3. Identification of the malignant thyroid nodule (primary diagnosis) – Thyroid Cancer
3.1 Epidemiology and prevalence of thyroid nodules and thyroid cancer
This chapter describes the epidemiology and prevalence of thyroid nodules in Germany and compares the figures with international data. In addition to the few published epidemiological studies, the data was mainly generated from the Robert Koch Institute's publication "Cancer in Germany".
3.1.1 Prevalence of thyroid nodules in Germany
The prevalence of thyroid nodules in Germany is high. In various broad-based studies from 2000 to 2006, prevalence rates ranging from 12.5% (for younger men) to over 80% (for older women) were reported, depending on region, age and gender [1], [2].
The most recent population study published on this topic from North East Germany [3] systematically compares the prevalence of goiter or thyroid nodules and iodine supply between the periods 1997-2001 and 2008-2012. The iodine supply deteriorated over time with values below the level considered sufficient by the WHO (100 µg/g creatinine) from 31% to 36% in men and from 46% to 54% in women. The frequency of goiter in men (thyroid volume > 25 ml) decreased significantly from 37% to 27%, while it remained the same in women (volume > 18 ml) at 34% and 33% respectively. The increase in the frequency of sonographically detectable nodules > 10 mm in diameter in men from 15 % to 24 % and in women from 23 % to 38 % was striking (both significant).
3.1.2 Thyroid cancer
Thyroid cancer is one of the rare forms of cancer. The latest figures from the regional German cancer registries are published in the 2018 report from the Robert Koch Institute's Center for Cancer Registry Data [4]. For the period 1999-2016, the number of people with a new diagnosis of thyroid cancer increased, while the mortality rate decreased for both women and men during this period. In 2017 and 2018, the number of new cases fell significantly. In 2018, 4,270 women and 1,930 men were newly diagnosed with thyroid cancer. This corresponds to a standardized incidence of 9.1 and 3.9 cases per 100,000 inhabitants respectively. The mean age at first diagnosis was 51 years for women and 56 years for men. The disease-related standardized mortality rate was 0.4 (per 100,000 inhabitants) for both men and women in 2017 and 2018. It was slightly higher for men in 2019 at 0.5. The average age at death for women was 80 years in 2019, for men 73 years).
The 5-year prevalence was 21,100 for women and 8,500 for men; the 10-year prevalence was 40,500 for women and 15,800 for men. The 25-year prevalence is 76,500 for women and 26,800 for men. The relative 5-year survival rate for all types of thyroid cancer was calculated at 91% for men and 95% for women. It should be noted that the survival rate is highly dependent on the type of thyroid cancer.
The prognostically favorable papillary microcarcinomas were predominantly diagnosed in younger people under the age of 60. The majority of thyroid carcinomas are detected at a very early tumor stage (UICC I) (88% in women, 75% in men).
This trend is also seen in many countries and is primarily attributed to expanded diagnostics and better examination methods [5][5], [6], [7], [8], [9]. A favorable T1 tumor stage was found in 62% of women and 52% of men. However, a more recent study [10] shows that there has also been an increase in higher stages and that improved diagnostics cannot be the sole explanation for the increase in prevalence.
The following distribution of histological subtypes of thyroid cancer was determined in 2015-2016 ([11]):
Table 7: Distribution of the histological subtypes of thyroid carcinoma
| Histological type | Women | Men |
| Papillary carcinomas | 78% | 68% |
| Follicular carcinomas | 11% | 14% |
| Medullary carcinomas | 4% | 7% |
| Anaplastic carcinomas | 2% | 4% |
| Other entities | 1% | 2% |
| Unspecified/no further details | 4% | 5% |
3.1.3 Comparison with other countries
In Denmark, an age-adjusted incidence of 4.5 cases per 100,000 inhabitants per year was registered in 2014 [12]. The annual percentage increase in the incidence of thyroid cancer was 2% in the years 1980-2006 and then accelerated sharply to 8.7% in women and from 1.3% to 8.9% in men.
In the United Kingdom, an average of 3,527 new cases of thyroid cancer were diagnosed between 2014-2016 in a population of around 65 million people, with 396 deaths caused by thyroid cancer in 2016, corresponding to a mortality rate of 11% [13]. A sharp increase in incidence of 155% was also observed in the United Kingdom compared to the early 1990s.
In the USA, the age-adjusted incidence of thyroid cancer rose from 5.7 to 13.8 per 100,000 inhabitants between 1992 and 2016, more than doubling during this period [8]. Since 2014, the incidence rate has been stable with a downward trend.
In the years 1999-2013, a disease-specific mortality rate of 0.44 per 100,000 inhabitants per year was recorded in the USA for both sexes [14].
With a significantly higher incidence rate of 28.28, the specific mortality rate in China (Zhejiang province) was just as high (0.44) as in the USA [15]. Both in the USA and in other countries, the increase in the incidence of thyroid cancer is almost exclusively due to an increase in the number of prognostically favorable papillary microcarcinomas, while the number of anaplastic carcinomas with a poor prognosis is stagnating or even decreasing [14], [12], [16], [17], [18].
In the south of Spain, the incidence for women was higher at 12.8 (men 4.9). This means that thyroid cancer is already the 8th most common cancer in women in this region. If explicit screening for thyroid nodules is carried out, the incidence rate of thyroid cancer rises very sharply, reaching an incidence rate of 64.1 cases per 100,000 inhabitants (women 107.3, men: 21.1) in South Korea in the years 2008-1010. This increase largely concerned papillary microcarcinomas, with no change in thyroid cancer mortality [19].
In summary, the German data are roughly comparable with the international data. The incidence of thyroid cancer is in the middle of the range of comparable countries [20]. Only in some regions of the world (explicitly China) are the incidences significantly higher. As in almost all countries, the incidence of thyroid cancer is rising, whereby this increase is largely due to the increased proportion of people with papillary microcarcinomas. It should be noted that Germany has a higher prevalence of thyroid nodules in international comparison, which conversely leads to a lower probability of malignant genesis per detected nodule and requires good pre-selection for possible invasive measures for further clarification.
3.2 Risk factors for the development of thyroid cancer
This chapter describes the various risk factors for thyroid cancer and considers endogenous and exogenous risk factors.
3.2.1 Hereditary or genetic factors
A family history of thyroid cancer, especially in first-degree relatives, is a risk factor for the development of differentiated thyroid cancer. Several hereditary tumor disposition syndromes (TDS) are associated with an increased likelihood of thyroid cancer.
Approximately 20-25% of medullary thyroid carcinomas are hereditary and associated with activating, pathogenic germline variants in the RET protooncogene [21], [22]. Clinically, a distinction is made between familial medullary thyroid carcinoma (FMTC) without further clinical manifestations and multiple endocrine neoplasia (MEN) type II A or type II B. In RET-associated MTC, genotype-phenotype correlations are well established [23] and can contribute to clinical decision-making [24].
In contrast, the molecular genetic causes of familial non-medullary thyroid carcinomas are less well understood. Familial NMTC (FNMTC) account for only a small proportion of NMTC, approximately 3 - 9% [25] and can be divided into two groups. The first group shows an increased prevalence of NMTC in the following hereditary TDS: familial adenomatous polyposis coli (FAP) [26], PTEN hamartoma tumor syndromes (PHTS, e.g. Cowden syndrome) [27], Carney complex [28], Werner syndrome [29] and DICER-1 syndrome [25]. Furthermore, numerous gene mutations have been identified that may be associated with FNMTC [30].
In the group of non-syndromic familial NMTC cases, a distinction is made between familial PTC (fPTC) with or without oxyphilia, fPTC with renal cell carcinoma, and fPTC with multinodal goiter. In all familial NMTC forms, a clear association with pathogenic germline variants could only be established in a fraction (approx. 5%) [31], [32], [33], [34], [35].
Certain morphological findings in the pathological examination can provide indications of the underlying hereditary TDS [36].
3.2.2 Environmental factors/external factors
A long-known risk factor for the development of thyroid cancer is previous radiotherapy of the neck, but also of the mediastinum, head or whole body [37]. This is most frequently seen after previous radiotherapy. The lower the age at the time of radiation exposure, the higher the risk of developing thyroid cancer. In more recent studies, RET/PTC rearrangements were frequently found in papillary thyroid carcinomas after radiation exposure [37]. Previous radioiodine therapy is not considered a risk factor for the development of thyroid cancer. Although a single paper from 2019 reported a possible indication of a slight increase in risk after radioiodine therapy [38], the authors themselves pointed out methodological limitations that prevent a conclusive evaluation of the data. Other studies were unable to identify a link between thyroid cancer and previous radioiodine therapy [39].
3.2.3 Hormonal factors
There are several publications that show a weak influence of hormonal factors on the development of thyroid carcinoma: For papillary thyroid carcinoma, but not for follicular carcinoma, there is evidence for a discrete increase in incidence with increasing basal TSH levels [40]. Reproductive/gynecological factors may also have an - albeit weak - influence on the development of thyroid cancer [41], [42]: there appears to be a slightly higher risk with increasing duration of endogenous exposure to female sex hormones.
3.2.4 Immunological factors/immunosuppression
Patients with Hashimoto's thyroiditis have a slightly higher incidence of thyroid cancer than the general population. This was only seen for patients with euthyroidism or a low need for thyroid hormone replacement, not for late stages in patients with a high or very high need for replacement [43]. The extent to which this observation is due to the fact that patients with pre-existing thyroid disease may be subject to better thyroid diagnostics, which alone may lead to an increase in the detection of thyroid cancer in the patient group, remains unclear. One study found a higher probability of malignancy in punctured thyroid nodules in patients with Hashimotothyroiditis compared to patients without autoimmune thyroiditis (10.0% versus 6.4%; [44]).
After transplantation of a solid organ, a US study showed an increased risk of developing malignancies, including thyroid cancer. The risk was higher after kidney transplantation than after other organ transplants [45]. It is not yet clear what roles the usually long-term immunosuppression and the underlying disease that led to the organ transplant respectively play [46].
3.2.5 Iodine supply
3.3 Clinical examination
A clinical examination should be carried out before a sonographical examination of the thyroid gland and neck.
- Consensus
- Strong consensus (100%)
Depending on the symptoms and the clinical question, the clarification of changes in the thyroid gland or thyroid carcinoma includes clinical examinations. This includes inspection of the neck and palpation of the thyroid gland or thyroid lobe and the neck and nape region. A reclination of the head is helpful here. On palpation, look for increased consistency in the thyroid gland or thyroid lobe, the nature and displacement of nodules, swallowing displacement of the thyroid gland as well as redness and overheating of the skin and tenderness. Nodular palpation findings should be correlated with sonography and, if necessary, scintigraphy.
On palpation of the lymph node stations, the localization and nature of palpable lymph nodes (size, hardness, displacement) are documented.
3.4 Sonography (evidence and performance of sonography)
3.4.1 Sonographic individual criteria for malignancy assessment
Standardized B-mode sonography shall be used for risk stratification of thyroid nodules.
- Consensus
- Strong consensus (100%)
Sonography is a widely used examination method among general practitioners and specialists. Thyroid nodules and thyroid carcinomas are often found during routine examinations. Sonographic screening for thyroid nodules is not useful as this leads to overdiagnosis [19], [48]. This chapter describes the importance of sonography in the diagnosis of thyroid cancer and provides information on how it is performed and the technical requirements for the examination. In addition to elastography, contrast-enhanced sonography, duplex sonography and lymph node sonography, standardized documentation is also addressed.
With B-mode sonography, various nodule characteristics such as singularity, composition (e.g. solid or cystic), echogenicity (reflex intensity of tissue), shape, edge characteristics and the presence of microcalcifications can be recorded and assessed in a standardized manner. In addition, the position of nodules within the thyroid gland is documented.
A standardized nomenclature with regard to echogenicity is particularly important. The following Table Nomenclature of the echogenicity of thyroid nodules is helpful for this purpose:
Table 8: Nomenclature of the echogenicity of thyroid nodules
| Description of the nodule | DEGUM nomenclature | Synonyms |
| Nodule is more echogenic than healthy thyroid tissue | more echogenic | echogenic, hyperechogenic |
| Nodule is as echogenic as healthy thyroid tissue | echogenic, isoechogenic | isoechogenic |
| Nodule is less echogenic than healthy thyroid tissue | less echogenic | weaker echogenic |
| Nodule is less echogenic than the neck muscles (infrahyal, sternocleidomastoid muscle) | very weakly echogenic | strongly hypoechogenic |
| Node shows no echogenicity | anechoic | cystic |
In a large meta-analysis by Remonti et al., who evaluated 52 retrospective observational studies with over 12,000 nodules (up to 2012), microcalcifications, greater depth than width growth of the nodule ("taller-than-wide" shape: larger diameter in the sagittal than in the transverse plane) and irregular nodule margins were associated with a higher risk of malignancy, although no single criterion led to a clinically relevant increase in diagnostic accuracy [49]. In a further meta-analysis specifically on the characteristics of medullary thyroid carcinomas, which included six studies up to 2013, calcifications and a "taller-than-wide" shape were associated with a higher probability of a malignant nodule, while a spongiform appearance of the nodules (multiple small cystic internal structures, spongy nodule structure) or cystic nodules were associated with a low probability [50]. The authors also came to the conclusion that none of the sonographic criteria, considered in isolation, represent a sufficient predictive factor for thyroid cancer. It must be critically noted that both meta-analyses demonstrated a high degree of heterogeneity in the study characteristics and results. Although fewer studies (n=6) or nodules (n=5,439) were included in the meta-analysis by Wolinski et al. than in the two previously cited meta-analyses, no significant heterogeneity or publication bias could be demonstrated for any of the individual criteria examined. The highest pooled PPV and the highest pooled specificity were calculated at 76% and 96% for the "taller-than-wide" shape, but the pooled sensitivity of 26% was the lowest of all criteria examined. For the other individual criteria, the values for the pooled PPV were between 23.5% and 42.3% [51]. In a further meta-analysis of 12 studies on young patients under 21 years of age, calcifications were associated with a higher probability of a malignant nodule, whereas cystic nodules were associated with benignity [52]. Here too, however, the view is shared that individual criteria are not sufficiently accurate predictors.
Table 9: B-mode individual criteria for the assessment of thyroid nodules
| Criterion |
| 1. solid or cystic |
| 2. echogenicity (strongly echogenic, isoechogenic, weakly echogenic, strongly weakly echogenic, anechoic - see Table Nomenclature of the echogenicity of thyroid nodules) |
| 3. border (smooth incl. halo, lobulated, irregular, blurred) |
| 4. calcifications (microcalcifications, macrocalcifications, marginal calcifications) |
| 5. configuration (wider-than-tall, taller-than-wide) |
| 6. specific characteristics (spongiform, conglomerate, cyst) |
| Additional documentation of the location within the thyroid gland |
3.4.2 Use of standardized risk stratification systems in thyroid ultrasonography (TIRADS)
Thyroid Imaging Reporting and Data Systems (TIRADS) are available for standardized sonography of the thyroid gland, taking into account the number or combination of individual sonographic criteria. They enable risk stratification by classifying nodules into low, intermediate, and high malignancy risk (risk stratification systems). Various classification systems are currently still used worldwide [56], [57], [58], [59], [24], [60], [61].
In the systematic literature search on the diagnostic value of TIRADS classifications, a total of 3 meta-analyses were identified. One meta-analysis, which included 4 retrospective and 2 prospective studies with a total of almost 11,000 thyroid nodules, examined the classification system according to Kwak [55]. It showed a pooled sensitivity of 91% (88-94%) and specificity of 35% (31 to 39%) for the diagnosis of thyroid cancer. Another meta-analysis evaluated 12 studies on TIRADS classification systems that included over 10,000 thyroid nodules [53]. The European study by Russ et al. [59] contributed almost half of the nodules examined. The sensitivity was determined to be 79% (77% - 81%), the specificity was 71% (70 - 72%). The authors point out that different standards in pathological assessment lead to heterogeneity in the results. In an earlier study by the same authors, the evaluation of older studies showed a pooled sensitivity of 72 - 78% and specificity of 68 - 70% [54]. The results of the studies included in the meta-analyses show considerable heterogeneity. What they all have in common, however, is that the findings are standardized and therefore objectively comprehensible and reproducible, which leads to a positive recommendation in the case of low confidence in the quality of the evidence, which is not least a consequence of the currently competing systems.
The various systems differ in their application and in some cases there are clear differences with regard to the recommendation for fine needle aspiration. In this respect, ACR TI-RADS appears to be superior to other systems [62], [63], [64], [65].
For Germany, a multicenter study comparing five TIRADS (Kwak-TIRADS, EU-TIRADS, ACR TI-RADS, K-TIRADS and ATA) was published by Seifert et al. in which non-autonomous thyroid nodules were prospectively classified [66]. The diagnostic accuracies of Kwak-TIRADS (79%), ACR TI-RADS (78%) and K-TIRADS (82%) were slightly superior to EU-TIRADS (70%). ATA classification showed good diagnostic accuracy (79%), but 11% of nodules could not be classified. Yoon et al. found a lack of classifiability of even 18% of nodules in the ATA system [67]. In summary, a preference for a TIRADS classification system cannot be stated at present.
The "International Thyroid Nodule Working Group", which is made up of radiologists, endocrinologists and surgeons from various organizations (including the American Thyroid Association, European Thyroid Association, Korean Society of Thyroid Radiology), began developing an internationally applicable "I-TIRADS" in 2018. Information and online calculators for TIRADS can be found at http://tiradscalculator.com, http://aace-thyroid.deontics.com and http://tirads.de. If sonographic follow-up checks of existing thyroid nodules are necessary, the existing risk stratification systems offer assistance with regard to follow-up. Corresponding follow-up intervals are stored there [61], [68].
3.4.3 Elastography of the thyroid gland
If available, elastography should be performed together with standardized B-mode ultrasonography for risk stratification of thyroid nodules.
Elastographic methods, which include qualitative strain elastography (SE) and quantitative shear wave elastography (SWE) and acoustic radiation force impulse (ARFI), are used to measure tissue hardness during sonography.
In their review, Nattabi et al. analyzed prospective and retrospective studies (n=14) that compared the results of shear wave elastography of 2,851 thyroid nodules, of which 1,092 were malignant and 1,759 benign, with the findings of fine needle aspiration cytology (FNAC) or histopathology of surgical specimens [69]. The overall sensitivity for the detection of malignant nodules was 66% (CI 64% - 69%) with a specificity of 78% (CI 76% - 80%).
Nell et al. analyzed prospective and retrospective studies (n=20) on the diagnostic performance of qualitative elastography compared to fine needle aspiration cytology (FNAC) or histology from surgical specimens [70]. They found a sensitivity of 85% (79% - 90%) with a specificity of 80% (73% - 86%).
