CC BY
13DOI: 10.24411/2181-0443/2020-10159
ДИАГНОСТИКА УЗЛОВОГО ЗОБА
Тян Алеся Алишеровна Рашидова Шахло Урмановна
Андижанский государственный медицинский институт
Рассмотрен вопрос о современных возможностях комплексной диагностики образования узлов щитовидной железы. Несмотря на многочисленные исследования, не всегда удается поставить точный морфологический диагноз узелков щитовидной железы, что свидетельствует о необходимости совершенствования существующих и поиска новых методов диагностики. В связи с этим весьма перспективными представляются сообщения об использовании измерения тканевого давления в щитовидной железе для дифференциальной диагностики различных патологий этого органа. В настоящее время ультразвуковое исследование является эффективным методом диагностики. В этой статье обсуждаются узлы щитовидной железы и их диагностика.
Ключевые слова: Щитовидная железа, морфологическая форма, узелковое образование, узелок щитовидной железы, ультразвуковое исследование.
QALQONSIMON BEZ TUGUNLARI DIAGNOSTIKASI
Qalqonsimon bez tuguni shakllanishini kompleks diagnostikasining zamonaviy imkoniyatlari masalasi ko'rib chiqilmoqda. Ko'p sonli tadqiqotlar o'tkazilishiga qaramay, qalqonsimon bez tugunlarining aniq morfologik diagnostikasini har doim ham to'g'ri yo'lga qo'yish mumkin emas, bu mavjud bo'lganlarni takomillashtirish va yangi diagnostik usullarni izlash zarurligini ko'rsatadi. Shu nuqtai nazardan, ushbu organning turli xil patologiyalarini differentsial diagnostika qilish uchun qalqonsimon bezlarda to'qima bosimini o'lchashni qo'llash bo'yicha hisobotlar juda istiqbolli ko'rinadi. Hozirda ultratovush tekshiruv usuli samarali diagnostik usul hisoblanadi. Ushbu maqolada qalqonsimon bez tugunlari va uning diagnostikasi muhokama qilinadi.
Kalit so'zlar: Qalqonsimon bez, morfologik shakl, tugun shakllanishi, qalqonsimon bez tuguni, ultratovush tekshiruvi.
DIAGNOSIS OF THYROID NODULES
The question of modern possibilities of complex diagnostics of nodular formations of the thyroid gland is considered. Despite the large number of studies conducted, it is not always possible to correctly establish the exact morphological diagnosis of thyroid nodules, which indicates the need to improve existing and search for new more informative diagnostic methods. In this respect, reports on the use of tissue pressure measurements in the thyroid glands for differential diagnosis of various pathologies of this organ appear to be very promising. Currently, ultrasound is an effective diagnostic method. This article discusses thyroid nodules and its diagnosis.
Keywords: Thyroid gland, morphological form, nodal formation, thyroid nodule, ultrasound diagnosis.
Introduction: Thyroid nodule is a discrete lesion in the thyroid gland that is radiologically distinct from the surrounding thyroid parenchyma. Thyroid nodules are common; their prevalence in the general population is high, the percentages vary depending on
the mode of discovery: 2-6 % (palpation), 19-35 % (ultrasound) and 8-65 % (autopsy data). They are discovered either clinically on self-palpation by a patient, or during a physical examination by the clinician or incidentally during a radiologic
procedure such as ultrasonography (US) imaging, computed tomography (CT) or magnetic resonance imaging (MRI) of the neck, or fluorodeoxyglucose (FDG) positron emission tomography; with the increased use of sensitive imaging techniques, thyroid nodules are being diagnosed incidentally with increasing frequency in the recent years. Though thyroid nodules are common, their clinical significance is mainly related to excluding malignancy (4.0 to 6.5% of all thyroid nodules), evaluating their functional status and if they cause pressure symptoms.
