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13 Thyroid andParathyroid Glands
Table 13.1 The diagnostic value of CEUS in thyroid cancer
Author Year Sensitivity (%) Specicity (%) PPV (%) NPV (%) Accuracy (%) AUC (95% CI)
Nemec etal. [7] 2010 76.9 84.8 66.7 90.3 82.6 –
Li etal. [8] 2013 82.9 81.4 67.5 88.9 82.6 –
Giusti etal. [17] 2013 68.0 67.0 76.0 – 64.0 –
Pan etal. [37] 2013 86.7 95.8 – – 91.0 –
Cantisani etal. [16] 2013 79.0 91.0 83.0 89.0 – –
Ma etal. [38] 2014 – – – – – 0.910
Deng etal. [10] 2014 82.1 84.9 71.9 91.0 84.0 –
Jiang etal. [11] 2015 89.8 91.8 93.1 91.0 88.0 0.908
(0.847–0.969)
Schleder etal. [39] 2015 81.0 92.0 97.0 63.0 – –
Li etal. [12] 2015 88.0 80.0 – – 85.0 –
Sui etal. [40] 2016 81.8 90.7 93.1 90.7 85.3 0.883 (0.810 ±
0.956)
Prieditis etal. [32] 2016 82.0 57.0 – 70.0 – –
Chen etal. [41] 2016 87.5 86.3 90.3 86.8 82.6 –
Zhang etal. [42] 2017 77.3 93.9 79.5 93.5 90.0 –
Rakitina etal. [29] 2017 94.1 87.5 97.0 77.8 92.8 –
Zhang etal. [13] 2017 97.6 98.7 97.6 98.7 98.3 –
Tian etal. [43] 2018 86.7 91.3 – – – 0.862
(0.813-0.924)
Sencha etal. [24] 2018 64.9 85.0
Xu etal. [44] 2019 85.7 83.3 88.4 79.7 – 0.867
(0.830–0.905)
243
Table 13.2 The diagnostic value of CEUS on the data of meta-analyses
Number
Number
Author Year
Yu etal. [26] 2014 7 597 257 0.853
Sun etal.
[27]
Ma etal. [45] 2015 13 1127 0.900
Liu etal. [28] 2018 33 3808 1840 0.880
of studies
2015 25 1154 424 0.880
of thyroid
lesions
increased vascularization. The authors skipped
the grading and the specication of the UCA distribution. With the accumulation of knowledge,
the descriptive part of the qualitative CEUS has
expanded, but it is more of a recommendation
than a standardized one [47].
Number of
thyroid
malignancies
Overall
sensitivity
(%) (CI)
(0.80–0.89)
(0.85–0.91)
(0.88–0.93)
(0.85–0.91)
Regarding the qualitative characteristics of
CEUS, it is important to note that benign lesions
are characterized by several types of enhancement. Peripheral rim-shaped enhancement is
highly specic for benign lesions [15, 32, 38,
48]. Distinct margins and uniform character of
Overall
specicity
(%) (CI)
0.876
(0.84–0.91)
0.900
(0.88–0.92)
0.860
(0.83–0.89)
0.880
(0.83–0.91)
PPV (%)
(CI)
5.822
(3.51–
9.66)
8.690
(5.76–
13.09)
7.400
(3.63–
15.08)
7.100
(5.2–9.8)
NPV (%)
(CI) AUC
0.195
(0.13–
0.30)
0.150
(0.12–
0.19)
0.160
(0.09–
0.28)
0.130
(0.10–
0.18)
0.916
0.946
0.940
0.940
244
Table 13.3 The diagnostic value of the “heterogeneous enhancement” parameter of CEUS in the diagnosis of thyroid
carcinoma
Author Year Sensitivity (%) Specicity (%) PPV (%) NPV (%) Accuracy (%)
Zhang etal. [15] 2010 88.2 92.5 91.8 89.1 90.4
Ma etal. [38] 2014 90.4 91.0 – – –
Yuan etal. [52] 2015 78.4 85.4 82.9 81.4 –
Deng etal. [53] 2015 73.1 75.3 74.8 –
Wu etal. [19] 2016 50.6 90.7 77.6 74.3 75.1
Prieditis etal. [32] 2016 88.0 34.0 56.0 78.0 62.0
Ma etal. [54] 2017 83.5 82.9 88.0 78.3 83.7
Ballal etal. [48] 2017 92.5 93.2 95.2 88.2 92.4
Zhang etal. [14] 2017 40.5 92.3 73.9 74.2 74.2
Zhao etal. [55] 2018 82.0 74.0 82.0 74.0 78.7
Table 13.4 The diagnostic value of the “hypoenhancement” parameter of CEUS in the diagnosis of thyroid
carcinoma
Author Year Sensitivity (%) Specicity (%) PPV (%) NPV (%) Accuracy (%)
Deng etal. [10] 2013 82.1 84.9 71.9 91.0 84.0
Ma etal. [38] 2014 66.0 82.1 – – –
Yuan etal. [52] 2015 78.4 95.1 93.6 83.0 –
Zhao etal. [18] 2015 97.6 85.7 93.0 94.7 93.5
Deng etal. [53] 2015 73.1 80.2 – – 78.8
Wu etal. [19] 2016 41.6 95.7 86.1 72.0 74.7
Prieditis etal. [32] 2016 82.0 56.0 64.0 77.0 69.0
Ma etal. [54] 2017 78.5 55.4 71.3 64.6 68.9
Ballal etal. [48] 2017 82.4 96.9 97.8 76.8 89.3
Zhang etal. [14] 2017 40.5 92.3 73.9 74.2 74.2
Zhao etal. [55] 2018 56.7 73.3 75.5 53.9 63.5
E. A. Sencha and A. N. Sencha
enhancement are also considered benign features
[29, 40, 49].