Overall, the results are heterogeneous, which is not least due to the current lack of universal standardization of the method. Nevertheless, the use of elastography increases diagnostic certainty when the respective method is performed correctly and allows a high negative predictive value to make a malignancy unlikely, provided the lump is completely soft. Based on the results of the systematic reviews and their low reliability, a moderate recommendation for the use of elastography for risk stratification of thyroid nodules is derived and its use is recommended accordingly.
Knowledge of the underlying technical principles and limitations (presence of calcifications and cystic changes, location of the nodule) is essential [71], [72][72]. When comparing the elastographic methods, SWE proved to be less examiner-dependent than SE in most studies [71].
3.4.4 Duplex sonography of the thyroid gland
Color-coded duplex sonography (CCD) can be used to assess thyroid nodules. However, this is not useful for the assessment of thyroid nodules with regard to malignancy and is therefore unnecessary.
- Consensus
- Strong consensus (95,5%)
The use of color-coded duplex sonography to assess the vascularization pattern of thyroid nodules is widespread in routine clinical practice, as almost all modern sonography devices support CCD for visualizing blood flow and the examination can therefore be completed quickly and easily. In contrast, however, the significance of the method in the dignity assessment of thyroid nodules is low [73]. Three meta-analyses identified in the primary search consistently showed a low sensitivity for the criterion of intranodular/central vascularization of 40%, 44%, and 46% [51], [74], [49]. The specificities varied between 61% [74] and 82% [51]. Overall, however, the study data are difficult to compare with each other, which is also reflected in significant heterogeneity, with the exception of the meta-analysis by Wolinski et al. [51].
In a retrospective study based on 1,083 nodules with 269 malignancies, it was shown that the description of the vascularization pattern of thyroid nodules has no added value to B-mode sonography in their dignity assessment [75]. This has been confirmed in more recent studies [76], [77]. However, CCD can be helpful in assessing the extent, limitation, and invasiveness of thyroid nodules [78].
Among the limitations of CCD are the strong dependence on the user and the sonography device used. There are no recommendations for standardized examination parameters such as flow rate amplification or frequency setting. With regard to the categorization of the vascularization pattern, various visual classification systems are described in the literature. The intensity and localization (peripheral versus intranodular) of the vascularization pattern are decisive [75], [79], [80]. In summary, according to the current literature, CCD alone cannot be used to assess the dignity of thyroid nodules, but it can be helpful for assessing the extent and borders of poorly delineated thyroid nodules in B-mode sonography.
3.4.5 Contrast-enhanced sonography (CEUS) of the thyroid gland
Contrast-enhanced ultrasonography (CEUS) should currently not be routinely performed as a complementary method to B-mode ultrasonography.
- Recommendation grade
- B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
- Level of evidence
- 2b
- Consensus
- Strong consensus (100%)
- References
- [81]
The current data on CEUS is summarized in the meta-analysis by Liu [81]. 33 studies (24 from China and 4 from Europe) with a total of 3,442 nodules were included, which compared the result of CEUS with cytology or histology. They showed a sensitivity of 88% (85-91%) and a specificity of 88% (83-91%) for the differentiation between malignant and benign thyroid nodules. Similar results (sensitivity 90% and specificity 86%) are shown in a meta-analysis by Ma et al. that includes 13 publications, including 7 Asian and 6 non-Asian studies [82]. The authors also carried out a subgroup analysis regarding the origin of the studies. The authors found significant heterogeneity in the Asian studies compared to the non-Asian studies. In addition, the sensitivity in the non-Asian subgroup was lower than in the Asian subgroup with the same specificity (77% vs. 92%) [81]. Limitations of the method are that there is currently no standardized examination algorithm for CEUS. In addition, the examination is quite expensive and only one node can be assessed at a time. The invasiveness of the examination must also be taken into account when using CEUS (additional information, consideration of contraindications, intravenous administration of contrast medium, follow-up observation of the patient). Despite the favorable results of the study by Liu et al., which is based predominantly on Chinese data, it currently appears too early for a conclusive evaluation, taking into account the above-mentioned aspects and the limited experience in Europe.
3.4.6 Lymph node sonography
No recommendation can be made for or against the use of elastography to assess the dignity of lymph nodes in the lymph drainage areas of the thyroid region in thyroid nodules suspected of being malignant.
- Level of evidence
- 2
- Consensus
- Consent (94,7%)
- References
- [91]
Due to its very high specificity and therefore high positive predictive value for lymph node metastases, neck sonography shall be used preoperatively in cases of confirmed or suspected thyroid malignancy. However, with limited sensitivity, the examination cannot rule out lymphonodal metastasis preoperatively.
Table 10: Important aspects of structured sonographic documentation of cervical lymph nodes
| Important aspects |
| Completeness of coverage of all lymph node compartments in the neck area |
| Description of unclear or suspicious lymph nodes including their localization in relation to anatomical structures |
| Size of these lymph nodes in three dimensions |
| Shape (oval, round, polylobulated, blurred) |
| Presence or absence of a hilar sign |
| Echogenicity (weaker or stronger echogenicity, isoechogenicity) |
| Presence of cystic areas |
| Presence and localization of calcifications (micro- and macrocalcifications) |
| Doppler sonography features of vascularization (hilar, central, peripheral, diffuse, capsule penetrating) |
Normal lymph nodes are oval, slightly less echogenic with a more echogenic hilus with a corresponding hilar vessel [96]. The hilus is not always detectable on B-image sonography, but can be visualized using color Doppler due to its vascularization. A hilus is found in about 90% of normal lymph nodes [90], [96], [97], [98]. Detection of the hilus almost always rules out malignancy [90], [96], [97], [98].
As the diameter in the long axis has only a low diagnostic value for the question of malignancy, the use of the short axis or the Steinkamp quotient (L/S, quotient of long to short axis in diameter) is recommended [99].
The preoperative detection of suspicious lymph nodes has prognostic value and can influence the surgical strategy [84], [85][85].
In metastatic PTC, up to 70% of lymph node metastases are found in the central and lateral lymph node compartment [86]. The specificity of sonography in detecting lymph node metastases of PTC is high and lies between 80% and 95%; Kim et al. found a specificity of 91% with a sensitivity of only 51% [93].
Typical sonographic signs of suspicious lymph nodes include microcalcifications, partly cystic parts, peripheral or diffusely increased vascularization with partly capsule-penetrating vessels, as well as a more echogenic appearance compared to normal lymph nodes, often comparable to the thyroid gland [90], [100]. The criteria are identical for preoperative and postoperative evaluation.
The size of cervical lymph node metastases from thyroid carcinoma can remain constant over several years [101]. A lack of growth in size is not a valid criterion for ruling out a lymph node metastasis. However, a growth in the size of lymph nodes of >3mm/year that is confirmed by several measurements is considered conspicuous [101].
The majority of lymph node metastases are found cervicocentrally (level III and IV or in level VI), usually unilaterally. Submandibular lymph node metastases are less common [102], [103]. However, the value of preoperative US differs for central and lateral lymph node metastases [92].
In studies, preoperative sonography showed lower sensitivity in the diagnosis of central cervical lymph node metastases and good diagnostic efficacy for lateral cervical lymph node metastases in PTC. Nineteen studies with 4,014 patients were included in a meta-analysis [87]. The pooled sensitivity, specificity, DOR and area under the curve (AUC) of sonography in detecting central LN metastases in PTC were 0.33 (95% confidence interval (95% CI): 0.31-0.35), 0.93 (95% CI: 0.92-0.94), 5.63 (95% CI: 3.50-9.04) and 0.69; for lateral LN metastases, these values were 0.70 (95% CI: 0.68-0.72), 0.84 (95% CI: 0.82-0.85), 18.7 (95% CI: 10.3-33.9) and 0.88, respectively. In this analysis, preoperative sonography showed low sensitivity in the diagnosis of central LN metastases and good diagnostic accuracy for lateral LN metastases in PTC. Another meta-analysis (Wu, L. M., 2012) included 13 studies with 1,020 patients and PTC [88]. The pooled sensitivity for sonography in the detection of LN metastases was 0.72 (95% CI, 0.46-0.88), the specificity was 0.98 (95% CI, 0.84-1.00) and the area under the curve (AUC) was 0.94 (95% CI, 0.92-0.0.96). The pooled sensitivity was 0.63 (95% CI, 0.47-0.76), the specificity 0.93 (95% CI, 0.73-0.99) and the AUC 0.81 (95% CI, 0.77-0.84). In the lesion-based analysis, the subgroup with lymph node involvement of the lateral compartment was found to have the highest sensitivity (0.72, 95% CI 0.68-0.75) and specificity (0.97, 95% CI 0.93-0.99) among the studies (p < 0.05). The authors conclude that preoperative ultrasonography is a good technique for preoperative lymph node staging of PTC and is helpful in detecting metastatic cervical LN in the lateral group.
Comparing ultrasonography with computed tomography, a meta-analysis including 10 studies with a total of 5,656 thyroid cancer patients showed that CT has a slightly higher sensitivity than US, while US has a higher specificity for the assessment of central, lateral and total cervical LN metastases [89].
Only "macroscopic" lymph node metastases can be detected preoperatively using US. However, the lack of detection of lymph node metastases of a PTC in the preoperative US is associated with a better prognosis for the patient [94].
Peripheral rather than hilar vascularization was described as the best single US criterion for malignancy of lymph nodes with a sensitivity of 86% and specificity of 82% [90]. However, peripheral vascularization is also found in up to 20% of benign lymph nodes [90], [96], [97], [98].
Table 11: B-mode criteria for differentiating normal, indeterminate and malignant lymph nodes
| Normal lymph node | Indeterminate lymph node | Suspected malignancy (at least one of the following characteristics) |
|
|
|
The data on US elastography of cervical lymph nodes is limited compared to its use in thyroid nodes. For lymph nodes, some prospective studies, in particular with shear wave elastography (Azizi, G., et. al. 2016), showed an additional benefit of elastography in the characterization of cervical lymph nodes, especially for lymph nodes <1cm [104], [105], [91]. Eight studies with a sample size of 481 patients with 647 cervical lymph nodes were included in a meta-analysis [103]; shear wave elastography showed a sensitivity of 81 % (95 % CI: 72-88 %) and a specificity of 85 % (95 % CI: 70-93 %). The results of the meta-regression analysis showed that the prevalence of malignant lymph nodes was a significant factor influencing the heterogeneity of the study (p < 0.01). The data situation and the number of lymph nodes examined are therefore not yet sufficient for a conclusive assessment.
CCDS was used in several studies to assess cervical lymph nodes. Increased vascularization (peripheral and intranodular) indicates malignancy of the examined lymph node [78], [90], [83], [106].
3.5 Thyroid scintigraphy ([⁹⁹ᵐTc]pertechnetate, ¹²³I, evidence and performance of thyroid scintigraphy)
This chapter deals with thyroid scintigraphy, which can be used to assess the function of thyroid nodules.
As part of a planned dignity assessment of thyroid nodules ≥ 1 cm, a thyroid scintigraphy shall be performed in adults - regardless of the TSH value.
- Consensus
- Consent (82,6%)
Thyroid scintigraphy (with iodine-123 (¹²³I) or with technetium-99m pertechnetate ([⁹⁹ᵐTc]TcO4-) is the only imaging procedure with which the expression and activity of the sodium iodide symporter (NIS) can be visualized in vivo. For practical reasons, scintigraphy is generally performed with [⁹⁹ᵐTc]pertechnetate. For special questions such as the clarification of substernal or ectopic or dystopic thyroid nodules, ¹²³I is superior.
Scintigraphy is performed in accordance with the S1 guideline of the German Society of Nuclear Medicine (AWMF Reg. No. 031-011), as standard quantitatively with determination of the uptake. In the context of this guideline, only the aspect of determining the dignity of thyroid nodules is discussed.
In the thyroid scintigram, a distinction is made in comparison to extranodular thyroid tissue between hyperfunctional nodules with increased enhancement, hypofunctional nodules with reduced enhancement, and indifferent nodules that appear isointense.
In the case of scintigraphic findings of a hyperfunctional (autonomous) nodule, no further clarification of dignity (beyond sonography) shall be performed.
- Consensus
- Strong consensus (100%)
The special clinical value of scintigraphy lies in the identification of autonomous adenomas as benign thyroid nodules. The scintigraphic findings of a hyperfunctional (autonomous) nodule cannot be predicted by any other method, including sonography [107] or ultrasound elastography [108], [109]. The majority of hyperfunctional nodules are detected by scintigraphy at the time of euthyroidism, as demonstrated by various studies [110], [111].
Scintigraphically enhanced nodules almost always correspond to focal autonomies [112], [113]. In a pathology-initiated review of 65 publications on thyroid malignancies presenting as hyperfunctioning nodules, only 10 withstood a critical review [114]. Malignancy of a hyperfunctioning thyroid nodule is therefore a rarity.
The scintigraphic findings of a hypofunctional nodule alone shall not be an indication for surgery.
- Consensus
- Strong consensus (100%)
Thyroid scintigraphy contributes to the risk stratification of thyroid nodules by enabling the selection of hypofunctional nodules whose dignity shall be further clarified. Thyroid scintigraphy can increase the positive predictive value of fine needle cytology from 1.5% for unselected clarification [115]. The desired pre-test probability of at least 5-10% can be achieved by combining sonographic and scintigraphic criteria.
For scintigraphically under-enriched nodules, the literature shows a wide range of malignancy prevalence from less than 3% in regions with iodine deficiency and 5.5% in regions without iodine deficiency [116], to 22% in a prospective study of 100 operated patients with a single thyroid nodule [117]. Thus, only in combination with other procedures (e.g. standardized sonography/ TIRADS, FNA, possibly US elastography) are predictive values achieved that provide a sufficiently reliable basis for a decision regarding the further procedure (e.g. surgery).
In the case of indifferent accumulation in thyroid nodules, a supplementary suppression scintigraphy can be performed.
- Consensus
- Strong consensus (100%)
No reliable data is available on the negative or positive predictive value of scintigraphically indifferent nodules. Such findings may be due to nodules that actually have an enhancement behavior comparable to the perinodular tissue, as well as nodules that do not demarcate due to their small size or position. In the latter cases, suppression of the perinodular tissue can make the hyperfunctionality of a nodule visible and thus practically rule out malignancy.
3.6 Determination of laboratory values
Some laboratory values, especially for the thyroid-stimulating hormone, are frequently examined in medical practice. This chapter describes the importance of laboratory tests in assessing the dignity of thyroid nodules.
3.6.1 Thyroid-stimulating hormone (TSH)
A TSH determination shall be carried out every time a lump is investigated.
- Consensus
- Strong consensus (100%)
In the case of thyroid nodules, low TSH values may indicate autonomic dysfunction [118], [119]. A TSH determination is therefore necessary in the investigation of thyroid nodules.
Some studies have found an association between higher TSH levels and the risk of a DTC occurring [120], [121], [122], [123], [124], [125], [126], [127], [128]. Huang et al. describe this only for men; in women, they found a higher risk with lower TSH values [126]. A correlation with the TSH level was also found for advanced tumor stages and aggressive tumor growth [129], [130], [131], [132]. One study describes the additional benefit of a TSH determination in cytologies of fine needle aspirates of thyroid nodules of undetermined significance [133]. In 127 Spanish patients with a Bethesda classification IV on fine needle aspiration, a higher rate of malignancy was found with higher TSH values [134]. Other authors could not find an association between higher preoperative TSH levels and tumor stage [122], [135], whereas one study described a lower risk of developing papillary thyroid carcinoma with lower TSH levels [136]. In a prospective collective, higher TSH levels in patients with histologically proven lymphocytic infiltration were not associated with a higher probability of carcinoma [137]. A German study shows an increased risk of carcinoma with both increased and decreased TSH values [138].
A meta-analysis with a total of 23,799 participants confirmed a slightly increased risk of DTC with higher TSH values [139]. However, the determination of a higher TSH value in an individual with nodules does not allow the prediction of malignancy.
3.6.2 Thyroglobulin
Thyroglobulin (Tg) is a well-validated tumor marker in the postoperative follow-up of patients with differentiated thyroid carcinoma [140]. In the preoperative diagnosis of thyroid nodules, thyroglobulin cannot reliably predict the presence of thyroid carcinoma [141]. The data on this is contradictory [142], [143], [144], [145], [146], [147]. There are no prospective studies that prove a sufficiently high significance of thyroglobulin determination in the preoperative clarification of thyroid nodules. Elevated thyroglobulin levels are also found in many patients with benign thyroid nodules, in goiters and in iodine deficiency [148], [149]. Comparatively high thyroglobulin levels are found more frequently in patients with lymphogenous metastatic tumors or radioiodine-refractory thyroid carcinomas [150], [151]. Some authors have calculated the ratio of TSH to thyroglobulin in order to improve the prediction of malignancy of thyroid nodules. Here too, only retrospective data is available [152], [153]. In individual cases, a thyroglobulin determination can be helpful in determining the further procedure, but a routine determination of thyroglobulin in the clarification of thyroid nodules is not useful.
A routine determination of thyroglobulin shall not be carried out as part of the clarification of thyroid nodules.
- Consensus
- Strong consensus (100%)
3.6.3 Thyroglobulin antibodies (TgAb)
In a larger patient population, the preoperative determination of TgAb was identified as an independent risk factor for the presence of lymph node involvement and extranodal tumor spread [154]. Li et al. confirmed the association of a higher risk of papillary thyroid carcinoma with positive TgAb, but saw less extrathyroidal tumor spread in this population [155]. This was also seen in retrospective studies [127], [132], [156], [157], [158], [159], [160]. In two studies with fine needle aspirates, the suspicion or detection of thyroid carcinoma was higher in TgAb-positive patients than in TgAB-negative individuals [161], [162]. An individual prediction of the presence of differentiated thyroid carcinoma is not possible with a determination of thyroglobulin antibodies. Karatzas et al. found more cases with multifocality, capsular penetration, and lymph node metastases in nodules with cytology of unknown significance in FNA in TgAb-positive patients with PTC [163]. The presence of TgAb may therefore indicate a higher tumor stage in the presence of thyroid carcinoma and methodological problems in the postoperative determination of the tumor marker thyroglobulin [164].