Due to the rapid development of medical imaging technology, the clinical detection of thyroid nodules has increased worldwide, allowing for higher rates of thyroid cancer diagnosis [1-3]. Acar et al [4] reported 51% of patients who had been referred to their radiology department undergoing highresolution ultrasonography (US) were found to have at least one thyroid nodule. Managing these thyroid nodules, making a treatment plan and predicting patient prognosis all require the clinician to accurately distinguish malignant from benign nodules, which remains a challenge for both doctors and sonographers [5]. Medical imaging is critical to the diagnosis of thyroid nodules. However, the limited resolution of cross-sections from computed tomography, magnetic resonance imaging and positron emission tomography provide little useful information for the diagnosis of small nodules [6-8]. Technological advances, including higher resolution and reproducibility, and the advantages associated with the lack of radiation, have pushed US imaging toward the frontline of differential diagnosis. The use of high-resolution US could remove the need for excessive fine needle aspiration (FNA) and also supply information for the design of appropriate surgical programs for cases of undetermined cytology [9]. In the past several years, the US-based
diagnosis of thyroid nodules has relied primarily upon conventional gray-scale US. Using this method, malignancy was shown to be associated with hypoechogenicity, height greater than length, blur margin and microcalcification [10,11]. However, small nodules, which make up the majority of observed nodules, appear with more atypical features on conventional grayscale US. Fortunately, new US techniques have been developed and clinically applied. For example, contrast-enhanced US (CEUS) employs a microbubble agent to enhance the backscatter signals of red blood cells and can be used to characterize local vascular perfusion. Several studies have explored the perfusion patterns of thyroid nodules using CEUS [12-14]. Elastosonography (ES) can be used to estimate malignancy by assessing the hardness of tissues [15]. Although the diagnostic accuracy of ES alone is not optimal, the information it supplies is useful when combined with that obtained via other US techniques [16]. These advanced integrative techniques reportedly improved the diagnostic accuracy of the thyroid image reporting and data system (TI-RADS) [17]. However, to the best of our knowledge, no previous study has provided a systematic method for integrating US parameters from multiple techniques; physicians and sonographers are sometimes overwhelmed by the large amount of information acquired [18]. In the present preliminary study, to establish an efficient strategy for differential diagnosis of thyroid nodules using a combination of US techniques, multiple features presented by conventional gray-scale US, color Doppler US (CDUS), ES and CEUS were assessed using univariate and multivariate logistic regression. The significant factors obtained were then integrated using a decision tree (DT) model. According to a group scientists [19], The demographic data and features
of the US images obtained for 289 nodules are shown in Table 1.
Table I
Final diagnosis of nodules.
Final diagnosis Total no. of nodules Pathological category No. of nodules
Histological results after 289 Follicular carcinomas 5
surgery
Medullary1 carcinoma 1
Papillary carcinomas 204
Nodular goiter 51
Adenoma 5
Inflammatory changes (Hashimoto's thyroiditis, subacute 23
thyroiditis or granuloma)
Cytological results after FNA 32 Benign follicular epithelial cells
Papillary carcinomas 1
For ES as a continuous variable, the cutoff point obtained using the ROC curve was 46.5% for area ratio and 1.215 for elasticity index. According to these values, area ratio was divided into two groups: >46.5% (55 benign and 93 malignant) and <46.5% (56 benign and 18 malignant). Elasticity index was categorized as follows: >1.215 (33 benign and 115 malignant) and <1.215 (38 benign and 36 malignant), which was used for logistic analysis. After univariate logistic analysis, as indicated, the P-values for sex, number of nodules and diffuse disease were >0.1 and so these factors were excluded from further analysis. The following parameters, with P<0.001, were employed for multivariate logistic analysis: Diameter, echogenicity, ring-halo sign, margin, shape, A/T ratio, micro-calcification, extent of blood flow, central vessels, surrounding vascularity, area ratio, elasticity index and enhancement patterns during the early, peak and late phases. The results of the multivariate logistic analysis demonstrated the significant effects of four parameters, which were selected for use in developing the DT. In the DT, peak-phase patterns on CEUS were evaluated as the first step, followed by area ratio on ES. CDUS and microcalcification on conventional gray-scale US were then used for further diagnosis. When the DT was retrospectively applied to the pathology or cytology