Heterogeneous arrival and distribution of
UCA in the lesion along with its hypoenhancement are specic qualitative characteristics for
thyroid carcinoma [18, 32, 41, 42, 48, 50, 51].
The diagnostic values of these qualitative parameters range in various studies and are presented in
Tables 13.3 and 13.4.
Additional qualitative features of malignant
lesions are irregular shape and indistinct boundaries of contrast enhancement [49, 50, 52, 54].
In recent studies, modern statistical analysis
methods, such as ROC analysis [30, 38, 40, 43,
44, 53, 56], and construction of multimodal diag-
nostic models [31, 50, 54, 55] have been used for
more effective evaluation of diagnostic parameters and prognosis.
Our study demonstrated a reliable difference
in the uniformity of enhancement and UCA
washout rate between the groups of malignant
and benign thyroid masses [24]. Pseudonodules
in autoimmune thyroid demonstrate uniform contrast enhancement and the UCA wash-in rate
comparable to the surrounding thyroid parenchyma. It distinguishes autoimmune thyroid disease from all other groups and permits using the
qualitative CEUS data for the differential diagnosis (Fig.13.2).
The combined group of thyroid malignancies
demonstrates a fast wash-out rate, which differentiates it from the group of benign lesions.
However, binary logistic regression with ROC
curves construction in the groups of benign and
malignant thyroid masses demonstrates a low
diagnostic value of individual qualitative
enhancement parameters (Figs.13.3, 13.4, 13.5,
and 13.6, Video 13.1).
Quantitative perfusion analysis software uses
raw data to construct time-intensity curves (TIC),
13 Thyroid andParathyroid Glands
a
245
b
Fig. 13.2 Autoimmune thyroid disease with pseudonodules. (a) Grayscale and color Doppler image (b). The arterial
phase CEUS image. The thyroid lesion and parenchyma exhibit identical homogeneous hyperenhancement
246
E. A. Sencha and A. N. Sencha
a
b
Fig. 13.3 Thyroid carcinoma. Irregular contrast enhancement of the lesion. CEUS images. (a) The arterial phase. (b)
The venous phase
13 Thyroid andParathyroid Glands
a
247
b
Fig. 13.4 Follicular thyroid adenoma. CEUS images. (a)
The arterial phase. The lesion demonstrates clear boundaries, hyperenhancement with fast wash-in. (b) The
venous phase. The wash-out rate of the lesion and the surrounding parenchyma is identical
248
E. A. Sencha and A. N. Sencha
a
b
Fig. 13.5 Complex cystic lesion, thyroid carcinoma. CEUS images. (a) The arterial phase. (b) The venous phase
13 Thyroid andParathyroid Glands
a
249
b
Fig. 13.6 Simple thyroid cyst with a single nonenhancing septum. (a) CEUS image. The early venous phase. (b)
Quantitative analysis demonstrates the perfusion defect in
the uid component (pink ROI). The enhancement of the
thyroid parenchyma is supplied for reference (yellow
ROI)
250
E. A. Sencha and A. N. Sencha
permits more accurate and objective estimation
of enhancement data, and increases intra- and
interobserver agreement [20, 26, 31, 47, 51].