3.6.4 TPO antibodies
Retrospectively, a large series of TPO-Ab-positive patients with diffuse lymphocytic infiltration of the thyroid gland showed more multifocal papillary carcinomas with a lower rate of extrathyroidal spread, but more tumors > 1 cm and more lymph node metastases. TPO-Ab-positivity without diffuse lymphatic infiltration showed no tendency towards increased tumor aggressiveness [165]. In a region with high to increased iodine supply, there was a higher rate of patients with papillary thyroid carcinomas with positive TPO-Ab [128]. With simultaneously elevated TPO and TgAb, Wu et al. showed a higher rate of papillary carcinomas [166]. A meta-analysis with over 64,000 patients shows an association between the presence of Hashimoto's thyroiditis and the occurrence of PTC. No information is provided on the level of TPO-Ab or the definition of Hashimoto's thyroiditis [167]. In the primary diagnosis of Hashimoto's thyroiditis with simultaneous detection of nodules, a significantly increased rate of papillary carcinomas was found in Italy. Extrathyroidal spread and lymph node metastasis were also associated with TPO positivity [168]. Song et al. showed that preoperative detectable TPO-Ab is associated with improved disease-free survival [169]. Further studies show an increased rate of PTC in patients with elevated TPO-Ab [170]. A meta-analysis with 18 included studies confirms these results [171].
3.6.5 Calcitonin
With regard to the determination of calcitonin in serum, please refer to Chapter 8.1.2.1 and Chapter 8.1.2.1.
3.7 Fine needle aspiration, incl. FNA of lymph nodes/punch biopsy
A fine needle aspiration of thyroid nodules (≥ 1 cm) shall only be performed after adequate pre-selection of suspicious nodules and if the puncture findings are included in the planning of the further procedure.
- Consensus
- Strong consensus (95,2%)
Nodules < 1 cm should only be punctured if there are risk factors present, and with the aid of sonography and a puncture specialist who has expertise.
- Consensus
- Strong consensus (95,5%)
Unselected fine needle aspiration of thyroid nodules shall not be performed.
- Consensus
- Strong consensus (95,8%)
In the case of suspected C-cell carcinoma of the thyroid gland (e.g. suspicious findings in the calcitonin determination - see Chapter Medullary thyroid carcinoma (MTC)), fine needle aspiration should not be performed.
- Consensus
- Consent (90,9%)
The following statements can be made about fine needle aspiration:
Fine-needle aspiration is a simple and safe procedure for obtaining cells from defined lesions ("nodules"), which can be used to make a diagnostic contribution to determining the biological nature and therefore dignity of these nodules.
Fine-needle aspiration cytology of the thyroid gland is referred to in international literature as fine-needle aspiration cytology "FNAC". If puncture is performed without aspiration, the term "FNC" is used.
The diagnosis of practically all thyroid neoplasms is based on special histological criteria and therefore cannot be made cytologically. The task of cytology is to identify lesions in which malignancy is likely or cannot be considered unlikely with the necessary certainty, and which are then subjected to surgery and subsequent histological clarification.
In contrast to the approach in other countries (especially in the USA/Canada), conspicuous nodules are more frequently diagnosed and operated on in the iodine deficiency region and thus subjected to histological dignity assessment; in this approach, the significance of FNAC must be assessed differently than, for example, in the ATA guidelines.
It is not possible to differentiate between adenomas and FTCs cytologically.
The establishment of the NIFTP made it necessary to redefine the morphological criteria for PTC. The criteria now include only histologically detectable aspects [172]. Whereas previously a PTC could be clearly diagnosed both cytologically and histologically on the basis of the characteristic nuclear features, the introduction of the NIFTP, for whose cytological prerequisites the detection of PTC-equivalent nuclear features is mandatory, means that further criteria - only detectable histologically - are necessary (invasion and/or clear papillae).
However, a fine-needle aspiration allows a good preselection of nodules that require histological clarification in the case of clinically and/or sonographically conspicuous nodules (see Chapter Sonography (evidence and performance of sonography)) with a size ≥ 1 cm after scintigraphic exclusion of focal autonomy. Smaller nodules (< 1 cm) are usually monitored sonographically, but they can also be punctured with sonographic guidance if the puncture specialist has the appropriate expertise and if there are particular risk factors [173], [174].
Puncturing nodes that do not meet this definition increases the number of unnecessary surgeries [115].
In cases where surgery would be indicated for various reasons even without the use of FNAC, FNAC can nevertheless provide decisive information for the preoperative management of the surgery (extent of the surgery, intraoperative frozen section, patient information).
The extent of surgical intervention in MTC is increasingly being made dependent on the detection of a desmoplastic stromal reaction (DSR) [175], [176], [177], [178], [179]. Thyroid fine needle aspiration can induce fibroblastic proliferation, which can mimic a tumor-induced DSR, and thus deprive corresponding surgical concepts based on intraoperative frozen section diagnostics of their foundation.
The fine-needle aspiration should be performed with sonographic guidance (this is mandatory for non-palpable nodules).
- Consensus
- Strong consensus (100%)
Material can be obtained by aspiration puncture or non-aspiration puncture when puncturing solid nodules (parts).
- Consensus
- Strong consensus (100%)
Sonographically guided puncture under control of the needle tip echo leads to greater accuracy and increases both the rate of diagnostic punctates and the diagnostic sensitivity [180], [181], [182].
Some studies have shown that small-lumen puncture needles (22 G to 25 G) produce a higher cell yield with a lower blood content than needles with a larger lumen [183], [184], [185], [186]. Ultimately, the choice of cannula thickness should be made in consultation with the cooperating pathology institution, taking into account the processing technique established there.
In the case of mixed cystic-solid nodules, sonographically guided material should be obtained from the solid parts to clarify the dignity (if necessary, repeat puncture after previous decompression puncture of larger cystic parts).
The puncture can be performed as a so-called aspiration puncture (possibly with the support of special suction pump systems) or non-aspiration puncture, in which the cytological material is obtained exclusively through the capillary action of the cannula [187], [188], [189], [190]. Non-aspiration puncture is particularly preferred for FNAC in children; otherwise, the studies cited did not show any clear superiority of either method.
Thicker cannulas are used for therapeutic puncture (reduction of cyst volume) of cystic thyroid lesions than for purely diagnostic FNAC; these cyst punctates should also be regularly subjected to cytological examination, as papillary carcinomas and metastases (e.g. of bronchial and renal carcinomas) may be cystically altered.
The cytologic material obtained by FNAC is usually spread directly onto slides. Depending on the staining method, the slides must then be air-dried or fixed accordingly. Alternatively, the puncture material can also be further processed using the thin-layer method [191], [192]. The material is transferred to a lysis reagent for (extensive) lysis of punctured erythrocytes (which is also used for transportation). After subsequent fixation, a defined number of cells are standardized and applied to a slide using special equipment. The mostly blood-free preparations can be microscopically assessed in a much less time-consuming manner. Disadvantages are the higher number of technically inadequate preparations and various specifics in the cytological assessment of the preparations.
With regard to hygiene requirements in Germany, the recommendations of the Commission for Hospital Hygiene and Infection Prevention (KRINKO) of the Robert Koch Institute (disinfection, sterile swab material, sterile gloves and sterile perforated cloth, sterile transducer cover if necessary) published in the Bundesgesundheitsblatt 2011 apply [193].
The intake of acetylsalicylic acid at a dose of 100 mg/die does not need to be paused [194]. A retrospective data analysis of 803 patients also showed no increased rate of bleeding complications with clopidrogel, coumarins, or newer oral anticoagulants (NOACs) such as rivaroxaban and ticagrelor [195]. The decision as to whether the puncture should be performed while the patient is still taking anticoagulants or after briefly discontinuing this medication (if necessary, a transient switch to heparin) requires an individual risk:benefit assessment. Relevant bleeding after thyroid fine needle puncture is the exception. Brief follow-up observation of the patient and, if necessary, a sonographic check after 15 - 30 minutes if bleeding is suspected further reduce the risk of complications.
3.7.1 Fine needle puncture of lymph nodes
In rare cases, sonographically assisted puncture of conspicuous lymph nodes (see Chapter Fine needle puncture of lymph nodes) in the neck area can be the primary diagnosis of thyroid carcinoma, especially if the thyroid gland shows no conspicuous nodes or only very small lesions [196], [197]. Sensitivity is high, but varies between examiners and regions as well as needle sizes used. One meta-analysis lists published sensitivities between 52 and 100% [198]. The specificity is given as between 71.4 and 100% [198], [199], [200], [201], [202].
If a high-grade thyroid carcinoma is already suspected or has already been detected, a supplementary puncture of sonographically conspicuous lymph nodes may be useful if the result of the puncture changes the surgical procedure [203], [204]. Lymph node involvement indicates a higher tumor stage and can lead to an extended resection strategy.
In individual cases and if technically feasible, a molecular genetic analysis of the punctate can be performed. A BRAF mutation is of particular importance in the diagnosis of papillary thyroid carcinoma [205].
A fine-needle aspiration of sonographically and/or clinically abnormal lymph nodes should only be performed if this results in therapeutic consequences.
- Consensus
- Consent (95%)
3.7.2 Thyroglobulin determination in the punctate washout
Thyroglobulin can be determined in the punctate washout of a fine needle aspirate of sonographically and/or clinically conspicuous lymph nodes.
- Consensus
- Consent (90,5%)
The combination of FNAC and the measurement of thyroglobulin in fine needle washout can increase the accuracy of carcinoma prediction [199], [206], [207], [208], [209]. Tg determination in the fine needle aspirate of lymph nodes has a high sensitivity and specificity [210]. The preoperative Tg determination in the washout of a lymph node aspirate can also contribute to the decision on the type of surgical procedure [211]. The combination of cytology and Tg determination in the washout of the puncture achieves a sensitivity of 97% and a specificity of 93% [212].
3.7.3 Punch biopsy
A punch biopsy can be performed for non-diagnostic fine needle aspirations.
- Consensus
- Consent (80%)
In the primary diagnosis of thyroid nodules, punch biopsies have no advantage over FNAC [196], [198].
If there are severe macrocalcifications or significant regressive changes in the nodules, a punch biopsy may offer an advantage over FNAC [213], [214]. This also applies in the case of non-diagnostic FNAC [214]. FNAC cannot reliably differentiate follicular adenomas from follicular carcinomas. In this case, a "follicular neoplasia" is diagnosed. In this case, only histological confirmation by surgery can provide clarification. As a rule, however, less than 20% of the nodules operated on in this way are malignant, meaning that the majority of surgeries would have been unnecessary in retrospect. The distinction between follicular adenoma and follicular carcinoma is essentially made by vascular invasion. This can be seen to some extent in specimens from a punch biopsy, so that some data indicate that punch biopsy is significantly superior to FNAC in the diagnosis of follicular carcinoma [215].
FNAC is usually not able to reliably diagnose anaplastic carcinoma. In the case of clinical and sonographic suspicion of anaplastic carcinoma, the primary punch biopsy is significantly more informative. This also applies to suspected lymphoma or suspected non-organ metastases [216].
3.8 Further imaging procedures
This chapter describes supplementary imaging procedures that go beyond the usual primary diagnosis of thyroid carcinoma. MIBI scintigraphy, skeletal scintigraphy, conventional X-ray examinations, computer tomography including PET/CT and magnetic resonance imaging examinations are discussed.
3.8.1 Scintigraphy with ⁹⁹ᵐTc-MIBI
If fine needle aspiration is indicated, imaging with ⁹⁹ᵐTc-MIBI can be used if fine needle aspiration is not possible, has been rejected by the patient, is not representative, or has remained without meaningful findings.
Imaging with ⁹⁹ᵐTc-MIBI shall not be used for hyperfunctional and functionally indifferent thyroid nodules.
- Consensus
- Strong consensus (100%)
Imaging with ⁹⁹ᵐTc-MIBI shall not be used as a "screening procedure" for risk stratification of thyroid incidentalomas.
- Consensus
- Strong consensus (100%)
Imaging with 99mTc-MIBI is a non-invasive nuclear medicine molecular imaging procedure that is approved for cardiological ischemia and vitality diagnostics, for localization diagnostics of parathyroid adenomas in hyperparathyroidism and for the detection of breast cancer. It has been used clinically off-label for decades to assess the dignity of thyroid nodules. The off-label use must be explained.
Three meta-analyses were identified during the evidence search. The included studies examined the diagnostic accuracy of MIBI scintigraphy in comparison to cytologic or histologic findings.
In the meta-analysis by Wale et al. [219], the 10 included studies with a total of 712 patients consistently showed a high negative predictive value of 97% on average with a low PPV of 34%. Kim et al. [217] included 22 studies with 2,421 patients in their meta-analysis based on Medline and MBase and found a sensitivity of 87% (CI 76% - 93%) and a specificity of 78% (67% - 86%). Treglia et al. [218] also carried out a comprehensive literature search and included 21 publications in their meta-analysis. The overall evaluation resulted in a sensitivity of 85.1% (81.1 - 88.5%) and a specificity of 45.7% (42.7 - 48.7%). They point out that the specificity of the method is increased if MIBI scintigraphy is only used for scintigraphically hypofunctional nodules, which is good medical practice.
Fine-needle aspiration cytology is currently the gold standard if the punctate is conclusive. Due to the high sensitivity and the associated high negative predictive value, 99mTc-MIBI scintigraphy is an option. The low confidence in the evidence quality of the studies leads to the restrictions made in the recommendation.
3.8.2 PET in combination with CT or MRI
3.8.2.1 Incidental [¹⁸F]FDG uptake in the thyroid gland in PET
In the case of an incidental focal FDG accumulation in the thyroid gland, further clarification should be carried out to exclude malignancy if the diagnosis of thyroid carcinoma would lead to therapeutic consequences.
- Consensus
- Strong consensus (100%)
[¹⁸F]FDG-PET is increasingly used in combination with CT and MRI in patients with suspected or known malignant or inflammatory diseases. A focally increased glucose metabolism in [¹⁸F]FDG-PET in the thyroid gland is found incidentally in 1 to 2% of patients, a diffusely increased uptake in approx. 2% of patients [220], [221], [222], [223].
The focally increased [¹⁸F]FDG uptake usually corresponds to a clinically palpable thyroid nodule (> 1cm), so that further sonographic clarification is recommended. It must be taken into account that these thyroid nodules are malignant in approx. 35% of cases (relative frequency depends on the prevalence of autonomous nodules); on average, malignant nodules show a significantly higher SUVmax than benign nodules (6.9 vs. 4.8; p < 0.001) [223]. Accordingly, further clarification is recommended, taking into account the underlying disease (reason for performing the PET/CT). In one retrospective study by Pattison et al., only one of a total of 180 deceased patients died of their incidentally diagnosed medullary thyroid carcinoma [224]. Incidental focal accumulations in the thyroid gland also occur in the much less frequently performed PET/CT examinations with DOTATOC, DOTATATE, and PSMA and must be recognized in the clinical context.
A diffusely increased glucose metabolism of the thyroid gland is usually the result of a benign change (inflammatory genesis). It does not require the exclusion of malignancy but may require further clinical evaluation for thyroiditis.
3.8.2.2 [¹⁸F]FDG-PET for the assessment of nodules with inconclusive cytological findings
In thyroid nodules > 1.5 cm with sonographic malignancy criteria and hypofunctionality in thyroid scintigraphy, [¹⁸F]FDG-PET (as PET/CT or PET/MRI) can be performed due to the high negative predictive value if a dignity classification is/was not possible using fine needle aspiration.
- Consensus
- Strong consensus (95,7%)
The benefit of [¹⁸F]FDG-PET/CT for the assessment of nodules with inconclusive cytologic findings has been the subject of three meta-analyses to date [225], [226], [227]. In this patient population, the ability of [¹⁸F]FDG-PET/CT to differentiate between benign and malignant lesions can be described as moderate [227]. Overall, [¹⁸F]FDG-PET showed a sensitivity of 89%, a specificity of 55%, a positive predictive value of 41%, and a high negative predictive value of 93% [226].
Especially in patients with nodules >1.5 cm who had inconclusive cytologic findings, a negative [¹⁸F]FDG-PET scan led to improved diagnostic accuracy [225].
Vriens et al. conducted a cost-benefit analysis in Dutch patients scheduled for thyroid surgery due to inconclusive fine-needle biopsy cytology findings and demonstrated that the implementation of preoperative [¹⁸F]FDG-PET/CT would have prevented up to 47% of surgical procedures retrospectively deemed unnecessary, led to a small increase in health-related quality of life, and may reduce costs compared to diagnostic surgery and molecular testing [228].
In a single prospective study, [¹⁸F]FDG-PET showed no additional diagnostic benefit or improved risk classification compared to thyroid sonography in multivariate analysis [229]. However, other recent prospective studies again show added value in the inclusion of [¹⁸F]FDG-PET in the diagnostic workup of cytologically indeterminate thyroid nodules [230], [231]. Even though the majority of the available literature supports the use of [¹⁸F]FDG-PET/CT in this patient population, further prospective studies are necessary, as the currently available data provide partly controversial results regarding the added value of [¹⁸F]FDG-PET/CT in differentiating between benign and malignant lesions in cytologically indeterminate thyroid nodules.
A comparison with MIBI imaging in terms of sensitivity and specificity as well as cost-effectiveness has not yet been carried out.
3.8.2.3 Preoperative sectional imaging using PET/CT
Regular preoperative [¹⁸F]FDG-PET/CT should not be performed.
- Consensus
- Strong consensus (100%)
A [¹⁸F]FDG-PET (in combination with CT or MRI) can be performed preoperatively to diagnose spread in "high-risk" patients with an extensive tumor, high-grade lymph node metastases, clinically aggressive progression, suspected distant metastases, and tumors with indications of aggressiveness in the biopsy. The examination shall then be carried out promptly.
- Consensus
- Strong consensus (95,2%)
A [¹⁸F]FDG-PET (in combination with CT or MRI) should be performed promptly if anaplastic thyroid carcinoma is clinically suspected (see also Chapter Imaging).
- Consensus
- Strong consensus (100%)
The majority of differentiated thyroid carcinomas show relatively slow growth. Sometimes the tumor can also be [¹⁸F]FDG-negative [222]. With regard to the local findings and the locoregional lymph nodes, [¹⁸F]FDG-PET/CT only provides limited information compared to preoperative sonography [230], [232], [233], [234]. The method showed very low sensitivity (10%) and low NPV (50%) but high specificity (90%) for locoregional lymph node metastases in the study by Kim et al. [235]. Since only 4-7% of patients with differentiated thyroid carcinoma have distant metastases at initial presentation, routine, preoperative/perioperative use of [¹⁸F]FDG-PET/CT imaging is generally not recommended [222], [236].
For the detection of distant metastases, [¹⁸F]FDG-PET shows a high sensitivity of up to 85% and specificity of up to 95% in several studies [24]. Therefore, [¹⁸F]FDG-PET/CT plays a role in the initial staging of patients who have a significant risk of distant metastasis or who are clinically suspected of having distant metastases [222].
In the study by Rosenbaum-Krumme et al., patients with extensive or metastatic, differentiated "high-risk" thyroid carcinoma who received [¹⁸F]FDG PET/CT after initial radioiodine therapy were examined [237]. Of these, 29% had FDG-avid tumor lesions, 36% had iodine-avid lesions, and 8% had concordant FDG- and iodine-avid metastases. The [¹⁸F]FDG-PET/CT examination performed led to a change in patient management in 21% of cases (especially in patients with stage pT3bN1 and distant metastases).