results of the 99 test nodules, it displayed a sensitivity of 98.6% (95% CI: 91.6-99.9%), specificity of 80.1% (95% CI: 60.0-92.7%), positive predictive value of 93.5% (95% CI: 84.897.6%) and negative predictive value of 95.5% (95% CI: 75.1-99.8%). US techniques offer much useful information for differentiating benign from malignant thyroid nodules. However, in some cases the information obtained from various US techniques can be contradictory and these various pieces of information need to be integrated efficiently. Although the combined application of multiple US techniques has been reported previously, the current study established a novel algorithm to integrate four different techniques to improve the differential diagnosis of thyroid nodules. CEUS patterns have been shown to be useful in differentiating benign from malignant thyroid lesions. Ring enhancement was mostly considered a predictive sign of benignity, whereas heterogeneous hypoenhancement was predictive of malignant lesions [20-25]. The results of the present study were consistent with these findings, and malignant nodules were also detectable by homogeneous isoenhancement. Some inflammatory nodules presented hypoenhancement similar to that of malignant nodules. Thus, the CEUS patterns of thyroid nodules with overlapping characteristics
between benign and malignancy appear to be relatively more complex than those of liver lesions. Additional parameters will need to be considered for the development of a thorough predictive model. Previously developed algorithms for diagnosing thyroid nodules have integrated ES analysis. In a study of 141 nodules, most of the benign nodules scored in the range 2-3, while malignant nodules scored ~5. Giusti et al [26] reported that the information added by CEUS is less sensitive than that provided by US and ES. However, the results of that study may have been influenced by the relatively small number of malignant lesions. In the current study, area ratio was found to be a useful factor in logistic multivariate regression. In the DT algorithm, nodules with homogenous isoenhancement, moderate blood flow and ES area ratio >46.5% were classified as malignant.
On conventional gray-scale US, spongiform and cystic features seem to provide sufficient information to confidently rule out cancer and calcification is regarded as a significant indicator of malignancy. In the current study, on conventional gray-scale US only 'micro-calcification' was included in the final algorithm, while shape, margin and echogenicity were excluded. This may be explained in several ways. First, there could be a parallel statistical influence of a given parameter on multiple techniques. For example, the US 'halo-ring' may also be related to ring enhancement on CEUS. Second, in this retrospective study, some patients underwent CEUS only after uncovering an atypical appearance using conventional gray-scale US. Thus, the data from conventional gray-scale US were not necessarily the most useful. Finally, 52 of 222 nodules were depicted with diffuse changes to the thyroid gland, influencing appearance and the diagnostic accuracy of conventional gray-scale US. As some nodules appear to show atypical features on conventional gray-scale US, especially in
the background of an inflamed thyroid, it has always been a challenge to confirm diagnosis using conventional gray-scale US. In the current study, 18 of these 24 inflammatory nodules were depicted with hypoenhancement with a low to medium level of blood flow, a similar appearance to that observed in malignant nodules. However, most of these nodules (15 of 18) had an area ratio <46.5% on ES, which meant there was low stiffness within these nodules, implying benignity. These findings imply that a DT algorithm combining four US techniques may supply a new method for the diagnosis of inflammatory nodules. The current preliminary study has several limitations. First, as this is a retrospective study, the patients were examined as part of routine work and their images were reviewed. Therefore, the number of nodules was limited as cases lacking pathological or cytological results were excluded. Second, nodules identified as 'typical' by US were not further examined using CEUS and thus were not included in this study, perhaps influencing the results of the DT. Finally, in testing 99 nodules with the final DT, five nodules were falsely identified as malignant, including four with diameter <10 mm. One false benign nodule <10 mm in diameter presented isoenhancement on CEUS. The results of this study therefore need to be verified in more patients and future analysis of typical and very small nodules would be beneficial. In conclusion, combining the parameters available on CEUS, conventional gray-scale US and ES with CDUS in this preliminary study allowed establishment of a DT algorithm that could be helpful for the differential diagnosis of thyroid nodules. Use of this algorithm could allow clinicians to integrate information from multiple US techniques and clarify an otherwise ambiguous diagnosis, leading to improved treatment options and prognosis.
