Differential Diagnosis of Thyroid Nodules by Elastography

In This Article

Abstract and Introduction

Abstract

Background: Fine needle aspiration is the gold standard for differential diagnosis of thyroid nodules; however, the malignancy rate for indeterminate cytology is 20% to 50%.

Objective: We evaluated the efficacy of shear wave elastography added to ultrasonography for differential diagnosis of thyroid nodules.

Methods: We retrospectively reviewed the medical records of 258 consecutive patients. Thyroid nodules were divided into 4 categories according to maximum elasticity (E_Max) and nodule depth/width (D/W) ratio: Category 1 (E_Max ≥ 42.6 kPa; D/W < 0.9); Category 2 (E_Max < 42.6 kPa; D/W < 0.9); Category 3 (E_Max ≥ 42.6 kPa; D/W ≥ 0.9); and Category 4 (E_Max < 42.6 kPa; D/W ≥ 0.9). The E_Max cutoff value was set using receiver operating characteristic (ROC) curve analysis to predict nodular hyperplasia (NH) vs follicular neoplasm (FN). Cutoff value for nodule D/W ratio was set using ROC curve analysis for malignancy.

Results: NH was the most prevalent pathology group in Category 1, FN in Category 2, and papillary thyroid carcinoma in Category 3. Category 3 demonstrated the highest rate of malignancy (81.8%) and had 55.4% sensitivity and 90% specificity for predicting malignancy. When assessing the benign pathology of NH in follicular patterned lesion, Category 1 demonstrated the highest NH prevalence of 88.9% (34/37) and had 73.9% sensitivity and 85.0% specificity.

Conclusion: The performance for malignancy was highest in Category 3 and predictive ability for benign pathology of NH in follicular lesion was highest in Category 1. The information of E_Max and nodule D/W ratio was useful to predict the pathology of thyroid nodules.

Introduction

Thyroid nodule is a common disease that is found in up to 60% of the population on ultrasound (USG) examination^[1,2] and its malignancy rate is 5% to 15%.^[3] Fine needle aspiration (FNA) is the first step in differentiating malignant thyroid nodules. Papillary thyroid carcinoma (PTC), which accounts for 80% to 90% of thyroid cancer, has several characteristic findings on USG and FNA,^[4–6] which allows for an accurate diagnosis. On the other hand, differential diagnosis of follicular patterned lesions, including nodular hyperplasia (NH), follicular adenoma (FA), follicular thyroid carcinoma (FTC), and follicular variant papillary carcinoma (FVPTC), is challenging because of the lack of distinguishing and overlapping features on FNA^[7–9] and USG.^[10,11]

According to the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) classification^[3] and the 2015 American Thyroid Association guidelines^[12] for thyroid nodules in the indeterminate FNA including category III (atypia or follicular lesion of undetermined significance) and category IV (follicular neoplasm or suspicious for follicular neoplasm), diagnostic surgery (lobectomy) is recommended. The malignancy rate of thyroid nodules of indeterminate category has been reported to be in the range of 20% to 50%, resulting in 50% to 80% of patients with unnecessary diagnostic surgery.^{[3,7,8,13–18]} Therefore, additional tools are needed for the further differential diagnosis of thyroid nodules.

USG elastography has been reported to be useful in differentiating benign and malignant thyroid nodules.^[19–23] Strain elastography was initially developed for this purpose but had high operator dependence in terms of compression and absence of sufficient quantitative information.^[24,25] Shear wave elastography (SWE) has sufficient quantitative information and is operator-independent in terms of compression, so SWE is more reproducible than strain elastography, and 2-dimensional SWE (2D-SWE) illustrates the focal tissue stiffness map.^[26,27] Thyroid nodules usually show heterogeneous images of elasticity index (EI) within the nodule on 2D-SWE, so the selection of a different location for the region of interest (ROI) within a nodule displays different EI.^[26,28] Recently, we reported that the EI in the total nodular ROI showed higher reproducibility and better agreement in intra- and interrater assay than in the focal nodular ROI, possibly due to the avoidance of the subjective variance of ROI placement in the focal nodular area.^[29] In addition, our study showed that EI correlates with the degree of fibrosis, and that the location of fibrosis of surgical pathology is concordant with high EI area on SWE.^[29]