Promising results were also shown by [¹⁸F]FDG-PET/CT studies in tumor subtypes considered more aggressive, such as Hürthle cell tumor or the large cell variant [238], [239], [240]. In the study by Pryma et al. [240], 44 patients with Hürthle cell carcinoma were examined, with [¹⁸F]FDG-PET/CT showing a sensitivity of 96% and a specificity of 95% and the intensity of FDG uptake in the tumor lesions providing additional important prognostic information. Nascimento et al. [239] examined 38 patients with different aggressive subtypes, for example the large cell or diffuse sclerosing variant, using [¹⁸F]FDG-PET/CT. A total of 86 lesions were found in 20 patients in the PET/CT and the post-therapeutic whole-body scintigram. Here, 41% of the lesions could only be detected by [¹⁸F]FDG-PET/CT.
[¹⁸F]FDG-PET/CT can also be used for risk stratification. A retrospective evaluation by Robbins et al. [241] in 400 thyroid cancer patients showed that patients with a significantly increased [¹⁸F]FDG uptake had a 7-fold higher risk of death compared to the patient group that had no [¹⁸F]FDG-positive lesions. It can therefore be concluded that patients with non-[¹⁸F]FDG-avid lesions tend to have a better outcome than those who have a significantly increased glucose metabolism.
In the preoperative setting, the value of [¹⁸F]FDG-PET (in combination with CT or MRI) lies in sensitive whole-body staging (without the use of iodine-containing X-ray contrast medium) in high-risk constellations for distant metastasis. If distant metastases are detected, the intervention in the neck area would be less extensive in many cases. It also seems possible to make a statement about the prognosis.
With regard to the preoperative use of [¹⁸F]FDG-PET in anaplastic thyroid carcinoma, please refer to Chapter Imaging (CT, MRI, PET/CT).
3.8.3 Skeletal scintigraphy, chest X-ray, CT or MRI
3.8.3.1 Skeletal scintigraphy
Skeletal scintigraphy can be performed as part of initial staging in cases of suspected osseous metastasis if [¹⁸F]FDG-PET (in combination with CT or MRI) is not available.
- Consensus
- Consent (90%)
There are no studies with large numbers of patients and no randomized studies. In recent years, studies with smaller case numbers have been published, mostly comparing planar bone scintigraphy, [¹⁸F]FDG-PET, and [¹⁸F]fluoride PET.
In several studies, planar bone scintigraphy showed a sensitivity of 64% to 85% for the detection of bone metastases in thyroid cancer [242], [243], [244], [245]. The specificity in these studies is given as 81 - 95 %. The use of SPECT technology has significantly increased the sensitivity of planar bone scintigraphy; up to 100% has been published here, although this must be critically questioned [244]. For other tumor entities such as prostate and breast cancer, it has been shown that the use of SPECT or SPECT-CT can significantly increase the sensitivity and specificity in the detection of bone metastases compared to planar bone scintigraphy alone [246].
In a study published in 2007 on 47 patients with thyroid cancer, planar bone scintigraphy showed a sensitivity of 78 % and a specificity of 91.4 % [245]. Another study in 2012 found a sensitivity of 79% and a specificity of 83% in 80 patients with thyroid cancer using the planar technique; SPECT was not used here [243].
Studies comparing [¹⁸F]FDG-PET/CT with planar bone scintigraphy show different results. While in one study [¹⁸F]FDG-PET/CT shows higher sensitivity and specificity compared to planar bone scintigraphy, another study only shows better specificity with the same sensitivity [243]. In a more recent study from 2014, the sensitivity of planar bone scintigraphy improved to a level above that of [¹⁸F]FDG-PET/CT due to the additional use of the SPECT technique, although this was a small patient population of 11 patients [244]. Skeletal metastases of a differentiated thyroid carcinoma can present as "cold lesions". A two-phase acquisition technique with early images can increase the identification of skeletal metastases by identifying hyperemic marginal enhancement
3.8.3.2 Chest X-ray examination
X-ray examination of the thorax should not be used as initial routine staging for thyroid cancer.
- Consensus
- Strong consensus (95,7%)
The benefit of performing a routine chest X-ray is limited and questionable [247].
3.8.3.3 Computed tomography (CT)
Computed tomography should not be performed as initial routine staging for thyroid cancer.
- Consensus
- Strong consensus (100%)
Native computed tomography can be performed initially if lung metastasis is suspected.
- Consensus
- Strong consensus (95,7%)
If a differentiated thyroid carcinoma has been ruled out, a contrast-enhanced CT should be performed for staging in the case of advanced tumors, with [¹⁸F]FDG-PET if available in a timely manner.
In exceptional cases, this may also apply to differentiated thyroid carcinoma.
- Consensus
- Strong consensus (100%)
The value of preoperative computed tomography (CT) was investigated in 2019 in a prospective study of 111 patients with differentiated thyroid carcinoma (tumor diameter < 4 cm); a change in the surgical procedure was described here in 22.5% of cases due to the use of preoperative CT, but it should be noted that the most frequent change was the performance of a central lymph node dissection, which, however, is usually performed in Germany with previously confirmed carcinoma [248]. The rate of false-positive findings was 44% centrally.
The additional performance of a CT scan of the thorax can be useful for the assessment of advanced thyroid cancer, as it can be used to assess extrathyroidal spread, particularly posteriorly or mediastinally [249].
A study published in 2015 shows that the combined use of sonography and CT as part of preoperative imaging can have advantages over sonography alone [250].
It should be noted that contrast-enhanced CT makes radioiodine therapy impossible in the narrow time interval after surgery due to the high amount of iodine. From a clinical point of view, postponing radioiodine therapy (if clinically indicated) is possible in many cases, but this can lead to considerable psychological stress, especially in patients with postoperative tumor manifestations that can be detected macroscopically.
3.8.3.4 Magnetic resonance imaging (MRI)
Magnetic resonance imaging can be performed initially in the case of locally advanced cervical tumors or suspected metastasis.
- Consensus
- Strong consensus (100%)
The administration of iodine-containing contrast media or other substances with a high iodine content should be avoided in cases of thyroid carcinoma.
- Consensus
- Strong consensus (95,2%)
Magnetic resonance imaging (MRI) is often used for tumors in the head and neck region to assess tumor spread and, above all, to rule out infiltrative growth. However, a 2014 study on thyroid cancer patients showed a lower sensitivity in the assessment of extrathyroidal spread of the carcinoma compared to sonographic examinations [251].
3.9 Preoperative vocal fold diagnostics and laryngological diagnostics
Before any thyroid surgery, a laryngoscopic check of the respiratory mobility of the vocal folds shall be performed and subjective voice, breathing and swallowing complaints shall be recorded. A phoniatric voice examination should be performed in the event of functional limitations.
- Consensus
- Strong consensus (96%)
References
[1] Meisinger, C, Ittermann, T, Wallaschofski, H, Heier, M, Below, H, Kramer, A, et.al. Geographic variations in the frequency of thyroid disorders and thyroid peroxidase antibodies in persons without former thyroid disease within Germany., Eur J Endocrinol, 2012. 167 (3)(3): p. 363-71., https://pubmed.ncbi.nlm.nih.gov/22700599/
[2] Reiners, C, Wegscheider, K, Schicha, H, Theissen, P, Vaupel, R, Wrbitzky, R, et.al. Prevalence of thyroid disorders in the working population of Germany: ultrasonography screening in 96,278 unselected employees., Thyroid, 2004. 14 (11)(11): p. 926-32., https://pubmed.ncbi.nlm.nih.gov/15671771/
[3] Khattak, RM, Ittermann, T, Nauck, M, Below, H, Völzke, H, Monitoring the prevalence of thyroid disorders in the adult population of Northeast Germany., Popul Health Metr, 2016. 14 (): p. 39., https://pubmed.ncbi.nlm.nih.gov/27833458/
[4] Krebs in Deutschland, in Schilddrüse, 2021. p. 126 - 129., https://www.krebsdaten.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/kid_2021/kid_2021_c73_schilddruese.pdf?__blob=publicationFile
[5] Brenner, DR, Ruan, Y, Shaw, E, O'Sullivan, D, Poirier, AE, Heer, E, et.al. Age-standardized cancer-incidence trends in Canada, 1971-2015., CMAJ, 2019. 191 (46)(46): p. E1262-E1273., https://pubmed.ncbi.nlm.nih.gov/31740536/
[6] Dal Maso, L, Panato, C, Franceschi, S, Serraino, D, Buzzoni, C, Busco, S, et.al. The impact of overdiagnosis on thyroid cancer epidemic in Italy,1998-2012., Eur J Cancer, 2018. 94 (): p. 6-15., https://pubmed.ncbi.nlm.nih.gov/29502036/
[7] Seib, CD, Sosa, JA, Evolving Understanding of the Epidemiology of Thyroid Cancer., Endocrinol Metab Clin North Am, 2019. 48 (1)(1): p. 23-35., https://pubmed.ncbi.nlm.nih.gov/30717905/
[8] Powers, AE, Marcadis, AR, Lee, M, Morris, LGT, Marti, JL, Changes in Trends in Thyroid Cancer Incidence in the United States, 1992 to 2016., JAMA, 2019. 322 (24)(24): p. 2440-2441., https://pubmed.ncbi.nlm.nih.gov/31860035/
[9] Wiltshire, JJ, Drake, TM, Uttley, L, Balasubramanian, SP, Systematic Review of Trends in the Incidence Rates of Thyroid Cancer., Thyroid, 2016. 26 (11)(11): p. 1541-1552., https://pubmed.ncbi.nlm.nih.gov/27571228/
[10] Farahati, J, Mäder, U, Gilman, E, Görges, R, Maric, I, Binse, I, et.al. Changing trends of incidence and prognosis of thyroid carcinoma., Nuklearmedizin, 2019. 58 (2)(2): p. 86-92., https://pubmed.ncbi.nlm.nih.gov/30917397/
[11] Krebs in Deutschland, in Schilddrüse, 2019. p. 118 - 121., https://www.krebsdaten.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/kid_2019/kid_2019_c73_schilddruese.pdf?__blob=publicationFile
[12] Mirian, C, Grønhøj, C, Jensen, DH, Jakobsen, KK, Karnov, K, Jensen, JS, et.al. Trends in thyroid cancer: Retrospective analysis of incidence and survival in Denmark 1980-2014., Cancer Epidemiol, 2018. 55 (): p. 81-87., https://pubmed.ncbi.nlm.nih.gov/29852396/
[13] Cancer Research UK, Thyroid cancer statistics, 2025., https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/thyroid-cancer#thyroid_stats0
[14] Lim, H, Devesa, SS, Sosa, JA, Check, D, Kitahara, CM, Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013., JAMA, 2017. 317 (13)(13): p. 1338-1348., https://pubmed.ncbi.nlm.nih.gov/28362912/
[15] Ren, YJ, Liu, QM, Ge, MH, Li, HZ, Liu, B, Zhang, Y, et.al. [Incidence and mortality of thyroid cancer in cancer registries of Zhejiang Province, 2010-2014]., Zhonghua Yu Fang Yi Xue Za Zhi, 2019. 53 (10)(10): p. 1062-1065., https://pubmed.ncbi.nlm.nih.gov/31607057/
[16] Lin, B, Ma, H, Ma, M, Zhang, Z, Sun, Z, Hsieh, IY, et.al. The incidence and survival analysis for anaplastic thyroid cancer: a SEER database analysis., Am J Transl Res, 2019. 11 (9)(9): p. 5888-5896., https://pubmed.ncbi.nlm.nih.gov/31632557/
[17] Borges, AKDM, Miranda-Filho, A, Koifman, S, Koifman, RJ, Thyroid Cancer Incidences From Selected South America Population-Based Cancer Registries: An Age-Period-Cohort Study., J Glob Oncol, 2018. 4 (): p. 1-11., https://pubmed.ncbi.nlm.nih.gov/30241178/
[18] Safavi, A, Azizi, F, Jafari, R, Chaibakhsh, S, Safavi, AA, Thyroid Cancer Epidemiology in Iran: a Time Trend Study., Asian Pac J Cancer Prev, 2016. 17 (1)(1): p. 407-12., https://pubmed.ncbi.nlm.nih.gov/26838247/
[19] Ahn, HS, Kim, HJ, Kim, KH, Lee, YS, Han, SJ, Kim, Y, et.al. Thyroid Cancer Screening in South Korea Increases Detection of Papillary Cancers with No Impact on Other Subtypes or Thyroid Cancer Mortality., Thyroid, 2016. 26 (11)(11): p. 1535-1540., https://pubmed.ncbi.nlm.nih.gov/27627550/
[20] Miranda-Filho, A, Lortet-Tieulent, J, Bray, F, Cao, B, Franceschi, S, Vaccarella, S, et.al. Thyroid cancer incidence trends by histology in 25 countries: a population-based study., Lancet Diabetes Endocrinol, 2021. 9 (4)(4): p. 225-234., https://pubmed.ncbi.nlm.nih.gov/33662333/
[21] Eng, C, Mulligan, LM, Healey, CS, Houghton, C, Frilling, A, Raue, F, et.al. Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma., Cancer Res, 1996. 56 (9)(9): p. 2167-70., https://pubmed.ncbi.nlm.nih.gov/8616867/
[22] Marsh, DJ, Andrew, SD, Eng, C, Learoyd, DL, Capes, AG, Pojer, R, et.al. Germline and somatic mutations in an oncogene: RET mutations in inherited medullary thyroid carcinoma., Cancer Res, 1996. 56 (6)(6): p. 1241-3., https://pubmed.ncbi.nlm.nih.gov/8640806/
[23] Eng, C, Clayton, D, Schuffenecker, I, Lenoir, G, Cote, G, Gagel, RF, et.al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis., JAMA, 1996. 276 (19)(19): p. 1575-9., https://pubmed.ncbi.nlm.nih.gov/8918855/
[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/
[25] Cirello, V, Familial non-medullary thyroid carcinoma: clinico-pathological features, current knowledge and novelty regarding genetic risk factors., Minerva Endocrinol (Torino), 2021. 46 (1)(1): p. 5-20., https://pubmed.ncbi.nlm.nih.gov/33045820/
[26] Cetta, F, FAP Associated Papillary Thyroid Carcinoma: A Peculiar Subtype of Familial Nonmedullary Thyroid Cancer., Patholog Res Int, 2015. 2015 (): p. 309348., https://pubmed.ncbi.nlm.nih.gov/26697262/
[27] Tan, MH, Mester, JL, Ngeow, J, Rybicki, LA, Orloff, MS, Eng, C, Lifetime cancer risks in individuals with germline PTEN mutations., Clin Cancer Res, 2012. 18 (2)(2): p. 400-7., https://pubmed.ncbi.nlm.nih.gov/22252256/
[28] Kamilaris, CDC, Faucz, FR, Voutetakis, A, Stratakis, CA, Carney Complex., Exp Clin Endocrinol Diabetes, 2019. 127 (2-03)(2-03): p. 156-164., https://pubmed.ncbi.nlm.nih.gov/30428497/
[29] Lauper, JM, Krause, A, Vaughan, TL, Monnat, RJ, Spectrum and risk of neoplasia in Werner syndrome: a systematic review., PLoS One, 2013. 8 (4)(4): p. e59709., https://pubmed.ncbi.nlm.nih.gov/23573208/
[30] Hińcza, K, Kowalik, A, Kowalska, A, Current Knowledge of Germline Genetic Risk Factors for the Development of Non-Medullary Thyroid Cancer., Genes (Basel), 2019. 10 (7)(7):, https://pubmed.ncbi.nlm.nih.gov/31247975/
[31] Nosé, V, Familial follicular cell tumors: classification and morphological characteristics., Endocr Pathol, 2010. 21 (4)(4): p. 219-26., https://pubmed.ncbi.nlm.nih.gov/20878367/
[32] Sturgeon, C, Clark, OH, Familial nonmedullary thyroid cancer., Thyroid, 2005. 15 (6)(6): p. 588-93., https://pubmed.ncbi.nlm.nih.gov/16029126/
[33] Malchoff, CD, Sarfarazi, M, Tendler, B, Forouhar, F, Whalen, G, Joshi, V, et.al. Papillary thyroid carcinoma associated with papillary renal neoplasia: genetic linkage analysis of a distinct heritable tumor syndrome., J Clin Endocrinol Metab, 2000. 85 (5)(5): p. 1758-64., https://pubmed.ncbi.nlm.nih.gov/10843148/