According to a study by a group of scientists [27]: All ultrasound (US)
examinations were performed with a 5-to 12-MHz liner probe (iU22; Philips Medical System, Bothell, WA, United States). The CUS examination was performed with the standard equipment settings for thyroid glands. Standard machine settings for CEUS were used, and the contrast medium used was SonoVue (Bracco Imaging, Milan, Italy). With a 20- or 22-gauge peripheral intravenous cannula, SonoVue was injected intravenously as a bolus at a dose of 1.2 ml, followed by 5 ml of normal saline as a flush. The timer on the US machine was then started, and each contrast imaging acquisition lasted more than 2 min after the bolus injection; the imaging was digitally stored. During real-time elastography (RTE), the probe was positioned perpendicular to the skin, and no compression was applied at the skin above the targeted thyroid nodule. When there were two nodules in a patient, CEUS was performed on the second nodule after the first injected contrast agent was completely cleaned in the whole gland. CUS, RTE, and CEUS images and cine clips were analyzed by two radiologists with more than 5 years of experience in thyroid US. They were blinded to the patients' clinical data and pathological results. In cases of discrepancies between the two readers, a consensus was reached after discussion. The CUS features of all thyroid nodules were recorded according to the halo, echogenicity, internal component, echotexture (homogenous or heterogenous), calcifications, and vascularity. Halos were classified as absent, regularly thin, or irregular (including thick halos, incomplete halos, and halos of different widths). Echogenicity was classified as hypoechogenicity, isoechogenicity, hyperechogenicity, or marked hyperechogenicity relative to the surrounding normal parenchyma. The internal component of a nodule was classified as solid (defined as composed entirely or nearly entirely of soft tissue,
with only a few tiny cystic spaces) [28], predominantly solid, and predominantly cystic. Calcifications, when present, were categorized as microcalcifications, disrupted rim calcifications, and other types of calcifications.
Microcalcifications were defined as calcifications that were <1 mm in diameter and visualized as tiny hyperechoic foci. Disrupted rim calcifications were defined as interrupted peripheral calcifications in association with a soft tissue rim outside the calcification. When a nodule had both microcalcifications and other types of calcifications, it was classified as having microcalcifications. The vascularity of nodules was classified into five types by Frates [29] as follows: 0 for no visible flow, 1 for minimal internal flow without a peripheral ring, 2 for a peripheral ring of flow (defined as >25% of the nodule's circumference) with minimal or no internal flow, 3 for a peripheral ring of flow with a small to moderate amount of internal flow, and 4 for extensive internal flow with or without a peripheral ring. We regarded type 4 as increased intranodular vascularity. CEUS characteristics included peak intensity (categorized as low, equal, or high) and enhanced pattern (categorized as homogenous, heterogenous, or ring enhancing). Elastography score elasticity was classified in five different patterns, adding elastography score (ESS) 0 to the version of Asteria criteria [30]: ESS 0, red and blue, or blue and green, or red and green are layered distribution in cystic nodules or predominantly cystic nodules; ESS 1, homogenously in green (soft); ESS 2, predominantly in green with few blue areas/spots; ESS 3, predominantly in blue with a few green areas/spots; and ESS 4, completely in blue (hard). The results showed that, the clinical characteristics are summarized in Table 1.
Table 1.
Clinical Malignant Benign group P-value
characteristics group (n = 29) (n = 121)
Age (years) 44.0 ± 11.9 48.7 dfc 11.8 0.706
Sex 0.054
Female 17(58.6) 91 (75.2)
Male 12(41.4) 30 (24.8)
Mixed with HT 1 (3.4) 19(15.7) 0.081
Size (cm)* 2.1 ± 1.5 2.6 ± 1.4 0.675
HT, Hashimoto thyroiditis. 'For 163 nodules.
The age, gender, nodule size, and incidence of coexistence with Hashimoto thyroiditis (HT) did not significantly differ between the benign and malignant groups (P > 0.05). The results of the cytopathology and histopathology of the nine nodules that underwent FNA are summarized in Table 2. Histological pathology demonstrated that 29 lesions (17.8%) were malignant, and 134 lesions (82.2%) were benign. One hundred one nodular goiters (75.4%) constituted the majority of benign lesions, 18 of the 134 lesions were adenomatous nodules (ANs). The remainder of the benign lesions consisted of six follicular adenomas (FAs, 25.4%) and nine HTs (6.7%). Of the malignant lesions, 21 cases were PTCs, with 17 classical variant and 4 follicular variants, 7 cases were follicular carcinomas (FCs), and 1 case was medullary carcinoma (MC). Cervical lymph node metastasis was confirmed in one FC and six PTCs. Metastatic lesions were found in cervical striated muscles and fibrous connective tissues in another FC. The CEUS enhancement pattern is helpful for differentiating between benign and malignant nodules with an intermediate or low suspicion. Heterogenous enhancement is associated with malignant nodules, a finding that could modify the clinical
decision to avoid the misdiagnosis of FC in some patients. CUS characteristics, other qualitative CEUS indices, ES, and FNA have limited value.