We aimed to evaluate the efficacy of SWE in the differential diagnosis of follicular patterned lesions, which are the most frequently found entities, comprising more than 50% of FNA.^[1,6] The rate of malignancy of indeterminate follicular lesion (category IV) in diagnostic surgery is 20% to 50%,^{[3,7,8,13–18]} resulting in unnecessary diagnostic surgery for 50% to 80% of cases. Additionally, 30% to 50% of benign diagnostic surgery was revealed to be NH.^[14,30] Pathologically, NH shows focal nonneoplastic hyperplasia and subsequent involutional changes accompanied by various degenerative changes, including hemorrhage, infiltration of inflammatory cells, and fibrotic change with incomplete capsule formation,^[4,31] while FA is composed of neoplastic cells completely encapsulated and typically shows scanty interstitial tissue^[5] and is devoid of degenerative changes.^[32] Therefore, the degree and quantity of fibrosis is usually larger in NH than in FA.

A recent application of SWE showed that it was useful in the evaluation of fibrosis, especially in the evaluation of chronic liver disease and liver cirrhosis.^[33] Thus, we studied the diagnostic performance of SWE to differentiate follicular neoplasm (FN) from NH in follicular lesions of thyroid nodules.^[34] We analyzed the magnitude of EI; the E_Max, E_Mean, and E_SD were significantly lower in the FN than in the NH group (P < 0.001).^[34]

Our previous study suggested that SWE of thyroid nodules seemed to reflect the degree of fibrosis. Here, we aimed to evaluate the SWE EI in various pathology groups of thyroid nodules and further assessed whether SWE might provide further information when added to the result of B mode USG, especially nodule depth/width (D/W) ratio. We analyzed the patterns of EI and nodule D/W ratio in various pathology groups and evaluated whether SWE might be useful for predicting the histopathology of thyroid nodules.

Table 1. Elasticity index (kPa) on shear wave elastography according to the thyroid nodule pathology
Pathology	E_Mean	E_Min	E_Max	E_SD
FN (n = 27)	17.2 (13.7, 20.6)	3.6 (1.5, 8.2)	31.5 (28.8, 37.1)	5.6 (3.7, 6.1)
NH (n = 57)	29.5 (23.5, 38.0)	8.9 (2.0, 14.2)	61.7 (47.8, 82.9)	9.6 (7.5, 13.1)
CLT (n = 18)	28.6 (22.7, 45.2)	7.9 (1.8, 20.0)	52.0 (42.0, 76.5)	8.2 (6.0, 14.8)
ST (n = 5)	78.4 (59.0, 89.6)	4.4 (1.5, 5.1)	245.3 (202.1, 249.5)	39.3 (38.2, 56.4)
PTC (n = 70)	37.3 (26.6, 59.3)	15.5 (2.7, 28.9)	67.4 (45.3, 103.9)	11.2 (6.3, 19.2)
FVPTC (n = 2)	22.0 (14.1, 29.8)	11.1 (4.0, 18.2)	39.9 (35.8, 43.9)	NA
FA (n = 7)	14.0 (12.4, 15.5)	1.1 (0.8, 6.2)	32.0 (26.9, 39.5)	6.0 (4.8, 7.5)
HCA (n = 4)	10.7 (8.7, 16.0)	1.6 (0.4, 5.3)	28.6 (25.1, 31.2)	3.8 (3.1, 5.1)
FTC (n = 4)	17.9 (13.8, 19.7)	2.6 (2.5, 8.3)	30.0 (26.4, 31.1)	4.9 (3.6, 5.0)
MTC (n = 3)	25.6 (19.0, 26.0)	3.1 (1.6, 8.3)	63.2 (50.6, 65.8)	8.9 (8.8, 10.7)

Data are presented as median and interquartile range; 25th and 75th percentiles.
Abbreviations: CLT, chronic lymphocytic thyroiditis; E_Max, maximum elasticity; E_Mean, mean elasticity; E_Min, minimum elasticity; E_SD, 1 standard deviation of elastographic values; FA, follicular adenoma; FN, follicular neoplasm; FTC, follicular thyroid carcinoma; FVPTC, follicular variant of papillary thyroid carcinoma; HCA, Hürthle cell adenoma; NH, nodular hyperplasia; MTC, medullary thyroid carcinoma; PTC, papillary thyroid carcinoma; ST, subacute thyroiditis.