Many authors note that dynamic CEUS with
subsequent TIC analysis enables a better understanding of the pathophysiology of neoangiogenesis in various thyroid pathologies and expands
the prospects of the method in the differential
diagnosis of thyroid lesions [9, 33, 51, 57–60].
TIC analysis is reported as efcient in oncology
for objective evaluation of the tumor response to
treatment [33].
The technology of three-dimensional visualization of CEUS with the algorithms for assessing the spatial location of small blood vessels in
thyroid lesions is not widely available. It is analyzed in individual publications [46, 61], which
point to its prospects for the differential
diagnosis.
Although TIC analysis in thyroidology
became popular over the past 5 years, the data of
publications are still contradictory.
The rst attempts to differentiate between carcinoma and follicular adenoma based on TIC
characteristics were made by Spiezia et al. [1]
with the rst-generation UCA Levovist.
Malignant thyroid lesion, as compared with colloid nodule and adenoma, demonstrated earlier
contrast enhancement (8.1 ± 1.4 s vs. 19.6 ± 2.2
s, and 16.1 ± 2.8 s, respectively). However, there
were no reliable differences in the initial, peak,
and nal contrast intensity between benign and
malignant lesions.
The subsequent study by Argalia etal. [2] was
limited to a visual assessment of the UCA kinetic
without determining quantitative parameters.
Most of the thyroid lesions were hyperenhancing.
All nodules exhibited similar rapid distribution of
UCA.However, most benign lesions had uniform
monophase TIC, while thyroid carcinoma was
characterized by an uneven polyphasic curve.
The rst to provide quantitative parameters of
perfusion was Bartolotta etal. [5]. Levovist exposure was calculated in certain time intervals for
normal thyroid parenchyma and thyroid nodules.
Based on the obtained overlapping results of the
peak intensities of the studied lesions, the authors
concluded that the method is not applicable for
differential diagnosis in thyroid masses.
Similar contradictory data were obtained in
the studies with the second-generation UCAs
[14, 49]. The authors noted that time to peak
(TTP) enhancement and wash-out time do not
reliably differ in benign and malignant thyroid
masses and suggested that there are no specic
contrast enhancement features in thyroid lesions.
The study [7] presented a detailed quantitative
analysis in thyroid CEUS.In addition to such values of benign and malignant lesions as the peak
intensity (21.1± 4.0 dB and 22.8 ± 4.1 dB, respectively) and TTP (22.0 ± 6.9 s and 27.3 ± 11.1 s,
respectively), the ratio of absolute intensity to
base intensity in different time intervals of the
TIC was estimated. The last parameter demonstrated good diagnostic value. The test “intensity
ratio >2.35in 20 s after peak intensity—thyroid
carcinoma” demonstrated the sensitivity of
76.9% and accuracy of 82.6%.
CEUS quantication indices were also studied
[17]. The area under the curve for the peak
intensity index was 0.830, for the TTP intensity
index 0.860. In malignant lesions, peak intensity
index <0.99 demonstrated the sensitivity of
37.7% and specicity of 75.5%; TTP intensity
index >0.98–56.6% and 75.5%, respectively.
The study [11] considered maximum peak
intensity and TTP intensity. In papillary cancer,
the maximum peak intensity value was 84 ± 9
units and TTP intensity 17 ± 1 s and in benign
tumors 121 ± 17 and 14 ± 1 s, respectively.
However, the difference was statistically signicant only in the maximum peak intensity value
parameter (p < 0.05). In another study, the authors
report a statistically signicant difference in the
peak intensity values between malignant and
benign lesions (41.40 ± 14.10% and 85.58 ±
10.76, respectively) [30]. The area under the
curve was 0.908 ± 0.031 (95%CI 0.847–0.969).
The study [59] demonstrated that thyroid carcinomas (N = 20) had complete wash-out in the
late phase, which was not typical for benign
lesions and registered in 10% of adenomas. The
authors noted one enhancement feature. The TTP
enhancement between the central aspects of carcinoma and the surrounding parenchyma was different (p < 0.05), as well as TTP enhancement
between the borderline zone and the surrounding
tissues (p = 0.01). CEUS with TIC analysis per-
13 Thyroid andParathyroid Glands
251
mitted dynamic assessment of the thyroid microvascularization, which is useful for the
differentiation of benign and malignant nodules.
Relative values of perfusion for malignant
lesions are different from benign lesions [60].
Carcinomas are characterized by low relative
peak intensity, later relative rise time and TTP,
gentler maximum slope coefcient of wash-in,
and smaller area under the rising and falling
curves, earlier relative mean transit time (MTT).