[34] Liao, Shunyao, Song, Wenzhong, Liu, Yunqiang, Deng, Shaoping, Liang, Yaming, Tang, Zhenlin, et.al. Familial multinodular goiter syndrome with papillary thyroid carcinomas: mutational analysis of the associated genes in 5 cases from 1 Chinese family, 2013. 13(1): p. 48., https://doi.org/10.1186/1472-6823-13-48
[35] Malchoff, CD, Sarfarazi, M, Tendler, B, Forouhar, F, Whalen, G, Malchoff, DM, Familial papillary thyroid carcinoma is genetically distinct from familial adenomatous polyposis coli., Thyroid, 1999. 9 (3)(3): p. 247-52., https://pubmed.ncbi.nlm.nih.gov/10211600/
[36] Guilmette, J, Nosé, V, Hereditary and familial thyroid tumours., Histopathology, 2018. 72 (1)(1): p. 70-81., https://pubmed.ncbi.nlm.nih.gov/29239041/
[37] Iglesias, ML, Schmidt, A, Ghuzlan, AA, Lacroix, L, Vathaire, F, Chevillard, S, et.al. Radiation exposure and thyroid cancer: a review., Arch Endocrinol Metab, 2017. 61 (2)(2): p. 180-187., https://pubmed.ncbi.nlm.nih.gov/28225863/
[38] Kitahara, CM, Berrington de Gonzalez, A, Bouville, A, Brill, AB, Doody, MM, Melo, DR, et.al. Association of Radioactive Iodine Treatment With Cancer Mortality in Patients With Hyperthyroidism., JAMA Intern Med, 2019. 179 (8)(8): p. 1034-1042., https://pubmed.ncbi.nlm.nih.gov/31260066/
[39] Listewnik, MH, Birkenfeld, B, Chosia, M, Elbl, B, Niedziałkowska, K, Sawrymowicz, M, The occurrence of malignant thyroid lesions in patients after radioiodine treatment due to benign thyroid diseases., Endokrynol Pol, 2010. 61 (5)(5): p. 454-7., https://pubmed.ncbi.nlm.nih.gov/21049457/
[40] Hu, MJ, Zhang, C, Liang, L, Wang, SY, Zheng, XC, Zhang, Q, et.al. Fasting serum glucose, thyroid-stimulating hormone, and thyroid hormones and risk of papillary thyroid cancer: A case-control study., Head Neck, 2019. 41 (7)(7): p. 2277-2284., https://pubmed.ncbi.nlm.nih.gov/30759328/
[41] Cao, Y, Wang, Z, Gu, J, Hu, F, Qi, Y, Yin, Q, et.al. Reproductive Factors but Not Hormonal Factors Associated with Thyroid Cancer Risk: A Systematic Review and Meta-Analysis., Biomed Res Int, 2015. 2015 (): p. 103515., https://pubmed.ncbi.nlm.nih.gov/26339585/
[42] Braganza, MZ, Berrington de González, A, Schonfeld, SJ, Wentzensen, N, Brenner, AV, Kitahara, CM, Benign breast and gynecologic conditions, reproductive and hormonal factors, and risk of thyroid cancer., Cancer Prev Res (Phila), 2014. 7 (4)(4): p. 418-25., https://pubmed.ncbi.nlm.nih.gov/24449056/
[43] Paparodis, R, Imam, S, Todorova-Koteva, K, Staii, A, Jaume, JC, Hashimoto's thyroiditis pathology and risk for thyroid cancer., Thyroid, 2014. 24 (7)(7): p. 1107-14., https://pubmed.ncbi.nlm.nih.gov/24708347/
[44] Silva de Morais, N, Stuart, J, Guan, H, Wang, Z, Cibas, ES, Frates, MC, et.al. The Impact of Hashimoto Thyroiditis on Thyroid Nodule Cytology and Risk of Thyroid Cancer., J Endocr Soc, 2019. 3 (4)(4): p. 791-800., https://pubmed.ncbi.nlm.nih.gov/30963137/
[45] Kitahara, CM, Yanik, EL, Ladenson, PW, Hernandez, BY, Lynch, CF, Pawlish, KS, et.al. Risk of Thyroid Cancer Among Solid Organ Transplant Recipients., Am J Transplant, 2017. 17 (11)(11): p. 2911-2921., https://pubmed.ncbi.nlm.nih.gov/28397388/
[46] Lengwiler, E, Stampf, S, Zippelius, A, Salati, E, Zaman, K, Schäfer, N, et.al. Solid cancer development in solid organ transplant recipients within the Swiss Transplant Cohort Study., Swiss Med Wkly, 2019. 149 (): p. w20078., https://pubmed.ncbi.nlm.nih.gov/31104307/
[47] Lee, JH, Hwang, Y, Song, RY, Yi, JW, Yu, HW, Kim, SJ, et.al. Relationship between iodine levels and papillary thyroid carcinoma: A systematic review and meta-analysis., Head Neck, 2017. 39 (8)(8): p. 1711-1718., https://pubmed.ncbi.nlm.nih.gov/, 28513893/
[48] Vaccarella, S, Franceschi, S, Bray, F, Wild, CP, Plummer, M, Dal Maso, L, Worldwide Thyroid-Cancer Epidemic? The Increasing Impact of Overdiagnosis., N Engl J Med, 2016. 375 (7)(7): p. 614-7., https://pubmed.ncbi.nlm.nih.gov/27532827/
[49] Remonti, LR, Kramer, CK, Leitão, CB, Pinto, LC, Gross, JL, Thyroid ultrasound features and risk of carcinoma: a systematic review and meta-analysis of observational studies., Thyroid, 2015. 25 (5)(5): p. 538-50., https://pubmed.ncbi.nlm.nih.gov/25747526/
[50] Brito, JP, Gionfriddo, MR, Al Nofal, A, Boehmer, KR, Leppin, AL, Reading, C, et.al. The accuracy of thyroid nodule ultrasound to predict thyroid cancer: systematic review and meta-analysis., J Clin Endocrinol Metab, 2014. 99 (4)(4): p. 1253-63., https://pubmed.ncbi.nlm.nih.gov/24276450/
[51] Woliński, K, Szkudlarek, M, Szczepanek-Parulska, E, Ruchała, M, Usefulness of different ultrasound features of malignancy in predicting the type of thyroid lesions: a meta-analysis of prospective studies., Pol Arch Med Wewn, 2014. 124 (3)(3): p. 97-104., https://pubmed.ncbi.nlm.nih.gov/24473342/
[52] Al Nofal, A, Gionfriddo, MR, Javed, A, Haydour, Q, Brito, JP, Prokop, LJ, et.al. Accuracy of thyroid nodule sonography for the detection of thyroid cancer in children: systematic review and meta-analysis., Clin Endocrinol (Oxf), 2016. 84 (3)(3): p. 423-30., https://pubmed.ncbi.nlm.nih.gov/25845503/
[53] Wei, X, Li, Y, Zhang, S, Gao, M, Meta-analysis of thyroid imaging reporting and data system in the ultrasonographic diagnosis of 10,437 thyroid nodules., Head Neck, 2016. 38 (2)(2): p. 309-15., https://pubmed.ncbi.nlm.nih.gov/25244250/
[54] Wei, X, Li, Y, Zhang, S, Gao, M, Thyroid imaging reporting and data system (TI-RADS) in the diagnostic value of thyroid nodules: a systematic review., Tumour Biol, 2014. 35 (7)(7): p. 6769-76., https://pubmed.ncbi.nlm.nih.gov/24722822/
[55] Migda, B, Migda, M, Migda, MS, A systematic review and meta-analysis of the Kwak TIRADS for the diagnostic assessment of indeterminate thyroid nodules., Clin Radiol, 2019. 74 (2)(2): p. 123-130., https://pubmed.ncbi.nlm.nih.gov/30482561/
[56] Kwak, JY, Han, KH, Yoon, JH, Moon, HJ, Son, EJ, Park, SH, et.al. Thyroid imaging reporting and data system for US features of nodules: a step in establishing better stratification of cancer risk., Radiology, 2011. 260 (3)(3): p. 892-9., https://pubmed.ncbi.nlm.nih.gov/21771959/
[57] Horvath, E, Silva, CF, Majlis, S, Rodriguez, I, Skoknic, V, Castro, A, et.al. Prospective validation of the ultrasound based TIRADS (Thyroid Imaging Reporting And Data System) classification: results in surgically resected thyroid nodules., Eur Radiol, 2017. 27 (6)(6): p. 2619-2628., https://pubmed.ncbi.nlm.nih.gov/27718080/
[58] Tessler, FN, Middleton, WD, Grant, EG, Hoang, JK, Berland, LL, Teefey, SA, et.al. ACR Thyroid Imaging, Reporting and Data System (TI-RADS): White Paper of the ACR TI-RADS Committee., J Am Coll Radiol, 2017. 14 (5)(5): p. 587-595., https://pubmed.ncbi.nlm.nih.gov/28372962/
[59] Russ, G, Bonnema, SJ, Erdogan, MF, Durante, C, Ngu, R, Leenhardt, L, European Thyroid Association Guidelines for Ultrasound Malignancy Risk Stratification of Thyroid Nodules in Adults: The EU-TIRADS., Eur Thyroid J, 2017. 6 (5)(5): p. 225-237., https://pubmed.ncbi.nlm.nih.gov/29167761/
[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/
[61] Shin, JH, Baek, JH, Chung, J, Ha, EJ, Kim, JH, Lee, YH, et.al. Ultrasonography Diagnosis and Imaging-Based Management of Thyroid Nodules: Revised Korean Society of Thyroid Radiology Consensus Statement and Recommendations., Korean J Radiol, 2016. 17 (3)(3): p. 370-95., https://pubmed.ncbi.nlm.nih.gov/27134526/
[62] Wu, XL, Du, JR, Wang, H, Jin, CX, Sui, GQ, Yang, DY, et.al. Comparison and preliminary discussion of the reasons for the differences in diagnostic performance and unnecessary FNA biopsies between the ACR TIRADS and 2015 ATA guidelines., Endocrine, 2019. 65 (1)(1): p. 121-131., https://pubmed.ncbi.nlm.nih.gov/30830584/
[63] Middleton, WD, Teefey, SA, Reading, CC, Langer, JE, Beland, MD, Szabunio, MM, et.al. Comparison of Performance Characteristics of American College of Radiology TI-RADS, Korean Society of Thyroid Radiology TIRADS, and American Thyroid Association Guidelines., AJR Am J Roentgenol, 2018. 210 (5)(5): p. 1148-1154., https://pubmed.ncbi.nlm.nih.gov/29629797/
[64] Xu, T, Wu, Y, Wu, RX, Zhang, YZ, Gu, JY, Ye, XH, et.al. Validation and comparison of three newly-released Thyroid Imaging Reporting and Data Systems for cancer risk determination., Endocrine, 2019. 64 (2)(2): p. 299-307., https://pubmed.ncbi.nlm.nih.gov/30474824/
[65] Ha, EJ, Na, DG, Moon, WJ, Lee, YH, Choi, N, Diagnostic Performance of Ultrasound-Based Risk-Stratification Systems for Thyroid Nodules: Comparison of the 2015 American Thyroid Association Guidelines with the 2016 Korean Thyroid Association/Korean Society of Thyroid Radiology and 2017 American College of Radiology Guidelines., Thyroid, 2018. 28 (11)(11): p. 1532-1537., https://pubmed.ncbi.nlm.nih.gov/30311862/
[66] Seifert, P, Schenke, S, Zimny, M, Stahl, A, Grunert, M, Klemenz, B, et.al. Diagnostic Performance of Kwak, EU, ACR, and Korean TIRADS as Well as ATA Guidelines for the Ultrasound Risk Stratification of Non-Autonomously Functioning Thyroid Nodules in a Region with Long History of Iodine Deficiency: A German Multicenter Trial., Cancers (Basel), 2021. 13 (17)(17):, https://pubmed.ncbi.nlm.nih.gov/34503277/
[67] Yoon, JH, Lee, HS, Kim, EK, Moon, HJ, Kwak, JY, Malignancy Risk Stratification of Thyroid Nodules: Comparison between the Thyroid Imaging Reporting and Data System and the 2014 American Thyroid Association Management Guidelines., Radiology, 2016. 278 (3)(3): p. 917-24., https://pubmed.ncbi.nlm.nih.gov/26348102/
[68] Tessler, FN, Middleton, WD, Grant, EG, Thyroid Imaging Reporting and Data System (TI-RADS): A User's Guide., Radiology, 2018. 287 (1)(1): p. 29-36., https://pubmed.ncbi.nlm.nih.gov/29558300/
[69] Nattabi, HA, Sharif, NM, Yahya, N, Ahmad, R, Mohamad, M, Zaki, FM, et.al. Is Diagnostic Performance of Quantitative 2D-Shear Wave Elastography Optimal for Clinical Classification of Benign and Malignant Thyroid Nodules?: A Systematic Review and Meta-analysis., Acad Radiol, 2022. 29 Suppl 3 (): p. S114-S121., https://pubmed.ncbi.nlm.nih.gov/29054676/
[70] Nell, S, Kist, JW, Debray, TP, de Keizer, B, van Oostenbrugge, TJ, Borel Rinkes, IH, et.al. Qualitative elastography can replace thyroid nodule fine-needle aspiration in patients with soft thyroid nodules. A systematic review and meta-analysis., Eur J Radiol, 2015. 84 (4)(4): p. 652-61., https://pubmed.ncbi.nlm.nih.gov/25638577/
[71] Zhao, CK, Xu, HX, Ultrasound elastography of the thyroid: principles and current status., Ultrasonography, 2019. 38 (2)(2): p. 106-124., https://pubmed.ncbi.nlm.nih.gov/30690960/
[72] Bamber, J, Cosgrove, D, Dietrich, CF, Fromageau, J, Bojunga, J, Calliada, F, et.al. EFSUMB guidelines and recommendations on the clinical use of ultrasound elastography. Part 1: Basic principles and technology., Ultraschall Med, 2013. 34 (2)(2): p. 169-84., https://pubmed.ncbi.nlm.nih.gov/23558397/
[73] Chammas, MC, Moon, HJ, Kim, EK, Why do we have so many controversies in thyroid nodule Doppler US?, Radiology, 2011. 259 (1)(1): p. 304., https://pubmed.ncbi.nlm.nih.gov/21436101/
[74] Razavi, SA, Hadduck, TA, Sadigh, G, Dwamena, BA, Comparative effectiveness of elastographic and B-mode ultrasound criteria for diagnostic discrimination of thyroid nodules: a meta-analysis., AJR Am J Roentgenol, 2013. 200 (6)(6): p. 1317-26., https://pubmed.ncbi.nlm.nih.gov/23701071/
[75] Moon, HJ, Kwak, JY, Kim, MJ, Son, EJ, Kim, EK, Can vascularity at power Doppler US help predict thyroid malignancy?, Radiology, 2010. 255 (1)(1): p. 260-9., https://pubmed.ncbi.nlm.nih.gov/20308462/
[76] Mohebbi, M, Dehaki, MG, Mozaffari, M, Comparison between ultrasonographic findings and fine needle aspiration cytology in differentiating malignant and benign thyroid nodules., Eur J Transl Myol, 2019. 29 (3)(3): p. 8354., https://pubmed.ncbi.nlm.nih.gov/31579481/
[77] Debnam, JM, Vu, T, Sun, J, Wei, W, Krishnamurthy, S, Zafereo, ME, et.al. Vascular flow on doppler sonography may not be a valid characteristic to distinguish colloid nodules from papillary thyroid carcinoma even when accounting for nodular size., Gland Surg, 2019. 8 (5)(5): p. 461-468., https://pubmed.ncbi.nlm.nih.gov/31741876/
[78] Lacout, A, Chevenet, C, Salas, J, Marcy, PY, Thyroid Doppler US: Tips and tricks., J Med Imaging Radiat Oncol, 2016. 60 (2)(2): p. 210-5., https://pubmed.ncbi.nlm.nih.gov/26663777/
[79] Yang, GCH, Fried, KO, Most Thyroid Cancers Detected by Sonography Lack Intranodular Vascularity on Color Doppler Imaging: Review of the Literature and Sonographic-Pathologic Correlations for 698 Thyroid Neoplasms., J Ultrasound Med, 2017. 36 (1)(1): p. 89-94., https://pubmed.ncbi.nlm.nih.gov/27943373/
[80] Chammas, MC, Gerhard, R, de Oliveira, IR, Widman, A, de Barros, N, Durazzo, M, et.al. Thyroid nodules: evaluation with power Doppler and duplex Doppler ultrasound., Otolaryngol Head Neck Surg, 2005. 132 (6)(6): p. 874-82., https://pubmed.ncbi.nlm.nih.gov/15944558/
[81] Liu, Q, Cheng, J, Li, J, Gao, X, Li, H, The diagnostic accuracy of contrast-enhanced ultrasound for the differentiation of benign and malignant thyroid nodules: A PRISMA compliant meta-analysis., Medicine (Baltimore), 2018. 97 (49)(49): p. e13325., https://pubmed.ncbi.nlm.nih.gov/30544392/
[82] Ma, X, Zhang, B, Ling, W, Liu, R, Jia, H, Zhu, F, et.al. Contrast-enhanced sonography for the identification of benign and malignant thyroid nodules: Systematic review and meta-analysis., J Clin Ultrasound, 2016. 44 (4)(4): p. 199-209., https://pubmed.ncbi.nlm.nih.gov/26402325/
[83] Leenhardt, L, Erdogan, MF, Hegedus, L, Mandel, SJ, Paschke, R, Rago, T, et.al. 2013 European thyroid association guidelines for cervical ultrasound scan and ultrasound-guided techniques in the postoperative management of patients with thyroid cancer., Eur Thyroid J, 2013. 2 (3)(3): p. 147-59., https://pubmed.ncbi.nlm.nih.gov/24847448/
[84] Hwang, HS, Orloff, LA, Efficacy of preoperative neck ultrasound in the detection of cervical lymph node metastasis from thyroid cancer., Laryngoscope, 2011. 121 (3)(3): p. 487-91., https://pubmed.ncbi.nlm.nih.gov/21344423/
[85] O'Connell, K, Yen, TW, Quiroz, F, Evans, DB, Wang, TS, The utility of routine preoperative cervical ultrasonography in patients undergoing thyroidectomy for differentiated thyroid cancer., Surgery, 2013. 154 (4)(4): p. 697-701; discussion 701-3., https://pubmed.ncbi.nlm.nih.gov/24011674/
[86] Yeh, MW, Bauer, AJ, Bernet, VA, Ferris, RL, Loevner, LA, Mandel, SJ, et.al. American Thyroid Association statement on preoperative imaging for thyroid cancer surgery., Thyroid, 2015. 25 (1)(1): p. 3-14., https://pubmed.ncbi.nlm.nih.gov/25188202/
[87] Zhao, H, Li, H, Meta-analysis of ultrasound for cervical lymph nodes in papillary thyroid cancer: Diagnosis of central and lateral compartment nodal metastases., Eur J Radiol, 2019. 112 (): p. 14-21., https://pubmed.ncbi.nlm.nih.gov/30777203/
[88] Wu, LM, Gu, HY, Qu, XH, Zheng, J, Zhang, W, Yin, Y, et.al. The accuracy of ultrasonography in the preoperative diagnosis of cervical lymph node metastasis in patients with papillary thyroid carcinoma: A meta-analysis., Eur J Radiol, 2012. 81 (8)(8): p. 1798-805., https://pubmed.ncbi.nlm.nih.gov/21536396/
