. S., Cicale, N. R., Sonenberg, M., Rawson, R. W., The relation of radioiodine dosimetry to results and complications in the treatment of metastatic thyroid cancer, Am J Roentgenol Radium Ther Nucl Med, 1962. 87: p. 171-82., https://pubmed.ncbi.nlm.nih.gov/13867399/
[780] Chen, L., Shen, Y., Luo, Q., Yu, Y., Lu, H., Zhu, R., Pulmonary fibrosis following radioiodine therapy of pulmonary metastases from differentiated thyroid carcinoma, Thyroid, 2010. 20(3): p. 337-40., https://pubmed.ncbi.nlm.nih.gov/20187786/
[781] Sgouros, G., Song, H., Ladenson, P. W., Wahl, R. L., Lung toxicity in radioiodine therapy of thyroid carcinoma: development of a dose-rate method and dosimetric implications of the 80-mCi rule, J Nucl Med, 2006. 47(12): p. 1977-84.
[782] Silberstein, E. B., Alavi, A., Balon, H. R., Clarke, S. E., Divgi, C., Gelfand, M. J., et.al. The SNMMI practice guideline for therapy of thyroid disease with 131I 3.0, J Nucl Med, 2012. 53(10): p. 1633-51.
[783] Bledsoe, T. J., Nath, S. K., Decker, R. H., Radiation Pneumonitis, Clin Chest Med, 2017. 38(2): p. 201-208., https://pubmed.ncbi.nlm.nih.gov/28477633/
[784] Hanania, A. N., Mainwaring, W., Ghebre, Y. T., Hanania, N. A., Ludwig, M., Radiation-Induced Lung Injury: Assessment and Management, Chest, 2019. 156(1): p. 150-162., https://pubmed.ncbi.nlm.nih.gov/30998908/
[785] Fard-Esfahani, A., Emami-Ardekani, A., Fallahi, B., Fard-Esfahani, P., Beiki, D., Hassanzadeh-Rad, A., et.al. Adverse effects of radioactive iodine-131 treatment for differentiated thyroid carcinoma, Nucl Med Commun, 2014. 35(8): p. 808-17., https://pubmed.ncbi.nlm.nih.gov/24751702/
[786] Hebestreit, H., Biko, J., Drozd, V., Demidchik, Y., Burkhardt, A., Trusen, A., et.al. Pulmonary fibrosis in youth treated with radioiodine for juvenile thyroid cancer and lung metastases after Chernobyl, Eur J Nucl Med Mol Imaging, 2011. 38(9): p. 1683-90., https://pubmed.ncbi.nlm.nih.gov/21626048/
[787] Kim, KJ, Song, JE, Kim, JY, Bae, JH, Kim, NH, Yoo, HJ, et.al. Effects of radioactive iodine treatment on cardiovascular disease in thyroid cancer patients: a nationwide cohort study., Ann Transl Med, 2020. 8 (19)(19): p. 1235., https://pubmed.ncbi.nlm.nih.gov/33178767/
[788] Albano, D., Bertagna, F., Panarotto, M. B., Giubbini, R., Early and late adverse effects of radioiodine for pediatric differentiated thyroid cancer, Pediatr Blood Cancer, 2017. 64(11):, https://www.ncbi.nlm.nih.gov/pubmed/28436606
[789] Brown, A. P., Chen, J., Hitchcock, Y. J., Szabo, A., Shrieve, D. C., Tward, J. D., The risk of second primary malignancies up to three decades after the treatment of differentiated thyroid cancer, J Clin Endocrinol Metab, 2008. 93(2): p. 504-15., https://pubmed.ncbi.nlm.nih.gov/18029468/
[790] Shalet, S. M., Tsatsoulis, A., Whitehead, E., Read, G., Vulnerability of the human Leydig cell to radiation damage is dependent upon age, J Endocrinol, 1989. 120(1): p. 161-5.
[791] Rivkees, S. A., Mazzaferri, E. L., Verburg, F. A., Reiners, C., Luster, M., Breuer, C. K., et.al. The treatment of differentiated thyroid cancer in children: emphasis on surgical approach and radioactive iodine therapy, Endocr Rev, 2011. 32(6): p. 798-826.