Shear Wave Elastography in the Diagnosis of Thyroid Nodules: Feasibility in the Case of Coexistent Chronic Autoimmune Hashimoto's Thyroiditis.

SUMMARY

 Objective ShearWave™ Elastography (SWE) is real-time, quantitative and user-independent technique, recently introduced in the diagnostic work-up of thyroid nodules. Hashimoto’s thyroiditis (HT), characterized by variable degrees of lymphocytic infiltration and fibrosis, might affect shear wave propagation. The aim of this study was to assess the feasibility of SWE in cytologically benign thyroid nodules within both Hashimoto’s and nonautoimmune thyroid glands. The effect of autoimmunity on the gland stiffness was also evaluated.

 Design longitudinal study in a single centre.

 Patients SWE was performed in 75 patients with a benign thyroid nodule at cytology: 33 with Hashimoto’s thyroiditis (HT group) and 42 with uni- or multi-nodular goitre, negative for thyroid autoimmunity (non-HT group).

 Results The elasticity index (EI) of the extra-nodular tissue was greater, though not statistically significant, in the HT than in the non-HT group (24·0 ± 10·5 kPa vs 20·8 ± 10·4 kPa; P = 0·206). However, the EI of extra-nodular tissue was related to the TPOAb titre in the HT group (P = 0·02) and was significantly higher in patients with HT receiving L-thyroxine than in the euthyroid subjects (P = 0·02). The EI of thyroid nodules was similar in HT and non-HT groups. In both groups, the stiffness of nodules was significantly higher than that of the embedding tissue.

 Conclusions Our data indicate that SWE correctly defines the elasticity of thyroid nodules independently from the coexistence of autoimmune thyroiditis, always being able to differentiate nodular tissue from the surrounding parenchyma. In HT, the stiffness of extra-nodular tissue increases in relation to both the thyroid antibody titre and the degree of impairment of thyroid function.

BÀN LUẬN

Dữ liệu của chúng tôi  cho thấy kỹ thuật sử dụng siêu âm đàn hồi sóng biến dạng [shear wave elastograpphy, SWE] này có thể  xác định một cách chính xác độ đàn hồi của các hạt giáp, độc lập với nền  tuyến giáp cứng như trong viêm giáp Hashimoto (HT). Một gradient độ cứng đã được quan sát thấy trong tất cả các bệnh nhân, với các hạt giáp là cứng hơn đáng kể  so với các mô xung quanh, cả trong HT và trong các nhóm không-HT.

Viêm giáp tự miễn mạn tính HT tự nó [per se]  và độ nặng của nó, theo đánh giá của hiệu giá TPOAb và cần có  liệu pháp thay thế với L-T4 cho suy giáp, làm tăng thêm chỉ số đàn hồi [elastic index, EI] nhu mô quanh hạt. Tuy nhiên, ngay cả trong viêm giáp Hashimoto, một gradient độ đàn hồi đáng kể được duy trì giữa các hạt lành tính và mô-ngoài-hạt, chỉ số EI của hạt luôn lớn hơn so với nhu mô tuyến giáp mà hạt nhúng vào. Trong chấp nhận và thống nhất với phát hiện này, thấy có  quan hệ trực tiếp giữa các chỉ số đàn hồi EI của mô quanh hạt  và chỉ số EI các hạt lành tính ở viêm giáp Hashimoto.

Siêu âm đàn hồi sóng biến dạng SWE là một công cụ mạnh mẽ cho việc chẩn đoán các hạt giáp ác tính, chỉ số EI của hạt ác tính cao hơn đáng kể so với hạt lành tính.Theo chúng tôi biết, đây là nghiên cứu  khảo sát đầu tiên ảnh hưởng của viêm giáp HT  trên tính năng đàn hồi hạt giáp. Cũng được biết rõ rằng viêm giáp tự miễn mạn tính HT, được đặc trưng bằng thâm nhiễm tế bào lympho  và xơ hóa, làm thay đổi siêu cấu trúc [ultrastructure] tuyến giáp  gây cứng mô tuyến. Trong bệnh to cực [acromegaly], một nguyên do đặc trưng khác gây  xơ hóa  tuyến giáp, siêu âm đàn hồi đã cho thấy là không ích lợi  trong việc dự đoán tính chất ác tính của các hạt giáp. Điều này do bệnh nhân bệnh to cực dường như có một tỷ lệ  hạt cứng lớn hơn, nhưng không phải ác tính trên mô bệnh học. Ở những bệnh nhân này, xơ hóa và kết quả là độ cứng có thể do tăng tổng hợp collagen và lắng đọng gây ra bởi GH và IGF1.  Mặc dù hạn chế bởi loạt bệnh nhân của chúng tôi không nhiêu, những phát hiện của nghiên cứu này cho thấy viêm giáp tự miễn mạn tính HT không làm giảm khả năng siêu âm đàn hồi  sóng biến dạng trong  đánh giá các hạt giáp ở viêm giáp tự miễn mạn tính HT.