[89] Xing, Z, Qiu, Y, Yang, Q, Yu, Y, Liu, J, Fei, Y, et.al. Thyroid cancer neck lymph nodes metastasis: Meta-analysis of US and CT diagnosis., Eur J Radiol, 2020. 129 (): p. 109103., https://pubmed.ncbi.nlm.nih.gov/32574937/
[90] Leboulleux, S, Girard, E, Rose, M, Travagli, JP, Sabbah, N, Caillou, B, et.al. Ultrasound criteria of malignancy for cervical lymph nodes in patients followed up for differentiated thyroid cancer., J Clin Endocrinol Metab, 2007. 92 (9)(9): p. 3590-4., https://pubmed.ncbi.nlm.nih.gov/17609301/
[91] Azizi, G, Keller, JM, Mayo, ML, Piper, K, Puett, D, Earp, KM, et.al. Shear Wave Elastography and Cervical Lymph Nodes: Predicting Malignancy., Ultrasound Med Biol, 2016. 42 (6)(6): p. 1273-81., https://pubmed.ncbi.nlm.nih.gov/26976785/
[92] Khokhar, MT, Day, KM, Sangal, RB, Ahmedli, NN, Pisharodi, LR, Beland, MD, et.al. Preoperative High-Resolution Ultrasound for the Assessment of Malignant Central Compartment Lymph Nodes in Papillary Thyroid Cancer., Thyroid, 2015. 25 (12)(12): p. 1351-4., https://pubmed.ncbi.nlm.nih.gov/26431908/
[93] Kim, E, Park, JS, Son, KR, Kim, JH, Jeon, SJ, Na, DG, Preoperative diagnosis of cervical metastatic lymph nodes in papillary thyroid carcinoma: comparison of ultrasound, computed tomography, and combined ultrasound with computed tomography., Thyroid, 2008. 18 (4)(4): p. 411-8., https://pubmed.ncbi.nlm.nih.gov/18358074/
[94] Moreno, MA, Edeiken-Monroe, BS, Siegel, ER, Sherman, SI, Clayman, GL, In papillary thyroid cancer, preoperative central neck ultrasound detects only macroscopic surgical disease, but negative findings predict excellent long-term regional control and survival., Thyroid, 2012. 22 (4)(4): p. 347-55., https://pubmed.ncbi.nlm.nih.gov/22280230/
[95] Ahuja, AT, Ying, M, Sonographic evaluation of cervical lymph nodes., AJR Am J Roentgenol, 2005. 184 (5)(5): p. 1691-9., https://pubmed.ncbi.nlm.nih.gov/15855141/
[96] U S, V, Shivalli, S, Rai, S, Haris, A, Madhurkar, R, Hemraj, S, Diagnostic accuracy of high resolution ultrasound to differentiate neoplastic and non neoplastic causes of cervical lymphadenopathy., J Clin Diagn Res, 2014. 8 (9)(9): p. RC05-7., https://pubmed.ncbi.nlm.nih.gov/25386501/
[97] Sohn, YM, Kwak, JY, Kim, EK, Moon, HJ, Kim, SJ, Kim, MJ, Diagnostic approach for evaluation of lymph node metastasis from thyroid cancer using ultrasound and fine-needle aspiration biopsy., AJR Am J Roentgenol, 2010. 194 (1)(1): p. 38-43., https://pubmed.ncbi.nlm.nih.gov/20028903/
[98] do Rosário, PW, Fagundes, TA, Maia, FF, Franco, AC, Figueiredo, MB, Purisch, S, Sonography in the diagnosis of cervical recurrence in patients with differentiated thyroid carcinoma., J Ultrasound Med, 2004. 23 (7)(7): p. 915-20; quiz 921-2., https://pubmed.ncbi.nlm.nih.gov/15292559/
[99] Steinkamp, HJ, Cornehl, M, Hosten, N, Pegios, W, Vogl, T, Felix, R, Cervical lymphadenopathy: ratio of long- to short-axis diameter as a predictor of malignancy., Br J Radiol, 1995. 68 (807)(807): p. 266-70., https://pubmed.ncbi.nlm.nih.gov/7735765/
[100] Kuna, SK, Bracic, I, Tesic, V, Kuna, K, Herceg, GH, Dodig, D, Ultrasonographic differentiation of benign from malignant neck lymphadenopathy in thyroid cancer., J Ultrasound Med, 2006. 25 (12)(12): p. 1531-7; quiz 1538-40., https://pubmed.ncbi.nlm.nih.gov/17121947/
[101] Tomoda, C, Sugino, K, Matsuzu, K, Uruno, T, Ohkuwa, K, Kitagawa, W, et.al. Cervical Lymph Node Metastases After Thyroidectomy for Papillary Thyroid Carcinoma Usually Remain Stable for Years., Thyroid, 2016. 26 (12)(12): p. 1706-1711., https://pubmed.ncbi.nlm.nih.gov/27616725/
[102] Kupferman, ME, Patterson, M, Mandel, SJ, LiVolsi, V, Weber, RS, Patterns of lateral neck metastasis in papillary thyroid carcinoma., Arch Otolaryngol Head Neck Surg, 2004. 130 (7)(7): p. 857-60., https://pubmed.ncbi.nlm.nih.gov/15262763/
[103] Onoda, N, Ishikawa, T, Kawajiri, H, Takashima, T, Hirakawa, K, Pattern of initial metastasis in the cervical lymph node from papillary thyroid carcinoma., Surg Today, 2013. 43 (2)(2): p. 178-84., https://pubmed.ncbi.nlm.nih.gov/22732927/
[104] Desmots, F, Fakhry, N, Mancini, J, Reyre, A, Vidal, V, Jacquier, A, et.al. Shear Wave Elastography in Head and Neck Lymph Node Assessment: Image Quality and Diagnostic Impact Compared with B-Mode and Doppler Ultrasonography., Ultrasound Med Biol, 2016. 42 (2)(2): p. 387-98., https://pubmed.ncbi.nlm.nih.gov/26617244/
[105] Xu, JM, Xu, XH, Xu, HX, Zhang, YF, Guo, LH, Liu, LN, et.al. Prediction of cervical lymph node metastasis in patients with papillary thyroid cancer using combined conventional ultrasound, strain elastography, and acoustic radiation force impulse (ARFI) elastography., Eur Radiol, 2016. 26 (8)(8): p. 2611-22., https://pubmed.ncbi.nlm.nih.gov/26560715/
[106] Görges, R, Eising, EG, Fotescu, D, Renzing-Köhler, K, Frilling, A, Schmid, KW, et.al. Diagnostic value of high-resolution B-mode and power-mode sonography in the follow-up of thyroid cancer., Eur J Ultrasound, 2003. 16 (3)(3): p. 191-206., https://pubmed.ncbi.nlm.nih.gov/12573788/
[107] Schenke, S, Seifert, P, Zimny, M, Winkens, T, Binse, I, Görges, R, Risk Stratification of Thyroid Nodules Using the Thyroid Imaging Reporting and Data System (TIRADS): The Omission of Thyroid Scintigraphy Increases the Rate of Falsely Suspected Lesions., J Nucl Med, 2019. 60 (3)(3): p. 342-347., https://pubmed.ncbi.nlm.nih.gov/30097501/
[108] Ruhlmann, M, Stebner, V, Görges, R, Farahati, J, Simon, D, Bockisch, A, et.al. Diagnosis of hyperfunctional thyroid nodules: impact of US-elastography., Nuklearmedizin, 2014. 53 (5)(5): p. 173-7., https://pubmed.ncbi.nlm.nih.gov/24898434/
[109] Trimboli, P, Paone, G, Zatelli, MC, Ceriani, L, Giovanella, L, Real-time elastography in autonomously functioning thyroid nodules: relationship with TSH levels, scintigraphy, and ultrasound patterns., Endocrine, 2017. 58 (3)(3): p. 488-494., https://pubmed.ncbi.nlm.nih.gov/28285385/
[110] Görges, R, Kandror, T, Kuschnerus, S, Zimny, M, Pink, R, Palmedo, H, et.al. [Scintigraphically "hot" thyroid nodules mainly go hand in hand with a normal TSH]., Nuklearmedizin, 2011. 50 (5)(5): p. 179-88., https://pubmed.ncbi.nlm.nih.gov/21789340/
[111] Graf, D, Helmich-Kapp, B, Graf, S, Veit, F, Lehmann, N, Mann, K, [Functional activity of autonomous adenoma in Germany]., Dtsch Med Wochenschr, 2012. 137 (41)(41): p. 2089-92., https://pubmed.ncbi.nlm.nih.gov/23033166/
[112] COLE, WH, MAJARAKIS, JD, SLAUGHTER, DP, Incidence of carcinoma of the thyroid in nodular goiter., J Clin Endocrinol Metab, 1949. 9 (10)(10): p. 1007-11., https://pubmed.ncbi.nlm.nih.gov/18142433/
[113] DOBYNS, BM, SKANSE, B, MALOOF, F, A method for the preoperative estimation of function in thyroid tumors; its significance in diagnosis and treatment., J Clin Endocrinol Metab, 1949. 9 (11)(11): p. 1171-84, illust., https://pubmed.ncbi.nlm.nih.gov/15395981/
[114] Schröder, S, Marthaler, B, [Autonomy and malignancy of thyroid glad tumors. A critical analysis of the literature on the existence of hyperfunctioning follicular and papillary thyroid gland carcinomas]., Pathologe, 1996. 17 (5)(5): p. 349-57., https://pubmed.ncbi.nlm.nih.gov/8992477/
[115] Schicha, H, Hellmich, M, Lehmacher, W, Eschner, W, Schmidt, M, Kobe, C, et.al. [Should all patients with thyroid nodules > or = 1 cm undergo fine-needle aspiration biopsy?]., Nuklearmedizin, 2009. 48 (3)(3): p. 79-83., https://pubmed.ncbi.nlm.nih.gov/19325991/
[116] Belfiore, A, La Rosa, GL, Padova, G, Sava, L, Ippolito, O, Vigneri, R, The frequency of cold thyroid nodules and thyroid malignancies in patients from an iodine-deficient area., Cancer, 1987. 60 (12)(12): p. 3096-102., https://pubmed.ncbi.nlm.nih.gov/3677033/
[117] Christensen, SB, Bondeson, L, Ericsson, UB, Lindholm, K, Prediction of malignancy in the solitary thyroid nodule by physical examination, thyroid scan, fine-needle biopsy and serum thyroglobulin. A prospective study of 100 surgically treated patients., Acta Chir Scand, 1984. 150 (6)(6): p. 433-9., https://pubmed.ncbi.nlm.nih.gov/6495973/
[118] Ross, DS, Burch, HB, Cooper, DS, Greenlee, MC, Laurberg, P, Maia, AL, et.al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis., Thyroid, 2016. 26 (10)(10): p. 1343-1421., https://pubmed.ncbi.nlm.nih.gov/27521067/
[119] Biondi, B, Bartalena, L, Cooper, DS, Hegedüs, L, Laurberg, P, Kahaly, GJ, The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism., Eur Thyroid J, 2015. 4 (3)(3): p. 149-63., https://pubmed.ncbi.nlm.nih.gov/26558232/
[120] Kim, HK, Yoon, JH, Kim, SJ, Cho, JS, Kweon, SS, Kang, HC, Higher TSH level is a risk factor for differentiated thyroid cancer., Clin Endocrinol (Oxf), 2013. 78 (3)(3): p. 472-7., https://pubmed.ncbi.nlm.nih.gov/22924613/
[121] Fighera, TM, Perez, CL, Faris, N, Scarabotto, PC, da Silva, TT, Cavalcanti, TC, et.al. TSH levels are associated with increased risk of thyroid carcinoma in patients with nodular disease., Endokrynol Pol, 2015. 66 (6)(6): p. 480-5., https://pubmed.ncbi.nlm.nih.gov/26662646/
[122] Batool, S, Afridi, MS, Khoja, A, Islam, N, Pre-operative serum TSH levels: A risk factor for advanced metastatic differentiated thyroid carcinoma., Pak J Med Sci, 2019. 35 (5)(5): p. 1312-1317., https://pubmed.ncbi.nlm.nih.gov/31488998/
[123] Boelaert, K, Horacek, J, Holder, RL, Watkinson, JC, Sheppard, MC, Franklyn, JA, Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration., J Clin Endocrinol Metab, 2006. 91 (11)(11): p. 4295-301., https://pubmed.ncbi.nlm.nih.gov/16868053/
[124] Khan, MA, Malik, N, Khan, KH, Shahzad, MF, Association of Preoperative Serum Thyroid-stimulating Hormone Levels with Thyroid Cancer in Patients with Nodular Thyroid Disease., World J Nucl Med, 2017. 16 (3)(3): p. 202-205., https://pubmed.ncbi.nlm.nih.gov/28670178/
[125] Zafón, C, Obiols, G, Mesa, J, Preoperative TSH level and risk of thyroid cancer in patients with nodular thyroid disease: nodule size contribution., Endocrinol Nutr, 2015. 62 (1)(1): p. 24-8., https://pubmed.ncbi.nlm.nih.gov/25066642/
[126] Huang, H, Rusiecki, J, Zhao, N, Chen, Y, Ma, S, Yu, H, et.al. Thyroid-Stimulating Hormone, Thyroid Hormones, and Risk of Papillary Thyroid Cancer: A Nested Case-Control Study., Cancer Epidemiol Biomarkers Prev, 2017. 26 (8)(8): p. 1209-1218., https://pubmed.ncbi.nlm.nih.gov/28377419/
[127] Zhu, C, Li, S, Gao, X, Zhu, G, Song, M, Gao, F, Retrospective Analysis of Thyroid Nodules: Thyroid Cancer Risk Factors in Suzhou, China., Clin Lab, 2018. 64 (3)(3): p. 333-338., https://pubmed.ncbi.nlm.nih.gov/29739119/
[128] Zhao, H, Li, H, Huang, T, High Urinary Iodine, Thyroid Autoantibodies, and Thyroid-Stimulating Hormone for Papillary Thyroid Cancer Risk., Biol Trace Elem Res, 2018. 184 (2)(2): p. 317-324., https://pubmed.ncbi.nlm.nih.gov/29164514/
[129] Haymart, MR, Repplinger, DJ, Leverson, GE, Elson, DF, Sippel, RS, Jaume, JC, et.al. Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage., J Clin Endocrinol Metab, 2008. 93 (3)(3): p. 809-14., https://pubmed.ncbi.nlm.nih.gov/18160464/
[130] Haymart, MR, Glinberg, SL, Liu, J, Sippel, RS, Jaume, JC, Chen, H, Higher serum TSH in thyroid cancer patients occurs independent of age and correlates with extrathyroidal extension., Clin Endocrinol (Oxf), 2009. 71 (3)(3): p. 434-9., https://pubmed.ncbi.nlm.nih.gov/19067720/
[131] Kim, SS, Lee, BJ, Lee, JC, Song, SH, Kim, BH, Son, SM, et.al. Preoperative serum thyroid stimulating hormone levels in well-differentiated thyroid carcinoma is a predictive factor for lateral lymph node metastasis as well as extrathyroidal extension in Korean patients: a single-center experience., Endocrine, 2011. 39 (3)(3): p. 259-65., https://pubmed.ncbi.nlm.nih.gov/21161440/
[132] Adhami, M, Michail, P, Rao, A, Bhatt, CR, Grodski, S, Serpell, JW, et.al. Anti-Thyroid Antibodies and TSH as Potential Markers of Thyroid Carcinoma and Aggressive Behavior in Patients with Indeterminate Fine-Needle Aspiration Cytology., World J Surg, 2020. 44 (2)(2): p. 363-370., https://pubmed.ncbi.nlm.nih.gov/31502005/
[133] Cappelli, C, Pirola, I, Gandossi, E, Rotondi, M, Lombardi, D, Casella, C, et.al. Could Serum TSH Levels Predict Malignancy in Euthyroid Patients Affected by Thyroid Nodules with Indeterminate Cytology?, Int J Endocrinol, 2020. 2020 (): p. 7543930., https://pubmed.ncbi.nlm.nih.gov/32377187/
[134] Fernández-Trujillo, C, Pérez-Zaballos, J, Rodríguez-Pérez, CA, López-Plasencia, Y, Marrero-Arencibia, D, Cabrera-Galván, JJ, et.al. TSH Level and Risk of Malignancy in Patients with Bethesda Category IV Thyroid Nodules., Horm Cancer, 2020. 11 (3-4)(3-4): p. 200-204., https://pubmed.ncbi.nlm.nih.gov/32266672/
[135] Ahn, D, Sohn, JH, Kim, JH, Shin, CM, Jeon, JH, Park, JY, Preoperative subclinical hypothyroidism in patients with papillary thyroid carcinoma., Am J Otolaryngol, 2013. 34 (4)(4): p. 312-9., https://pubmed.ncbi.nlm.nih.gov/23357595/
[136] Fiore, E, Rago, T, Provenzale, MA, Scutari, M, Ugolini, C, Basolo, F, et.al. Lower levels of TSH are associated with a lower risk of papillary thyroid cancer in patients with thyroid nodular disease: thyroid autonomy may play a protective role., Endocr Relat Cancer, 2009. 16 (4)(4): p. 1251-60., https://pubmed.ncbi.nlm.nih.gov/19528244/
[137] Paparodis, RD, Bantouna, D, Karvounis, E, Imam, S, Jaume, JC, Higher TSH Is Not Associated With Thyroid Cancer Risk in the Presence of Thyroid Autoimmunity., J Clin Endocrinol Metab, 2020. 105 (7)(7):, https://pubmed.ncbi.nlm.nih.gov/32391913/
[138] Schiffmann, L, Kostev, K, Kalder, M, Association between various thyroid gland diseases, TSH values and thyroid cancer: a case-control study., J Cancer Res Clin Oncol, 2020. 146 (11)(11): p. 2989-2994., https://pubmed.ncbi.nlm.nih.gov/32518973/
[139] Su, A, Zhao, W, Wu, W, Wei, T, Ruan, M, Li, Z, et.al. The association of preoperative thyroid-stimulating hormone level and the risk of differentiated thyroid cancer in patients with thyroid nodules: A systematic review and meta-analysis., Am J Surg, 2020. 220 (3)(3): p. 634-641., https://pubmed.ncbi.nlm.nih.gov/31955813/
[140] Eilsberger, F, Pfestroff, A, Librizzi, D, Luster, M, [Follow-up of differentiated thyroid cancer]., Dtsch Med Wochenschr, 2020. 145 (17)(17): p. 1236-1244., https://pubmed.ncbi.nlm.nih.gov/32634842/
[141] Suh, I, Vriens, MR, Guerrero, MA, Griffin, A, Shen, WT, Duh, QY, et.al. Serum thyroglobulin is a poor diagnostic biomarker of malignancy in follicular and Hurthle-cell neoplasms of the thyroid., Am J Surg, 2010. 200 (1)(1): p. 41-6., https://pubmed.ncbi.nlm.nih.gov/20637335/
[142] Trimboli, P, Treglia, G, Giovanella, L, Preoperative measurement of serum thyroglobulin to predict malignancy in thyroid nodules: a systematic review., Horm Metab Res, 2015. 47 (4)(4): p. 247-52., https://pubmed.ncbi.nlm.nih.gov/25384015/