Algorithm of thyroid nodule work up is presented at the end of the review (Fig. 1). Thyroid nodules can be caused by many disorders: benign (colloid nodule, Hashimoto's thyroiditis, simple or hemorrhagic cyst, follicular adenoma and subacute thyroiditis) and malignant (Papillary Cancer, Follicular Cancer, Hurthle Cell (oncocytic) Cancer, Anaplastic Cancer, Medullary Cancer, Thyroid Lymphoma and metastases -3 most common primaries are renal, lung & head-neck) [31-33]. Initial assessment of a patient found to have a thyroid nodule either clinically or incidentally should include a detailed and relevant history plus physical examination. Laboratory tests should begin with measurement of serum thyroid-stimulating hormone (TSH). Thyroid scintigraphy/radionuclide thyroid scan should be performed in patients presenting with a low serum TSH [34]. Thyroid ultrasound should be performed in all those suspected or known to have a nodule to confirm the presence of a nodule, evaluate for additional nodules and cervical lymph nodes and assess for suspicious sonographic features. The next step in
the evaluation of a thyroid nodule, if they meet the criteria as discussed later, is a fine needle aspiration (FNA) biopsy.
Table 2.
Module number
FNA cytopathology
Histological pathology
1
2
3
4
5
6 7
8
A small amount of thyroid follicular Thyroid atypical adenoma epithelial ceils and no tumor cells
Thyroid follicular epithelial cells and Thyroid adenoma no tumor celfs
Suspicious for a follicular neoplasm
Thyroid follicular epithelial cells and no tumor cells
No exception of follicular adenoma
Thyroid follicular carcinoma Thyroid follicular carcinoma
Thyroid follicular adenoma
Tumor-like lesion from thyroid follicular epithelial cells. Tumor or adenomatous charge cannot be distinguished because no specific capsule was seen.
Consistent with thyroid follicular neoplasm, and thyroid adenoma was considered
Thyroid follicular epithelial cells and no tumor cells
Nodular goiter with adenomatous hyperplasia
Nodular goiter with adenomatous hyperplasia Nodular hashimoto thyroiditis
Nodular goiter with adenomatous hyperplasia
Nodular goiter
Thyroid Ultrasound (US) is a noninvasive imaging technique that should be performed on all patients with nodules suspected clinically or incidentally noted on other imaging studies such as carotid ultrasound, CT, MRI, or 18-FDG-PET scan. Ultrasound will help confirm the thyroid nodule/s, assess the size, location and evaluate the composition, echogenicity, margins, presence of calcification, shape and vascularity of the nodules and the adjacent structures in the neck including the lymph nodes. If there are multiple nodules, all the nodules should be assessed for suspicious US characteristics. FNA decision making is
guided by both nodule size and ultrasound characteristics, the latter being more predictive of malignancy than size [35, 36]. The nodular characteristics that are associated with a higher likelihood of malignancy include a shape that is taller than wide measured in the transverse dimension, hypoechogenicity, irregular margins, microcalcifications, and absent halo [3541]. The feature with the highest diagnostic odds ratio for malignancy was suggested to be the nodule being taller than wider [42]. The more suspicious characteristics that the nodule has, it increases the likelihood of malignancy. In contrast, benign nodule
predicting US characteristics include purely cystic nodule (< 2 % risk of malignancy) [39], spongiform appearance (99.7 % specific for benign thyroid nodule) [40, 42-44]. The recent ATA guidelines classify nodules into 5 risk groups based on US results. However, the current AACE guidelines suggest a more practical, 3-tier risk classification: low risk, intermediate risk and high risk thyroid lesions, based on their US characteristics. In patients with thyroid nodules and low TSH who have undergone thyroid scintigraphy, ultrasound is useful to check for concordance of the nodule and hyperfunctioning area on the scan, which do not need FNA and to evaluate other nonfunctional or intermediate
nodules, which may require FNA based on sonographic criteria. Conclusion: Despite the large number of studies conducted, it is not always possible to correctly establish the exact morphological diagnosis of thyroid nodules, which indicates the need to improve existing and search for new more informative diagnostic methods. However, in this article we have discussed thyroid nodules and their diagnosis. We especially focused on the ultrasound examination. We used the opinions of several groups of research scientists and the most up-to-date research results. We hope that this article will provide at least some impetus for further in-depth research.