Điều này có liên quan đặc biệt bởi vì: (i) HT ảnh hưởng đến ít nhất 5% dân số nói chung,  (ii) bệnh nhân với HT có nhiều khả năng để phát triển các hạt giáp, do, ít nhất là một phần, từ kích thích TSH mãn tính;  (iii) một số nghiên cứu cho thấy mối liên quan giữa HT và ung thư tuyến giáp loại nhú [papillary carcinoma];  và (iv) một tỷ lệ cao  các kết quả  FNAC đáng ngờ hoặc không xác định được báo cáo khi kiểm tra hạt trong viêm giáp tự miễn Hashimoto.  Theo quan điểm này, việc xác định độ đàn hồi chính xác trở nên quan trọng trong quy trình  chẩn đoán các  hạt trong viêm giáp tự miễn  Hashimoto.

Để  kết luận, dữ liệu của chúng tôi cho thấy siêu âm đàn hồi sóng biến dạng SWE xác định  chính xác độ đàn hồi của các hạt giáp độc lập với viêm tuyến giáp tự miễn mạn tính cùng tồn tại, luôn  có khả năng phân biệt mô hạt từ nhu mô xung quanh. Trong viêm giáp  HT, độ cứng  mô ngoài hạt tăng thêm  trong tương quan cả hiệu giá kháng thể tuyến giáp  [thyroid antibody] lẫn mức độ suy giảm chức năng tuyến giáp, cao hơn ở những bệnh nhân đòi hỏi phải điều trị  L-thyroxine.

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INTRODUCTION

Elastography is an evolving technique aimed at differentiating benign from malignant thyroid nodules. This technique allows in vivo estimation of the tissue mechanical properties using a conventional ultrasound (US) system with modified software. Similarly to palpation, the rationale of elastography is that a cancerous nodule is stiffer, with less elastic deformation compared with the surrounding thyroid tissue or a benign thyroid nodule. This issue is of particular interest because thyroid nodules are commonly encountered in clinical practice, being detected by US in 19–67% of randomly selected individuals.^1,2 As only a minority of these are malignant (5–15%^3,4), selecting the malignant ones for thyroid surgery represents a major clinical issue.

Elastosonography, and in particular real-time US-elastography (US-E), was recently investigated as a tool for stratifying the presurgical risk of malignancy in nodules with indeterminate or nondiagnostic cytology.⁵ Rago et al.⁶ evaluated tissue stiffness by US-E in a large group of patients with thyroid nodules who underwent surgery for compressive symptoms or suspicion of malignancy at fine-needle aspiration cytology (FNAC). US-E displayed a sensitivity of 97%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 98%, independently from nodule size. Recently, the same approach was applied to patients bearing nodules with indeterminate or nondiagnostic cytology, confirming the association of nodular stiffness with malignancy.⁶ Although promising, static US-E is biased by several factors, such as poor reproducibility, inter-observer variability and lack of quantitative information.^7–9 Furthermore, US-E was mainly evaluated in highly selected patients, excluding those with cystic nodules and nodules with eggshell calcification.^10,11 As the estimation of elasticity is altered by the presence of a nearby hard area, this technique is not reliable in the study of multi-nodular goitres, which represent about 40% of all nodular thyroid glands.¹²