[143] Hulikal, N, Re, A, Banoth, M, Chowhan, AK, Yutla, M, Sachan, A, Can preoperative serum thyroglobulin levels predict the risk of malignancy? Results from prospective analysis of biochemical predictors of malignancy in thyroid nodules., Acta Otorhinolaryngol Ital, 2020. 40 (1)(1): p. 33-37., https://pubmed.ncbi.nlm.nih.gov/32275647/
[144] Lee, EK, Chung, KW, Min, HS, Kim, TS, Kim, TH, Ryu, JS, et.al. Preoperative serum thyroglobulin as a useful predictive marker to differentiate follicular thyroid cancer from benign nodules in indeterminate nodules., J Korean Med Sci, 2012. 27 (9)(9): p. 1014-8., https://pubmed.ncbi.nlm.nih.gov/22969246/
[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/
[146] Kang, M, Wang, TS, Yen, TW, Doffek, K, Evans, DB, Dream, S, The Clinical Utility of Preoperative Thyroglobulin for Surgical Decision Making in Thyroid Disease., J Surg Res, 2022. 270 (): p. 230-235., https://pubmed.ncbi.nlm.nih.gov/34710703/
[147] Petric, R, Besic, H, Besic, N, Preoperative serum thyroglobulin concentration as a predictive factor of malignancy in small follicular and Hürthle cell neoplasms of the thyroid gland., World J Surg Oncol, 2014. 12 (): p. 282., https://pubmed.ncbi.nlm.nih.gov/25213012/
[148] Ma, ZF, Skeaff, SA, Thyroglobulin as a biomarker of iodine deficiency: a review., Thyroid, 2014. 24 (8)(8): p. 1195-209., https://pubmed.ncbi.nlm.nih.gov/24762031/
[149] Zimmermann, MB, Aeberli, I, Andersson, M, Assey, V, Yorg, JA, Jooste, P, et.al. Thyroglobulin is a sensitive measure of both deficient and excess iodine intakes in children and indicates no adverse effects on thyroid function in the UIC range of 100-299 μg/L: a UNICEF/ICCIDD study group report., J Clin Endocrinol Metab, 2013. 98 (3)(3): p. 1271-80., https://pubmed.ncbi.nlm.nih.gov/23345097/
[150] Cheng, X, Xu, S, Zhu, Y, Wu, J, Bao, J, Yu, H, et.al. Markedly elevated serum preoperative thyroglobulin predicts radioiodine-refractory thyroid cancer., Eur J Clin Invest, 2022. 52 (4)(4): p. e13721., https://pubmed.ncbi.nlm.nih.gov/34855206/
[151] Kim, H, Park, SY, Choe, JH, Kim, JS, Hahn, SY, Kim, SW, et.al. Preoperative Serum Thyroglobulin and Its Correlation with the Burden and Extent of Differentiated Thyroid Cancer., Cancers (Basel), 2020. 12 (3)(3):, https://pubmed.ncbi.nlm.nih.gov/32182688/
[152] Wang, L, Li, H, Yang, Z, Guo, Z, Zhang, Q, Preoperative Serum Thyrotropin to Thyroglobulin Ratio Is Effective for Thyroid Nodule Evaluation in Euthyroid Patients., Otolaryngol Head Neck Surg, 2015. 153 (1)(1): p. 15-9., https://pubmed.ncbi.nlm.nih.gov/25883100/
[153] Karvounis, E, Kappas, I, Angelousi, A, Makris, GM, Siamatras, TD, Kassi, E, The diagnostic and predictive accuracy of thyroglobulin to TSH ratio and TSH to thyroglobulin ratio in detecting differentiated thyroid carcinoma in normothyroid patients with thyroid nodules: A retrospective cohort study and systematic review of the literature., Oncol Rev, 2020. 14 (2)(2): p. 439., https://pubmed.ncbi.nlm.nih.gov/33505608/
[154] Noel, JE, Thatipamala, P, Hung, KS, Chen, J, Shi, RZ, Orloff, LA, Pre-Operative Antithyroid Antibodies in Differentiated Thyroid Cancer., Endocr Pract, 2021. 27 (11)(11): p. 1114-1118., https://pubmed.ncbi.nlm.nih.gov/34217894/
[155] Li, L, Shan, T, Sun, X, Lv, B, Chen, B, Liu, N, et.al. Positive Thyroid Peroxidase Antibody and Thyroglobulin Antibody are Associated With Better Clinicopathologic Features of Papillary Thyroid Cancer., Endocr Pract, 2021. 27 (4)(4): p. 306-311., https://pubmed.ncbi.nlm.nih.gov/33645517/
[156] Jo, K, Kim, MH, Ha, J, Lim, Y, Lee, S, Bae, JS, et.al. Prognostic value of preoperative anti-thyroglobulin antibody in differentiated thyroid cancer., Clin Endocrinol (Oxf), 2017. 87 (3)(3): p. 292-299., https://pubmed.ncbi.nlm.nih.gov/28493284/
[157] Kim, ES, Lim, DJ, Baek, KH, Lee, JM, Kim, MK, Kwon, HS, et.al. Thyroglobulin antibody is associated with increased cancer risk in thyroid nodules., Thyroid, 2010. 20 (8)(8): p. 885-91., https://pubmed.ncbi.nlm.nih.gov/20465529/
[158] Vasileiadis, I, Boutzios, G, Charitoudis, G, Koukoulioti, E, Karatzas, T, Thyroglobulin antibodies could be a potential predictive marker for papillary thyroid carcinoma., Ann Surg Oncol, 2014. 21 (8)(8): p. 2725-32., https://pubmed.ncbi.nlm.nih.gov/24595799/
[159] Hosseini, S, Payne, RJ, Zawawi, F, Mlynarek, A, Hier, MP, Tamilia, M, et.al. Can preoperative thyroglobulin antibody levels be used as a marker for well differentiated thyroid cancer?, J Otolaryngol Head Neck Surg, 2016. 45 (1)(1): p. 31., https://pubmed.ncbi.nlm.nih.gov/27179632/
[160] Jia, X, Pang, P, Wang, L, Zhao, L, Jiang, L, Song, Y, et.al. Clinical Analysis of Preoperative Anti-thyroglobulin Antibody in Papillary Thyroid Cancer Between 2011 and 2015 in Beijing, China: A Retrospective Study., Front Endocrinol (Lausanne), 2020. 11 (): p. 452., https://pubmed.ncbi.nlm.nih.gov/32760349/
[161] Grani, G, Calvanese, A, Carbotta, G, D'Alessandri, M, Nesca, A, Bianchini, M, et.al. Thyroid autoimmunity and risk of malignancy in thyroid nodules submitted to fine-needle aspiration cytology., Head Neck, 2015. 37 (2)(2): p. 260-4., https://pubmed.ncbi.nlm.nih.gov/24375752/
[162] Wong, SL, Grodski, S, Yeung, MJ, Serpell, JW, Anti-thyroid antibodies as a predictor of thyroid cancer., ANZ J Surg, 2015. 85 (11)(11): p. 849-53., https://pubmed.ncbi.nlm.nih.gov/24299506/
[163] Karatzas, T, Vasileiadis, I, Zapanti, E, Charitoudis, G, Karakostas, E, Boutzios, G, Thyroglobulin antibodies as a potential predictive marker of papillary thyroid carcinoma in patients with indeterminate cytology., Am J Surg, 2016. 212 (5)(5): p. 946-952., https://pubmed.ncbi.nlm.nih.gov/27324384/
[164] Knappe, L, Giovanella, L, Life after thyroid cancer: the role of thyroglobulin and thyroglobulin antibodies for postoperative follow-up., Expert Rev Endocrinol Metab, 2021. 16 (6)(6): p. 273-279., https://pubmed.ncbi.nlm.nih.gov/34693849/
[165] Lee, YK, Park, KH, Park, SH, Kim, KJ, Shin, DY, Nam, KH, et.al. Association between diffuse lymphocytic infiltration and papillary thyroid cancer aggressiveness according to the presence of thyroid peroxidase antibody and BRAF, Head Neck, 2018. 40 (10)(10): p. 2271-2279., https://pubmed.ncbi.nlm.nih.gov/29935011/
[166] Wu, X, Lun, Y, Jiang, H, Gang, Q, Xin, S, Duan, Z, et.al. Coexistence of thyroglobulin antibodies and thyroid peroxidase antibodies correlates with elevated thyroid-stimulating hormone level and advanced tumor stage of papillary thyroid cancer., Endocrine, 2014. 46 (3)(3): p. 554-60., https://pubmed.ncbi.nlm.nih.gov/24338678/
[167] Resende de Paiva, C, Grønhøj, C, Feldt-Rasmussen, U, von Buchwald, C, Association between Hashimoto's Thyroiditis and Thyroid Cancer in 64,628 Patients., Front Oncol, 2017. 7 (): p. 53., https://pubmed.ncbi.nlm.nih.gov/28443243/
[168] Boi, F, Pani, F, Calò, PG, Lai, ML, Mariotti, S, High prevalence of papillary thyroid carcinoma in nodular Hashimoto's thyroiditis at the first diagnosis and during the follow-up., J Endocrinol Invest, 2018. 41 (4)(4): p. 395-402., https://pubmed.ncbi.nlm.nih.gov/28875268/
[169] Song, E, Oh, HS, Jeon, MJ, Chung, KW, Hong, SJ, Ryu, JS, et.al. The value of preoperative antithyroidperoxidase antibody as a novel predictor of recurrence in papillary thyroid carcinoma., Int J Cancer, 2019. 144 (6)(6): p. 1414-1420., https://pubmed.ncbi.nlm.nih.gov/30357831/
[170] Krátký, J, Ježková, J, Kosák, M, Vítková, H, Bartáková, J, Mráz, M, et.al. Positive Antithyroid Antibodies and Nonsuppressed TSH Are Associated with Thyroid Cancer: A Retrospective Cross-Sectional Study., Int J Endocrinol, 2018. 2018 (): p. 9793850., https://pubmed.ncbi.nlm.nih.gov/30258461/
[171] Lai, X, Xia, Y, Zhang, B, Li, J, Jiang, Y, A meta-analysis of Hashimoto's thyroiditis and papillary thyroid carcinoma risk., Oncotarget, 2017. 8 (37)(37): p. 62414-62424., https://pubmed.ncbi.nlm.nih.gov/28977955/
[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.
[173] Accurso, A, Rocco, N, Palumbo, A, Feleppa, C, Usefulness of ultrasound-guided fine-needle aspiration cytology in the diagnosis of non-palpable small thyroid nodules: our growing experience., J Endocrinol Invest, 2009. 32 (2)(2): p. 156-9., https://pubmed.ncbi.nlm.nih.gov/19411815/
[174] Słowińska-Klencka, D, Popowicz, B, Lewiński, A, Sporny, S, Klencki, M, The fine-needle aspiration biopsy efficacy of small thyroid nodules in the area of recently normalized iodine supply., Eur J Endocrinol, 2008. 159 (6)(6): p. 747-54., https://pubmed.ncbi.nlm.nih.gov/18794209/
[175] Scheuba, C, Kaserer, K, Kaczirek, K, Asari, R, Niederle, B, Desmoplastic stromal reaction in medullary thyroid cancer-an intraoperative "marker" for lymph node metastases., World J Surg, 2006. 30 (5)(5): p. 853-9., https://pubmed.ncbi.nlm.nih.gov/16680600/
[176] Koperek, O, Scheuba, C, Cherenko, M, Neuhold, N, De Micco, C, Schmid, KW, et.al. Desmoplasia in medullary thyroid carcinoma: a reliable indicator of metastatic potential., Histopathology, 2008. 52 (5)(5): p. 623-30., https://pubmed.ncbi.nlm.nih.gov/18370959/
[177] Machens, A, Dralle, H, Clinical relevance of desmoplasia in medullary thyroid carcinoma., Histopathology, 2008. 53 (4)(4): p. 481; author reply 482-3., https://pubmed.ncbi.nlm.nih.gov/18764881/
[178] Niederle, MB, Riss, P, Selberherr, A, Koperek, O, Kaserer, K, Niederle, B, et.al. Omission of lateral lymph node dissection in medullary thyroid cancer without a desmoplastic stromal reaction., Br J Surg, 2021. 108 (2)(2): p. 174-181., https://pubmed.ncbi.nlm.nih.gov/33704404/
[179] Machens, A, Kaatzsch, P, Lorenz, K, Horn, LC, Wickenhauser, C, Schmid, KW, et.al. Abandoning node dissection for desmoplasia-negative encapsulated unifocal sporadic medullary thyroid cancer., Surgery, 2022. 171 (2)(2): p. 360-367., https://pubmed.ncbi.nlm.nih.gov/34602296/
[180] Wu, M, A comparative study of 200 head and neck FNAs performed by a cytopathologist with versus without ultrasound guidance: evidence for improved diagnostic value with ultrasound guidance., Diagn Cytopathol, 2011. 39 (10)(10): p. 743-51., https://pubmed.ncbi.nlm.nih.gov/20949470/
[181] Conrad, R, Yang, SE, Chang, S, Bhasin, M, Sullivan, PS, Moatamed, NA, et.al. Comparison of Cytopathologist-Performed Ultrasound-Guided Fine-Needle Aspiration With Cytopathologist-Performed Palpation-Guided Fine-Needle Aspiration: A Single Institutional Experience., Arch Pathol Lab Med, 2018. 142 (10)(10): p. 1260-1267., https://pubmed.ncbi.nlm.nih.gov/29697276/
[182] Taha, I, Al-Thani, H, El-Menyar, A, Asim, M, Al-Sulaiti, M, Tabeb, A, Diagnostic accuracy of preoperative palpation- versus ultrasound-guided thyroid fine needle aspiration cytology: an observational study., Postgrad Med, 2020. 132 (5)(5): p. 465-472., https://pubmed.ncbi.nlm.nih.gov/32163318/
[183] Zhang, L, Liu, Y, Tan, X, Liu, X, Zhang, H, Qian, L, Comparison of Different-Gauge Needles for Fine-Needle Aspiration Biopsy of Thyroid Nodules., J Ultrasound Med, 2018. 37 (7)(7): p. 1713-1716., https://pubmed.ncbi.nlm.nih.gov/29288581/
[184] İnci, MF, Özkan, F, Yüksel, M, Şalk, İ, Şahin, M, The effects of sonographic and demographic features and needle size on obtaining adequate cytological material in sonography-guided fine-needle aspiration biopsy of thyroid nodules., Endocrine, 2013. 43 (2)(2): p. 424-9., https://pubmed.ncbi.nlm.nih.gov/22956413/
[185] Moss, WJ, Finegersh, A, Pang, J, Califano, JA, Coffey, CS, Orosco, RK, et.al. Needle Biopsy of Routine Thyroid Nodules Should Be Performed Using a Capillary Action Technique with 24- to 27-Gauge Needles: A Systematic Review and Meta-Analysis., Thyroid, 2018. 28 (7)(7): p. 857-863., https://pubmed.ncbi.nlm.nih.gov/29742978/
[186] Tanaka, A, Hirokawa, M, Higuchi, M, Kanematsu, R, Suzuki, A, Kuma, S, et.al. Optimal needle size for thyroid fine needle aspiration cytology., Endocr J, 2019. 66 (2)(2): p. 143-147., https://pubmed.ncbi.nlm.nih.gov/30464152/
[187] Pothier, DD, Narula, AA, Should we apply suction during fine needle cytology of thyroid lesions? A systematic review and meta-analysis., Ann R Coll Surg Engl, 2006. 88 (7)(7): p. 643-5., https://pubmed.ncbi.nlm.nih.gov/17132312/
[188] Song, H, Wei, C, Li, D, Hua, K, Song, J, Maskey, N, et.al. Comparison of Fine Needle Aspiration and Fine Needle Nonaspiration Cytology of Thyroid Nodules: A Meta-Analysis., Biomed Res Int, 2015. 2015 (): p. 796120., https://pubmed.ncbi.nlm.nih.gov/26491689/
[189] Wang, D, Fu, HJ, Xu, HX, Guo, LH, Li, XL, He, YP, et.al. Comparison of fine needle aspiration and non-aspiration cytology for diagnosis of thyroid nodules: A prospective, randomized, and controlled trial., Clin Hemorheol Microcirc, 2017. 66 (1)(1): p. 67-81., https://pubmed.ncbi.nlm.nih.gov/28128748/
[190] Nagarajah, J, Sheu-Grabellus, SY, Farahati, J, Kamruddin, KA, Bockisch, A, Schmid, KW, et.al. Ultrasound-guided fine-needle aspiration biopsy of clinically suspicious thyroid nodules with an automatic aspirator: a novel technique., Thyroid, 2012. 22 (7)(7): p. 695-8., https://pubmed.ncbi.nlm.nih.gov/22524469/
[191] Chong, Y, Ji, SJ, Kang, CS, Lee, EJ, Can liquid-based preparation substitute for conventional smear in thyroid fine-needle aspiration? A systematic review based on meta-analysis., Endocr Connect, 2017. 6 (8)(8): p. 817-829., https://pubmed.ncbi.nlm.nih.gov/29018157/
[192] Nagarajan, N, Schneider, EB, Ali, SZ, Zeiger, MA, Olson, MT, How do liquid-based preparations of thyroid fine-needle aspiration compare with conventional smears? An analysis of 5475 specimens., Thyroid, 2015. 25 (3)(3): p. 308-13., https://pubmed.ncbi.nlm.nih.gov/25420135/
[193] [Public health requirements in punctures and injections]., Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz, 2011. 54 (9)(9): p. 1135-44., https://pubmed.ncbi.nlm.nih.gov/21887628/
[194] Lyle, MA, Dean, DS, Ultrasound-guided fine-needle aspiration biopsy of thyroid nodules in patients taking novel oral anticoagulants., Thyroid, 2015. 25 (4)(4): p. 373-6., https://pubmed.ncbi.nlm.nih.gov/25584817/
[195] Khadra, H, Kholmatov, R, Monlezun, D, Kandil, E, Do anticoagulation medications increase the risk of haematoma in ultrasound-guided fine needle aspiration of thyroid lesions?, Cytopathology, 2018. 29 (6)(6): p. 565-568., https://pubmed.ncbi.nlm.nih.gov/29969159/
[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/
[197] Chen, JV, Morgan, TA, Liu, C, Khanafshar, E, Choi, HH, Cervical Lymph Node Features Predictive of Suboptimal Adequacy During Ultrasound-Guided Fine-Needle Aspiration in Thyroid Cancer Patients., J Ultrasound Med, 2022. 41 (1)(1): p. 135-145., https://pubmed.ncbi.nlm.nih.gov/33665844/
[198] Suh, CH, Baek, JH, Lee, JH, Choi, YJ, Kim, KW, Lee, J, et.al. The role of core-needle biopsy in the diagnosis of thyroid malignancy in 4580 patients with 4746 thyroid nodules: a systematic review and meta-analysis., Endocrine, 2016. 54 (2)(2): p. 315-328., https://pubmed.ncbi.nlm.nih.gov/27220941/
[199] Du, W, Fang, Q, Dai, L, Fan, J, Fine-needle aspiration biopsy versus frozen section examination in assessing cervical lymph node metastasis in primary clinically positive neck papillary thyroid carcinoma., Diagn Cytopathol, 2022. 50 (5)(5): p. 217-222., https://pubmed.ncbi.nlm.nih.gov/35103414/