Figure 1. Thyroid Nodule Workup Algorithm
REFERENCES:
1. Moon WJ, Baek JH, Jung SL, Moon WJ, Baek JH, Jung SL, Kim DW, Kim EK, Kim JY, Kwak JY, et al: Ultrasonography and the ultrasound-based management of thyroid nodules: Consensus statement and recommendations. Korean J Radiol. 12:1-14. 2011.
2. Wang Y and Wang W: Increasing incidence of thyroid cancer in Shanghai. China, 19832007. Asia Pac J Public Health. 27:NP223-NP229. 2015.
3. Kitahara CM and Sosa JA: The changing incidence of thyroid cancer. Nat Rev Endocrinol. 12:646-653. 2016.
4. Acar T, Ozbek SS and Acar S: Incidentally discovered thyroid nodules: Frequency in an adult population during Doppler ultrasonographic evaluation of cervical vessels. Endocrine. 45:73-78. 2014.
5. Paschke R, Hegedus L, Alexander E, Valcavi R, Papini E and Gharib H: Thyroid nodule guidelines: Agreement, disagreement and need for future research. Nat Rev Endocrinol. 7:354361. 2011.
6. Hoang JK, Riofrio A, Bashir MR, Kranz PG and Eastwood JD: High variability in radiologists' reporting practices for incidental thyroid nodules detected on CT and MRI. AJNR Am J Neuroradiol. 35:1190-1194. 2014.
7. Lim HK, Park ST, Ha H and Choi SY: Thyroid nodules detected by contrast-enhanced magnetic resonance angiography: Prevalence and clinical significance. PLoS One. 11(e0149811)2016.
8. Kim TH, Ji YB, Song CM, Kim JY, Choi YY, Park JS and Tae K: SUVmax of 18F-FDG PET/CT in the differential diagnosis of benign and malignant thyroid nodules according to tumor volume. World J Surg Oncol. 13(217)2015.
9. Richmond B, Statler K, Judhan R, Mangano W and Thompson S: Sonographic appearance is useful in predicting the extent of initial operative therapy for thyroid nodules classified as 'suspicious for malignancy'. Am Surg. 82:692-697. 2016.
10. Palaniappan MK, Aiyappan SK and Ranga U: Role of gray scale, color Doppler and spectral Doppler in differentiation between malignant and benign thyroid nodules. J Clin Diagn Res. 10:TC01-TC06. 2016.
11. Zhang Y, Luo YK, Tang J, Li M, Wang ZL and Wen Q: Clinical value of ultrasonography in diagnosing diffuse thyroid diseases accompanied with suspicious nodules. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 37:290-293. 2015.
12. Chen HY, Liu WY, Zhu H, Jiang DW, Wang DH, Chen Y, Li W and Pan G: Diagnostic value of contrast-enhanced ultrasound in papillary thyroid microcarcinoma. Exp Ther Med. 11:15551562. 2016.
13. He Y, Wang XY, Hu Q, Chen XX, Ling B and Wei HM: Value of Contrast-enhanced ultrasound and acoustic radiation force impulse imaging for the differential diagnosis of benign and malignant thyroid nodules. Front Pharmacol. 27(1363)2018.
14. Zhan J and Ding H: Application of contrast-enhanced ultrasound for evaluation of thyroid nodules. Ultrasonography. 37:288-297. 2018.
15. Magri F, Chytiris S and Chiovato L: The role of elastography in thyroid ultrasonography. Curr Opin Endocrinol Diabetes Obes. 23:416-422. 2016.
16. Cantisani V, D'Andrea V, Biancari F, Medvedyeva O, Di Segni M, Olive M, Patrizi G, Redler A, De Antoni EE, Masciangelo R, et al: Prospective evaluation of multiparametric ultrasound and quantitative elastosonography in the differential diagnosis of benign and malignant thyroid nodules: Preliminary experience. Eur J Radiol. 81:2678-2683. 2012.