Low values of the maximum peak intensity
were reported for malignant neoplasms as compared with benign lesions (42 ± 4.8 vs. 54 ± 5.4,
respectively) with no reliable difference in TTP
(19.21 ± 1.3 s vs. 17.77 ± 6.6, respectively) [48].
The quantitative parameter “peak intensity”
and the qualitative characteristic “enhancement
pattern” are reliably different between the groups
of malignant and benign thyroid lesions [18]. The
sensitivity, specicity, PPV, NPV, and accuracy
of heterogeneous enhancement were 97.6%,
85.7%, 93.0%, 94.7%, and 93.5%, respectively.
The sensitivity, specicity, PPV, NPV, and accuracy of low intensity at peak time were 85.4%,
52.4%, 77.8%, 64.7%, and 74.2%, respectively.
In our study, we obtained reliable differences
between benign and malignant lesions in the values of the peak intensity of the nodule and parenchyma, DT/2 of the nodule, DT/2 index,
descending velocity (DV) of the nodule, DV
index, DV difference (p < 0.05). The most valuable for the diagnosis of thyroid cancer were the
DT/2 index, DV index, and DV difference. The
test “DT/2 index >1.028—thyroid cancer” was
characterized by the sensitivity of 86.1%, the
specicity of 85.2%, PPV of 87.7%, NPV of
83.4%, and AUC of 0.872. The test “DV index
≤0.895—thyroid cancer” was characterized by
the sensitivity of 66.7%, the specicity of 95.1%,
PPV of 94.3%, NPV of 70.0%, and AUC of
0.840. The test “DV difference ≤-0.020 dB/s—
thyroid cancer” exhibited the sensitivity of
66.7%, specicity of 95.1%, PPV of 94.3%, NPV
of 70.0%, and AUC of 0.842 (Figs. 13.7 and
13.8).
CEUS is a promising non-invasive method for
the differential diagnosis of benign and malignant thyroid nodules and may complement neneedle aspiration biopsy. Quantitative analysis of
enhancement can help to improve the specicity
and accuracy of sonography [62–64]. Thyroid
CEUS is benecial in the nodules with calcication and exhibits the sensitivity of 90%, the specicity of 92%, PPV of 88%, NPV of 93%, and
accuracy of 91%, as compared to standard sonography (the sensitivity of 50%, the specicity of
77%, PPV of 59%, NPV of 69%, and accuracy of
66%) [30].
For parathyroid gland abnormalities, CEUS is
a new method, which depicts perfusion.
It is thought to improve the differential diagnosis of the diseases of the parathyroid glands
and other neck organs. It may appear especially
valuable in parathyroid lesions or hyperplasia,
which appear avascular with CDI and PDI and
demand differentiation from the thyroid lesions
and other neck masses [65]. CEUS can be proposed in selected patients in whom unenhanced
color Doppler provides uncertain ndings. The
contrast agent helps in visualizing typical signs
of the parathyroid lesions, such as “vascular
pole” and “mixed pattern.”
The lesions of parathyroid glands exhibit different contrast enhancement patterns. Their
enhancement intensity is usually compared with
the normal thyroid parenchyma. Parathyroid adenoma often demonstrates hyperenhancement,
while normal parathyroid glands, if identied,
are hypoenhanced (Fig.13.9).
However, the fact of increased perfusion of a
parathyroid lesion as compared with other masses
is remarkable. Further determination of the vascular pattern in parathyroid hyperplasia or adenoma does not inuence the conclusion and
further management (Figs. 13.10 and 13.11,
Video 13.2).
CEUS permits differentiation of parathyroid
adenoma in 99% of cases, as compared with 70%
with conventional echography [66]. The sensitivity of the method in the differentiation of abnormal parathyroid glands is 89.3–98.4% [64, 65,
67]. CEUS is also benecial for the differentia-
tion of abnormal parathyroid glands in concomitant thyroid nodules, after thyroid surgery, and in
neck tumors [60, 61, 63]. Parathyroid adenoma is
characterized by the time of complete washout of
30–60 s as opposed to the same of thyroid nodules of 120–180 s [66].
252
E. A. Sencha and A. N. Sencha
a
b
Fig. 13.7 Follicular thyroid carcinoma. (a) CEUS image in the venous phase. (b) The analysis of quantitative charac-
teristics of contrast enhancement. TICs for carcinoma (pink ROI) and intact thyroid parenchyma (yellow ROI)