[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/
[201] Landry, CS, Grubbs, EG, Busaidy, NL, Monroe, BJ, Staerkel, GA, Perrier, ND, et.al. Cystic lymph nodes in the lateral neck as indicators of metastatic papillary thyroid cancer., Endocr Pract, 2011. 17 (2)(2): p. 240-4., https://pubmed.ncbi.nlm.nih.gov/20713342/
[202] Jiang, HJ, Hsiao, PJ, Clinical application of the ultrasound-guided fine needle aspiration for thyroglobulin measurement to diagnose lymph node metastasis from differentiated thyroid carcinoma-literature review., Kaohsiung J Med Sci, 2020. 36 (4)(4): p. 236-243., https://pubmed.ncbi.nlm.nih.gov/31909556/
[203] Eun, NL, Son, EJ, Kim, JA, Gweon, HM, Kang, JH, Youk, JH, Comparison of the diagnostic performances of ultrasonography, CT and fine needle aspiration cytology for the prediction of lymph node metastasis in patients with lymph node dissection of papillary thyroid carcinoma: A retrospective cohort study., Int J Surg, 2018. 51 (): p. 145-150., https://pubmed.ncbi.nlm.nih.gov/29337176/
[204] Kahramangil, B, Kose, E, Donmez, M, Aydin, H, El-Dabh, D, Krishnamurthy, V, et.al. Efficacy of surgeon-performed, ultrasound-guided lymph node fine needle aspiration in patients with thyroid pathologic conditions., Surgery, 2018. 164 (4)(4): p. 657-664., https://pubmed.ncbi.nlm.nih.gov/30072253/
[205] Ke, Z, Liu, Y, Zhang, Y, Li, J, Kuang, M, Peng, S, et.al. Diagnostic value and lymph node metastasis prediction of a custom‑made panel (thyroline) in thyroid cancer., Oncol Rep, 2018. 40 (2)(2): p. 659-668., https://pubmed.ncbi.nlm.nih.gov/29901149/
[206] Jun, HH, Kim, SM, Kim, BW, Lee, YS, Chang, HS, Park, CS, Overcoming the limitations of fine needle aspiration biopsy: detection of lateral neck node metastasis in papillary thyroid carcinoma., Yonsei Med J, 2015. 56 (1)(1): p. 182-8., https://pubmed.ncbi.nlm.nih.gov/25510763/
[207] Zhu, XH, Zhou, JN, Qian, YY, Yang, K, Wen, QL, Zhang, QH, et.al. Diagnostic values of thyroglobulin in lymph node fine-needle aspiration washout: a systematic review and meta-analysis diagnostic values of FNA-Tg., Endocr J, 2020. 67 (2)(2): p. 113-123., https://pubmed.ncbi.nlm.nih.gov/31723088/
[208] Snozek, CL, Chambers, EP, Reading, CC, Sebo, TJ, Sistrunk, JW, Singh, RJ, et.al. Serum thyroglobulin, high-resolution ultrasound, and lymph node thyroglobulin in diagnosis of differentiated thyroid carcinoma nodal metastases., J Clin Endocrinol Metab, 2007. 92 (11)(11): p. 4278-81., https://pubmed.ncbi.nlm.nih.gov/17684045/
[209] Kim, DW, Jeon, SJ, Kim, CG, Usefulness of thyroglobulin measurement in needle washouts of fine-needle aspiration biopsy for the diagnosis of cervical lymph node metastases from papillary thyroid cancer before thyroidectomy., Endocrine, 2012. 42 (2)(2): p. 399-403., https://pubmed.ncbi.nlm.nih.gov/22350587/
[210] Salmaslıoğlu, A, Erbil, Y, Cıtlak, G, Ersöz, F, Sarı, S, Olmez, A, et.al. Diagnostic value of thyroglobulin measurement in fine-needle aspiration biopsy for detecting metastatic lymph nodes in patients with papillary thyroid carcinoma., Langenbecks Arch Surg, 2011. 396 (1)(1): p. 77-81., https://pubmed.ncbi.nlm.nih.gov/21052711/
[211] Uruno, T, Miyauchi, A, Shimizu, K, Tomoda, C, Takamura, Y, Ito, Y, et.al. Usefulness of thyroglobulin measurement in fine-needle aspiration biopsy specimens for diagnosing cervical lymph node metastasis in patients with papillary thyroid cancer., World J Surg, 2005. 29 (4)(4): p. 483-5., https://pubmed.ncbi.nlm.nih.gov/15776292/
[212] Xu, Y, Wu, D, Wu, W, Jiang, J, Xi, C, Ye, N, et.al. Diagnostic value of cytology, thyroglobulin, and combination of them in fine-needle aspiration of metastatic lymph nodes in patients with differentiated thyroid cancer: A systematic review and network meta-analysis., Medicine (Baltimore), 2019. 98 (45)(45): p. e17859., https://pubmed.ncbi.nlm.nih.gov/31702649/
[213] Yi, KS, Kim, JH, Na, DG, Seo, H, Min, HS, Won, JK, et.al. Usefulness of core needle biopsy for thyroid nodules with macrocalcifications: comparison with fine-needle aspiration., Thyroid, 2015. 25 (6)(6): p. 657-64., https://pubmed.ncbi.nlm.nih.gov/25851539/
[214] Na, DG, Kim, DS, Kim, SJ, Ryoo, JW, Jung, SL, Thyroid nodules with isolated macrocalcification: malignancy risk and diagnostic efficacy of fine-needle aspiration and core needle biopsy., Ultrasonography, 2016. 35 (3)(3): p. 212-9., https://pubmed.ncbi.nlm.nih.gov/26810196/
[215] Park, KW, Shin, JH, Hahn, SY, Oh, YL, Kim, SW, Kim, TH, et.al. Ultrasound-guided fine-needle aspiration or core needle biopsy for diagnosing follicular thyroid carcinoma?, Clin Endocrinol (Oxf), 2020. 92 (5)(5): p. 468-474., https://pubmed.ncbi.nlm.nih.gov/32012326/
[216] Ha, EJ, Baek, JH, Lee, JH, Kim, JK, Song, DE, Kim, WB, et.al. Core needle biopsy could reduce diagnostic surgery in patients with anaplastic thyroid cancer or thyroid lymphoma., Eur Radiol, 2016. 26 (4)(4): p. 1031-6., https://pubmed.ncbi.nlm.nih.gov/26201291/
[217] Kim, SJ, Lee, SW, Jeong, SY, Pak, K, Kim, K, Diagnostic Performance of Technetium-99m Methoxy-Isobutyl-Isonitrile for Differentiation of Malignant Thyroid Nodules: A Systematic Review and Meta-Analysis., Thyroid, 2018. 28 (10)(10): p. 1339-1348., https://pubmed.ncbi.nlm.nih.gov/30129898/
[218] Treglia, G, Caldarella, C, Saggiorato, E, Ceriani, L, Orlandi, F, Salvatori, M, et.al. Diagnostic performance of (99m)Tc-MIBI scan in predicting the malignancy of thyroid nodules: a meta-analysis., Endocrine, 2013. 44 (1)(1): p. 70-8., https://pubmed.ncbi.nlm.nih.gov/23529672/
[219] Wale, A, Miles, KA, Young, B, Zammit, C, Williams, A, Quin, J, et.al. Combined (99m)Tc-methoxyisobutylisonitrile scintigraphy and fine-needle aspiration cytology offers an accurate and potentially cost-effective investigative strategy for the assessment of solitary or dominant thyroid nodules., Eur J Nucl Med Mol Imaging, 2014. 41 (1)(1): p. 105-15., https://pubmed.ncbi.nlm.nih.gov/24030667/
[220] Schenke, SA, Klett, R, Wagner, PR, Mott, S, Zimny, M, Feek, U, et.al. Characteristics of different histological subtypes of thyroid nodules classified with 99mTc-methoxy-isobutyl-isonitrile imaging and Thyroid Imaging Reporting And Data System., Nucl Med Commun, 2021. 42 (1)(1): p. 73-80., https://pubmed.ncbi.nlm.nih.gov/33122502/
[221] Chen, W, Parsons, M, Torigian, DA, Zhuang, H, Alavi, A, Evaluation of thyroid FDG uptake incidentally identified on FDG-PET/CT imaging., Nucl Med Commun, 2009. 30 (3)(3): p. 240-4., https://pubmed.ncbi.nlm.nih.gov/19262287/
[222] Nishimori, H, Tabah, R, Hickeson, M, How, J, Incidental thyroid "PETomas": clinical significance and novel description of the self-resolving variant of focal FDG-PET thyroid uptake., Can J Surg, 2011. 54 (2)(2): p. 83-8., https://pubmed.ncbi.nlm.nih.gov/21251421/
[223] Marcus, C, Whitworth, PW, Surasi, DS, Pai, SI, Subramaniam, RM, PET/CT in the management of thyroid cancers., AJR Am J Roentgenol, 2014. 202 (6)(6): p. 1316-29., https://pubmed.ncbi.nlm.nih.gov/24848831/
[224] Soelberg, KK, Bonnema, SJ, Brix, TH, Hegedüs, L, Risk of malignancy in thyroid incidentalomas detected by 18F-fluorodeoxyglucose positron emission tomography: a systematic review., Thyroid, 2012. 22 (9)(9): p. 918-25., https://pubmed.ncbi.nlm.nih.gov/22827552/
[225] Pattison, DA, Bozin, M, Gorelik, A, Hofman, MS, Hicks, RJ, Skandarajah, A, None, J Nucl Med, 2018. 59 (5)(5): p. 749-755., https://pubmed.ncbi.nlm.nih.gov/29025986/
[226] Vriens, D, de Wilt, JH, van der Wilt, GJ, Netea-Maier, RT, Oyen, WJ, de Geus-Oei, LF, The role of [18F]-2-fluoro-2-deoxy-d-glucose-positron emission tomography in thyroid nodules with indeterminate fine-needle aspiration biopsy: systematic review and meta-analysis of the literature., Cancer, 2011. 117 (20)(20): p. 4582-94., https://pubmed.ncbi.nlm.nih.gov/21432844/
[227] Wang, N, Zhai, H, Lu, Y, Is fluorine-18 fluorodeoxyglucose positron emission tomography useful for the thyroid nodules with indeterminate fine needle aspiration biopsy? A meta-analysis of the literature., J Otolaryngol Head Neck Surg, 2013. 42 (1)(1): p. 38., https://pubmed.ncbi.nlm.nih.gov/24228840/
[228] Castellana, M, Trimboli, P, Piccardo, A, Giovanella, L, Treglia, G, Performance of , J Clin Med, 2019. 8 (9)(9):, https://pubmed.ncbi.nlm.nih.gov/31466411/
[229] Vriens, D, Adang, EM, Netea-Maier, RT, Smit, JW, de Wilt, JH, Oyen, WJ, et.al. Cost-effectiveness of FDG-PET/CT for cytologically indeterminate thyroid nodules: a decision analytic approach., J Clin Endocrinol Metab, 2014. 99 (9)(9): p. 3263-74., https://pubmed.ncbi.nlm.nih.gov/24873995/
[230] Deandreis, D, Al Ghuzlan, A, Auperin, A, Vielh, P, Caillou, B, Chami, L, et.al. Is (18)F-fluorodeoxyglucose-PET/CT useful for the presurgical characterization of thyroid nodules with indeterminate fine needle aspiration cytology?, Thyroid, 2012. 22 (2)(2): p. 165-72., https://pubmed.ncbi.nlm.nih.gov/22257371/
[231] Piccardo, A, Puntoni, M, Treglia, G, Foppiani, L, Bertagna, F, Paparo, F, et.al. Thyroid nodules with indeterminate cytology: prospective comparison between 18F-FDG-PET/CT, multiparametric neck ultrasonography, 99mTc-MIBI scintigraphy and histology., Eur J Endocrinol, 2016. 174 (5)(5): p. 693-703., https://pubmed.ncbi.nlm.nih.gov/26966173/
[232] Rosario, PW, Rocha, TG, Calsolari, MR, Fluorine-18-fluorodeoxyglucose positron emission tomography in thyroid nodules with indeterminate cytology: a prospective study., Nucl Med Commun, 2019. 40 (2)(2): p. 185-187., https://pubmed.ncbi.nlm.nih.gov/30444748/
[233] Urhan, M, Velioglu, M, Rosenbaum, J, Basu, S, Alavi, A, Imaging for the diagnosis of thyroid cancer., Expert Opin Med Diagn, 2009. 3 (3)(3): p. 237-49., https://pubmed.ncbi.nlm.nih.gov/23488460/
[234] Choi, WH, Chung, YA, Han, EJ, Sohn, HS, Lee, SH, Clinical value of integrated [18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in the preoperative assessment of papillary thyroid carcinoma: comparison with sonography., J Ultrasound Med, 2011. 30 (9)(9): p. 1267-73., https://pubmed.ncbi.nlm.nih.gov/21876098/
[235] Morita, S, Mizoguchi, K, Suzuki, M, Iizuka, K, The accuracy of (18)[F]-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography, ultrasonography, and enhanced computed tomography alone in the preoperative diagnosis of cervical lymph node metastasis in patients with papillary thyroid carcinoma., World J Surg, 2010. 34 (11)(11): p. 2564-9., https://pubmed.ncbi.nlm.nih.gov/20645089/
[236] Kim, BS, Kim, SJ, Kim, IJ, Pak, K, Kim, K, Factors associated with positive F-18 flurodeoxyglucose positron emission tomography before thyroidectomy in patients with papillary thyroid carcinoma., Thyroid, 2012. 22 (7)(7): p. 725-9., https://pubmed.ncbi.nlm.nih.gov/22524470/
[237] Chung, JK, So, Y, Lee, JS, Choi, CW, Lim, SM, Lee, DS, et.al. Value of FDG PET in papillary thyroid carcinoma with negative 131I whole-body scan., J Nucl Med, 1999. 40 (6)(6): p. 986-92., https://pubmed.ncbi.nlm.nih.gov/10452315/
[238] Rosenbaum-Krumme, SJ, Görges, R, Bockisch, A, Binse, I, ¹⁸F-FDG PET/CT changes therapy management in high-risk DTC after first radioiodine therapy., Eur J Nucl Med Mol Imaging, 2012. 39 (9)(9): p. 1373-80., https://pubmed.ncbi.nlm.nih.gov/22718304/
[239] Nascimento, C, Borget, I, Al Ghuzlan, A, Deandreis, D, Hartl, D, Lumbroso, J, et.al. Postoperative fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography: an important imaging modality in patients with aggressive histology of differentiated thyroid cancer., Thyroid, 2015. 25 (4)(4): p. 437-44., https://pubmed.ncbi.nlm.nih.gov/25633259/
[240] Pryma, DA, Schöder, H, Gönen, M, Robbins, RJ, Larson, SM, Yeung, HW, Diagnostic accuracy and prognostic value of 18F-FDG PET in Hürthle cell thyroid cancer patients., J Nucl Med, 2006. 47 (8)(8): p. 1260-6., https://pubmed.ncbi.nlm.nih.gov/16883003/
[241] Lowe, VJ, Mullan, BP, Hay, ID, McIver, B, Kasperbauer, JL, 18F-FDG PET of patients with Hürthle cell carcinoma., J Nucl Med, 2003. 44 (9)(9): p. 1402-6., https://pubmed.ncbi.nlm.nih.gov/12960183/
[242] Schoenberger, J, Fuchs, E, Fertig, V, Szikszai, A, Maenner, P, Eilles, C, Clinical value of planar and tomographic dual-isotope scintigraphy using 99mTc-methylene diphosphonate and 131I in patients with thyroid cancer., Nucl Med Commun, 2006. 27 (11)(11): p. 865-71., https://pubmed.ncbi.nlm.nih.gov/17021426/
[243] Qiu, ZL, Xue, YL, Song, HJ, Luo, QY, Comparison of the diagnostic and prognostic values of 99mTc-MDP-planar bone scintigraphy, 131I-SPECT/CT and 18F-FDG-PET/CT for the detection of bone metastases from differentiated thyroid cancer., Nucl Med Commun, 2012. 33 (12)(12): p. 1232-42., https://pubmed.ncbi.nlm.nih.gov/23111353/
[244] Ota, N, Kato, K, Iwano, S, Ito, S, Abe, S, Fujita, N, et.al. Comparison of ¹⁸F-fluoride PET/CT, ¹⁸F-FDG PET/CT and bone scintigraphy (planar and SPECT) in detection of bone metastases of differentiated thyroid cancer: a pilot study., Br J Radiol, 2014. 87 (1034)(1034): p. 20130444., https://pubmed.ncbi.nlm.nih.gov/24297809/
[245] Ito, S, Kato, K, Ikeda, M, Iwano, S, Makino, N, Tadokoro, M, et.al. Comparison of 18F-FDG PET and bone scintigraphy in detection of bone metastases of thyroid cancer., J Nucl Med, 2007. 48 (6)(6): p. 889-95., https://pubmed.ncbi.nlm.nih.gov/17504877/
[246] Huellner, MW, Strobel, K, Clinical applications of SPECT/CT in imaging the extremities., Eur J Nucl Med Mol Imaging, 2014. 41 Suppl 1 (): p. S50-8., https://pubmed.ncbi.nlm.nih.gov/23963296/
[247] Mikhael, A, Patell, R, Tabet, M, Bena, J, Berber, E, Nasr, C, Chest X-ray Prior to Thyroidectomy: Is It Really Needed?, World J Surg, 2018. 42 (5)(5): p. 1403-1407., https://pubmed.ncbi.nlm.nih.gov/29147894/
[248] Bongers, PJ, Verzijl, R, Dzingala, M, Vriens, MR, Yu, E, Pasternak, JD, et.al. Preoperative Computed Tomography Changes Surgical Management for Clinically Low-Risk Well-Differentiated Thyroid Cancer., Ann Surg Oncol, 2019. 26 (13)(13): p. 4439-4444., https://pubmed.ncbi.nlm.nih.gov/31583547/
[249] Ahn, JE, Lee, JH, Yi, JS, Shong, YK, Hong, SJ, Lee, DH, et.al. Diagnostic accuracy of CT and ultrasonography for evaluating metastatic cervical lymph nodes in patients with thyroid cancer., World J Surg, 2008. 32 (7)(7): p. 1552-8., https://pubmed.ncbi.nlm.nih.gov/18408961/
[250] Lesnik, D, Cunnane, ME, Zurakowski, D, Acar, GO, Ecevit, C, Mace, A, et.al. Papillary thyroid carcinoma nodal surgery directed by a preoperative radiographic map utilizing CT scan and ultrasound in all primary and reoperative patients., Head Neck, 2014. 36 (2)(2): p. 191-202., https://pubmed.ncbi.nlm.nih.gov/23554058/
[251] Kim, H, Kim, JA, Son, EJ, Youk, JH, Chung, TS, Park, CS, et.al. Preoperative prediction of the extrathyroidal extension of papillary thyroid carcinoma with ultrasonography versus MRI: a retrospective cohort study., Int J Surg, 2014. 12 (5)(5): p. 544-8., https://pubmed.ncbi.nlm.nih.gov/24631554/