17. Zhang Y, Zhou P, Tian SM, Zhao YF, Li JL and Li L: Usefulness of combined use of contrast-enhanced ultrasound and TI-RADS classification for the differentiation of benign from malignant lesions of thyroid nodules. Eur Radiol. 4:1527-1536. 2017.
18. Sui X, Liu HJ, Jia HL and Fang QM: Contrast-enhanced ultrasound and real-time elastography in the differential diagnosis of malignant and benign thyroid nodules. Exp Ther Med. 12:783-791. 2016.
19. Wen Luo Yunfei Zhang Jiani Yuan Xiao Yang Lina Pang Lei Ding Peidi Zhang Liwen Liu Xiaodong Zhou. Differential diagnosis of thyroid nodules through a combination of multiple ultrasonography techniques: A decision-tree model. doi.org/10.3892/etm.2020.8621.
20. Zhang YZ, Xu T, Gong HY, Li CY, Ye XH, Lin HJ, Shen MP, Yang DT and Wu XH: Application of high-resolution ultrasound, real-time elastography, and contrast-enhanced ultrasound in differentiating solid thyroid nodules. Medicine (Baltimore). 95(e5329)2016.
21. Reginelli A, Urraro F, di Grezia G, Napolitano G, Maggialetti N, Cappabianca S, Brunese L and Squillaci E: Conventional ultrasound integrated with elastosonography and B-flow imaging in the diagnosis of thyroid nodular lesions. Int J Surg. 12 (Suppl 1):S117-S122. 2014.
22. Zhao RN, Zhang B, Yang X, Jiang YX, Lai XJ and Zhang XY: Logistic regression analysis of contrast-enhanced ultrasound and conventional ultrasound characteristics of sub-centimeter thyroid nodules. Ultrasound Med Biol. 41:3102-3108. 2015.
23. Argalia G, De Bernardis S, Mariani D, Abbattista T, Taccaliti A, Ricciardelli L, Faragona S, Gusella PM and Giuseppetti GM: Ultrasonographic contrast agent: Evaluation of time-intensity curves in the characterisation of solitary thyroid nodules. Radiol Med. 103:407-413. 2002.
24. Zhang Y, Luo YK, Zhang MB, Li J, Li J and Tang J: Diagnostic accuracy of contrast-enhanced ultrasound enhancement patterns for thyroid nodules. Med Sci Monit. 22:4755-4764. 2016.
25. Jiang J, Shang X, Zhang H, Ma W, Xu Y, Zhou Q, Gao Y, Yu S and Qi Y: Correlation between maximum intensity and microvessel density for differentiation of malignant from benign thyroid nodules on contrast-enhanced sonography. J Ultrasound Med. 33:1257-1263. 2014.
26. Giusti M, Campomenosi C, Gay S, Massa B, Silvestri E, Monti E and Turtulici G: The use of semi-quantitative ultrasound elastosonography in combination with conventional ultrasonography and contrast-enhanced ultrasonography in the assessment of malignancy risk of thyroid nodules with indeterminate cytology. Thyroid Res. 7(9)2014.
27. Xuehua Xi, Luying Ga, Qiong Wu, Shibao Fang Jingzhu Xu, Ruyu Liu, Xiao Yang, Shenling Zhu, Ruina Zhao, Xingjian Lai, Xiaoyan Zhang, Bo Zhang and Yuxin Jiang. Differentiation of Thyroid Nodules Difficult to Diagnose With Contrast-Enhanced Ultrasonography and Real-Time Elastography. doi.org/10.3389/fonc.2020.00112.
28. Grant EG, Tessler FN, Hoang JK, Langer JE, Beland MD, Berland LL, et al. Thyroid ultrasound reporting lexicon: white paper of the ACR thyroid imaging, reporting and data system (TIRADS) committee. J* Am Coll Radiol. (2015) 12:1272-9. doi: 10.1016/j.jacr.2015.07.011.
29. Frates MC, Benson CB, Doubilet PM, Cibas ES, Marqusee E. Can color doppler sonography aid in the prediction of malignancy of thyroid nodules? J Ultrasound Med. (2003) 22:127-31. doi: 10.7863/jum.2003.22.2.127.