Shear Wave™ Elastography (SWE) is a new real-time imaging modality, which uses a linear US transducer operated with no added pressure. Transient pulses are used to generate propagating shear waves in the body, and elasticity is directly calculated by measuring the wave propagation speed. Currently, SWE is the only technique producing real-time quantitative information on selected areas of thyroid tissue.¹³ It is also claimed to be relatively operator-independent and reproducible. Sebag et al.¹⁴ investigated the efficiency of this technique in predicting malignancy in solitary or multiple thyroid nodules. Using a cut-off level of 65 kPa of elasticity index (EI), they could predict malignancy with a sensitivity of 85·2%, a specificity of 93·9% and a positive predictive value of 92·3%. However, the accuracy of SWE might be impaired in patients with acromegaly, in whom GH/IGF I-induced fibrosis has been reported to increase nodule hardness, as assessed by US-E, independently from the malignant nature of the lesion.¹⁵ A more common, potentially confounding condition, yet to be evaluated, is chronic autoimmune Hashimoto’s thyroiditis (HT) coexistent with thyroid nodules. At histology, HT is characterized by lymphocytic infiltration of the thyroid parenchyma associated with variable degrees of fibrosis. The characteristic US pattern of Hashimoto’s glands consists of an array of tiny hypoechoic nodules that may become confluent, interspersed with echogenic fibrous bands. These pathological changes might affect shear wave propagation, thus hampering the diagnostic potential of SWE in thyroid nodules. This issue is of particular interest for two reasons. First, an increased prevalence of thyroid cancer has been reported in patients with HT.^16,17 Second, the diagnostic accuracy of FNAC may be diminished in nodules within a Hashimoto’s gland, resulting in a higher rate of indeterminate or suspicious cytological reports.¹⁸

To answer the question of whether SWE might be feasible in nodules associated with HT, we investigated a series of benign thyroid nodules at cytology, which were harboured either within a Hashimoto’s gland or within a nonautoimmune thyroid.

PATIENTS and METHODS

Patients

The study enrolled 33 patients with HT harbouring one or more thyroid nodules (HT group) and 42 patients with uni-nodular or multi-nodular goitre, who had tested negative for thyroid antibodies and had a normal echo pattern at US (non-HT group).¹⁹ Inclusion criteria were a previous FNAC indicating that the nodule was benign and the absence of a dominant cystic component within the nodule.

The diagnosis of HT was made in the presence of a positive test for thyroglobulin antibody (TgAb) and/or thyroid peroxidase (TPOAb) antibody, and a hypoechoic pattern of the thyroid at US. Fifty-four patients were euthyroid without therapy, and 14, all of them belonging to the HT group, were euthyroid on L-thyroxine (L-T4) therapy. In patients with HT, the indication of LT4 treatment was a diagnosis of subclinical or overt hypothyroidism. Another seven patients, all with nodular goitre, were on L-T4 TSH-suppressive treatment. In patients in L-T4 replacement therapy and L-T4 TSH-suppressive therapy, the duration of L-T4 treatment ranged from 12 to 156 months (median 36·0 months).

All patients gave their informed consent to participate in the study.

Cytopathological diagnosis

Selection of nodules for FNAC was made according to the current guidelines.^20,21 FNAC was performed, under US guidance, by a skilled endocrinologist using a 23-gauge needle attached to a 5-ml syringe.

Shear Wave Elastography

After a preliminary US evaluation and a cytological diagnosis of a benign lesion, thyroid nodules were evaluated by SWE. Briefly, SWE generates a remote radiation force by focused ultrasonic beams, a patented technology called ‘Sonic Touch’. Several of these so-called pushing beams at increasing depths are transmitted to generate a quasi-plane shear wave frame that propagates throughout the whole imaging area. Then, an ultrafast echographic imaging sequence (Ultrafast Imaging System) is performed to acquire successive raw radiofrequency dots at a very high frame rate (up to 20,000 frames per second). From shear wave propagation speed, tissue elasticity can be derived based on Young’s modulus formula (E = σ/ε, where σ is stress and ε is strain). This results in a colour-coded image, blue representing softer tissue and red stiffer tissue. Quantitative information is delivered as EI expressed in kilo-Pascal (kPa).

Shear wave elastographic measurement was performed with the Aixplorer, developed by SuperSonic Imagine (Les Jardins de la Duranne, Aix en Provence, France).

RESULTS

Patients in the HT and non-HT groups were matched for age (Table 1). The calcitonin concentration was in the normal range in all patients, confirming the benign nature of the nodule.

Conventional US

Table 1 summarizes the main US features of evaluated nodules. In the HT group, the volumes of the thyroid and of the nodules were significantly lower than in the non-HT group. The main US features, which may suggest malignancy, such as hypoechogenicity, microcalcifications, absence of halo and increased vascularization were equally distributed in the HT and non-HT glands.

Shear Wave Elastography

 Effect of chronic autoimmune thyroiditis on the elasticity of extra-nodular thyroid parenchyma. The mean (±SD) EI of the extra-nodular tissue was higher in the HT than in the non-HT group, but the difference did not reach statistical significance (24·0 ± 10·5 kPa vs 20·8 ± 10·4 kPa; P = 0·2; Fig. 1). However, the severity of chronic autoimmune thyroiditis significantly affected the elasticity of extra-nodular thyroid parenchyma, as assessed by a significant direct relationship between the EI of extra-nodular tissue and the serum titre of TPOAb (P = 0·02). Moreover, the mean EI of the extra-nodular tissue was significantly higher in the 14 patients with HT who were on L-T4 substitution for hypothyroidism as compared with the 54 untreated euthyroid patients (27·3 ± 9·0 kPa vs 20·9 ± 10·4 kPa, respectively, P = 0·02).