Table 2. Distribution of the pathology groups according to the categories defined by E _Max and nodule depth/width ratio (D/W) of the thyroid nodules
	Category 1	Category 2	Category 3	Category 4
	E_Max ≥ 42.6 kPa & D/W < 0.9	E_Max < 42.6 kPa & D/W < 0.9	E_Max ≥ 42.6 kPa & D/W ≥ 0.9	E_Max < 42.6 kPa & D/W ≥ 0.9
CLT	8 (13.11%)	3 (10.34%)	3 (6.82%)	0 (0%)
FN	3 (4.92%)	14 (48.28%)	0 (0%)	3 (27.27%)
NH	34 (55.74%)	5 (17.24%)	5 (11.36%)	2 (18.18%)
PTC	14 (22.95%)	3 (10.34%)	33 (75%)	6 (54.55%)
Non-PTC	2 (3.28%)	4 (13.79%)	3 (6.82%)	0 (0%)
Total	61(100%)	29 (100%)	44(100%)	11 (100%)

Data are presented as numbers (percentages). Distribution patterns of the pathology groups in the 4 categories showed statistically significant difference between Category 1 vs 2, Category 1 vs 3, and Category 2 vs 3 by Fisher's exact test (P < 0.001).
Abbreviations: E_Max, maximum elasticity; FN, follicular neoplasm; NH, nodular hyperplasia; CLT, chronic lymphocytic thyroiditis; PTC, papillary thyroid carcinoma; non-PTC nonconventional papillary thyroid carcinoma including follicular variant of papillary thyroid carcinoma (n = 2), follicular thyroid carcinoma (n = 4), and medullary thyroid carcinoma (n = 3).

Table 3. Predictive ability of each category defined by E _Max (42.6 kPa) and D/W ratio (0.9) for malignancy
	Malignancy (%)	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)
Category 1 (E_Max ≥ 42.6 kPa & D/W < 0.9)	26.2 [16/61]	24.6 (14.7–36.9)	43.8 (32.7–55.3)	26.2 (15.8–39.1)	41.7 (31.0–52.9)
Category 2 (E_Max < 42.6 kPa & D/W < 0.9)	24.1 [7/29]	10.8 (4.4–20.9)	72.5 (61.4–81.9)	24.1 (10.3–43.5)	50.0 (40.6–59.4)
Category 3 (E_Max ≥ 42.6 kPa & D/W ≥ 0.9)	81.8 [36/44]	55.4 (42.5–67.7)	90.0 (81.2–95.6)	81.2 (67.3–91.8)	71.3 (61.4–80.0)
Category 4 (E_Max < 42.6 kPa & D/W ≥ 0.9)	54.5 [6/11]	9.2 (3.46–19.0)	93.8 (86.0–97.9)	54.6 (23.4–83.3)	56.0 (47.2–64.5)

Numbers in parentheses are 95% CIs and numbers in brackets are the data used to calculate percentages.
Abbreviations: D/W, nodule depth/width; E_Max, maximum elasticity; NPV, negative predictive value; PPV, positive predictive value.

Table 4. Performance of E _Max (42.6 kPa) and D/W ratio (0.9) for differentiating nodular hyperplasia from follicular neoplasm in follicular patterned lesions by fine needle aspiration cytology
	NH	FN	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)
Category 1 (E_Max ≥ 42.6 kPa & D/W < 0.9)	34	3	73.9 (58.9–85.7)	85.0 (62.1–96.8)	91.9 (78.1–98.3)	58.6 (38.9–76.5)
Category 2 (E_Max < 42.6 kPa & D/W < 0.9)	5	14	10.9 (3.6–23.6)	30.0 (11.9–54.3)	26.3 (9.2–5.1)	12.8 (4.8–25.7)
Category 3 (E_Max ≥ 42.6 kPa & D/W ≥ 0.9)	5	0	10.9 (3.6–23.6)	100 (83.2–100)	100 (47.8–100)	32.8 (21.3–46.0)
Category 4 (E_Max < 42.6 kPa & D/W ≥ 0.9)	2	3	4.4 (0.5–14.8)	85.0 (62.1–96.8)	40.0 (5.3–85.3)	27.9 (17.2–40.8)

Numbers in parentheses are 95% CIs.
Abbreviations: D/W, nodule depth/width; E_Max, maximum elasticity; FN, follicular neoplasm; NH, nodular hyperplasia; NPV, negative predictive value; PPV, positive predictive value.