30. Asteria C, Giovanardi A, Pizzocaro A, Cozzaglio L, Morabito A, Somalvico F, et al. US-elastography in the differential diagnosis of benign and malignant thyroid nodules. Thyroid. (2008) 18:523-31. doi: 10.1089/thy.2007.0323.
31. Hegedus L. Clinical practice. The thyroid nodule. N Engl J Med. 2004;351(17):1764-71.
32. Tan GH, Gharib H. Thyroid incidentalomas: management approaches to nonpalpable nodules discovered incidentally on thyroid imaging. Ann Intern Med. 1997;126(3):226-31.
33. Gharib H, Papini E. Thyroid nodules: clinical importance, assessment, and treatment. Endocrinol Metab Clin North Am. 2007;36(3):707-35. vi.
34. Haugen BR, Alexander EK, Bible KC, 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):1-133.
35. Leenhardt L, Hejblum G, Franc B, et al. Indications and limits of ultrasound-guided cytology in the management of nonpalpable thyroid nodules. J Clin Endocrinol Metab. 1999;84(1):24-8.
36. Papini E, Guglielmi R, Bianchini A, et al. Risk of malignancy in nonpalpable thyroid nodules: predictive value of ultrasound and color-Doppler features. J Clin Endocrinol Metab. 2002;87(5):1941-6.
37. Nam-Goong IS, Kim HY, Gong G, et al. Ultrasonography-guided fine-needle aspiration of thyroid incidentaloma: correlation with pathological findings. Clin Endocrinol (Oxf). 2004;60(1):21-8.
38. Cappelli C, Castellano M, Pirola I, et al. The predictive value of ultrasound findings in the management of thyroid nodules. QJM. 2007;100(1):29-35.
39. Frates MC, Benson CB, Doubilet PM, et al. Prevalence and distribution of carcinoma in patients with solitary and multiple thyroid nodules on sonography. J Clin Endocrinol Metab. 2006;91(9):3411-7.
40. Moon WJ, Jung SL, Lee JH, et al. Benign and malignant thyroid nodules: US differentiation-multicenter retrospective study. Radiology. 2008;247(3):762-70.
41. Remonti LR, Kramer CK, Leitao 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):538-50.
42. Brito JP, Gionfriddo MR, Al Nofal A, et al. The accuracy of thyroid nodule ultrasound to predict thyroid cancer: systematic review and meta-analysis. J Clin Endocrinol Metab. 2014;99(4):1253-63.
43. Bonavita JA, Mayo J, Babb J, et al. Pattern recognition of benign nodules at ultrasound of the thyroid: which nodules can be left alone? AJR Am J Roentgenol. 2009;193(1):207-13.
44. Moon WJ, Kwag HJ, Na DG. Are there any specific ultrasound findings of nodular hyperplasia ("leave me alone" lesion) to differentiate it from follicular adenoma? Acta Radiol. 2009;50(4):383-8.
45. URAZBAEV I. et al. DEVELOPMENT OF AGROTECHNICAL METHODS AND APPLICATION OF BIOMELIORANT PLANTS IN THE LOWER AREAS OF AMUDARYA //Journal of Critical Reviews. - 2020. - Т. 7. - №. 11. - С. 1327-1331.
46. Niyazova Z., Khegay L., Rakhmanov A. EVALUATION OF AN IRRITATING AND ALLERGIZING ACTION OF A BIOPELLICLE FOR THE TREATMENT OF PENETRATING EYE INJURIES //Journal of Critical Reviews. - 2020. - Т. 7. - №. 11. - С. 1321-1326.
47. Салахиддинов К. З. и др. Раневые покрытия-как эффективный метод лечения ожоговых ран.
48. Zebiniso N. et al. FEATURES OF PSYCHOLOGICAL REHABILITATION IN PATIENTS WITH EYE INJURIES.
49. Сыдиков А. А. и др. РЕЗУЛЬТАТЫ ПАТОМОРФОЛОГИЧЕСКОЙ ОЦЕНКИ ЭФФЕКТИВНОСТИ ПРИМЕНЕНИЯ ПЛЁНОЧНОГО БИОПОКРЫТИЯ «NOVACEL ZIYO» В ТЕРАПИИ ПРОНИКАЮЩИХ РАНЕНИЙ ГЛАЗ //Re-health journal. - 2020. - №. 3-2 (7).