Figure 1. Mean (±SD) elasticity index of extra-nodular thyroid parenchyma and of benign nodules in Hashimoto’s thyroiditis (HT) and non-HT groups of patients. 

 Effect of chronic autoimmune thyroiditis on the gradient of elasticity between thyroid nodules and extra-nodular tissue. The median EI was calculated for the whole cohort of patients, both for thyroid parenchyma (20·4 KPa) and for nodules (29·5 KPa). The percentage of patients having an EI of the thyroid parenchyma higher than the calculated median one did not differ in HT (51·3%) as compared with the non-HT group (48·7%). Similarly, HT and non-HT patients were equally distributed above and below the median value of elasticity measured in nodular tissue (46% and 54%, respectively).

The mean (±SD) EI of thyroid nodules did not significantly differ in the HT as compared with the non-HT group (Fig. 1). In the HT group, the EI of the extra-nodular tissue was significantly related to the EI of the thyroid nodules (r² = 0·196, P = 0·01). This association was absent in the non-HT group. The stiffness of thyroid nodules was always higher than that of the embedding tissue in both the HT and non-HT groups, and the difference between the two regions of interest was statistically significant (Fig. 2).

Figure 2. Mean (SD) elasticity index of benign nodules and extra-nodular thyroid parenchyma in Hashimoto’s thyroiditis (HT) and non HT groups of patients. 

DISCUSSION

Our data using shear wave elastography confirm the ability of this technique to correctly define the elasticity of thyroid nodules, independent from the presence of a stiffer gland as observed in HT. A gradient of stiffness was observed in all patients, with thyroid nodules being significantly harder than the surrounding tissue, both in HT and in the non-HT groups.

Chronic autoimmune HT per se and its severity, as assessed by TPOAb titres and by the need of replacement therapy with L-T4 for hypothyroidism, increases the EI of extra-nodular parenchyma. However, even in Hashimoto’s glands, a significant elasticity gradient is maintained between benign nodules and the extra-nodular tissue, the EI of nodules always being greater than that of the embedding thyroid parenchyma. In agreement with this finding, a significant direct relation was observed between the EI of the extra-nodular tissue and that of the benign nodules in Hashimoto’s glands.

Shear wave elastography has been reported to be a powerful tool for the diagnosis of malignant thyroid nodules, the EI being significantly greater in malignant as compared with benign nodules.¹⁴ To the best of our knowledge, this is the first study investigating the influence of HT on the elastographic features of thyroid nodules. It is well established that chronic autoimmune HT, being characterized by lymphocytic infiltration and fibrosis, modifies thyroid ultrastructure resulting in a stiffer gland. In acromegaly, another condition characterized by fibrosis of the thyroid, elastosonography was found to be useless in predicting the malignant nature of thyroid nodules. This is because patients with acromegaly seem to have a greater prevalence of hard nodules, which are not malignant at cytopathological examination.¹⁵ In these patients, fibrosis and consequent stiffness are probably due to increased collagen synthesis and deposition induced by GH and IGF1.²⁴ Although limited by the fact that our series of patients was not large, the findings of the present study indicate that chronic autoimmune HT does not impair the ability of shear wave elastography to evaluate thyroid nodules even in chronic autoimmune HT. This is of particular relevance because: (i) HT affects at least 5% of the general population;²⁵ (ii) patients with HT are more likely to develop thyroid nodules, due, at least in part, to a chronic TSH stimulation;²⁶ (iii) several studies indicate an association between HT and thyroid cancer of the papillary type;^16,27–32 and (iv) a higher prevalence of suspicious or indeterminate FNAC reports was reported when examining nodules harboured within a Hashimoto’s gland.³³ In view of these considerations, correctly defining elasticity becomes critically important in the diagnostic work-up of nodules within Hashimoto’s glands.

In conclusion, our data indicate that shear wave elastography correctly defines the elasticity of thyroid nodules independently from the coexistence of chronic autoimmune thyroiditis, always being able to differentiate nodular tissue from surrounding parenchyma. In HT glands, the stiffness of extra-nodular tissue increases in relation to both the thyroid antibody titre and the degree of thyroid function impairment, being higher in patients requiring L-thyroxine therapy.