Conventional , Doppler Ultrasound and Real Time Elastography in Diagnostic of Thyroid Solitary Nodules

In the presence of a solid thyroid nodule, the therapeutically approach is imposed by the probability of a malignancy. Ultrasound is considered to be “the” imagistic diagnostic tool, and the golden standard is represented by the FNAB. US elastography is currently used in differentiation of malignant from benign lesions. This prospective study included 112 patients, mean age 52.08±11.43 years, 65 females and 47 men, with solitary thyroid nodules on conventional US, with a volume higher than 0.50 ml. Complete ultrasound evaluation was performed for each case: gray scale, Doppler and strain elastography. All patients underwent surgery after complete evaluation. Extemporaneous and postsurgical histopathological exam were performed in all cases. We identified 19 cases with cancer and 93 benign lesions. We calculated the diagnostic value for each ultrasound parameter, and we saw that some parameters are significant in diagnosing thyroid malignancy: irregular margins (AUC =0.761, p = 0.00001), taller than wide (AUC = 0.723, p = 0.0001), positive calcification (AUC = 0.7416, p = 0.0001), absent halo sign (AUC = 0.717, p = 0.0001), extracapsular invasion (AUC = 0.684, p = 0.0012). The presence of 4 suspect signs increases diagnostic quality (AUC = 0.8529, p=0.000), and combined evaluation US-2B and Doppler have even better results (AUC = 0.8985, p=0.00001. Advances in Cancer Research & Treatment 2


Introduction
As Lazar F (2008) describes, cancer suspicion should be present in the presence of any thyroid nodule, thyroid nodule being the most frequent form of manifestation of differentiated thyroid carcinoma.Even if our region is an iodinereplete area, as states by Ghelase et al. (2007) thyroid nodules are a common pathology in our region.The prevalence is high, they are found clinically in 4-8% of cases, as in the paper of Hegedus et al. (2004), much higher, as Frates et al. (2005) describes, 19-55% with the use of ultrasound even higher, described by Harach et al. (1985), up to as high as 50% in autoptic studies.
Clinical signs in nodular thyroid pathology are specific, but only important thyroid masses are associated with compressive symptomatology.The dilemma of small thyroid masses, described by Papini et al. (2003) is the lack of specific clinical signs, but despite of this, Tan et al. (1995) recommend proper inspection, and palpation of the gland should be done.Regardless compressive symptoms, thyroid dysfunction signs or cosmetic reason, The Study Group of Korean Society of Radiology (2011) recommend the main goal for the clinician, the correct identification of the malignancy, even in small thyroid nodules.
The goal of the modern investigation techniques is to discriminate with as high as possible sensitivity and specificity suspicious from unsuspicious thyroid nodules.In the Romanian experience, Lazar F (2008) describes a sensitivity of up to 60% for the fine needle aspiration biopsy (FNAB) in diagnosing thyroid malignancy.Patient compliance and a trained thyroid cytologist are the most frequent limitation of the method.Tan et al. (1995) considers ultrasound to be the most sensitive noninvasive diagnosis tool of the thyroid nodules.There is no consensus regarding the importance of US in selecting the cases for FNAB, guiding the procedure or followup US criteria, or using US as a screening tool for thyroid cancer detection Tan et al. (1995), Moon et al. (2011), ATA Guidelines Task Force (2009) and AACE Guideline (2006).

Many
authors, recommend some characteristics to be followed: size, echogenicity, composition of the nodule, presence or absence of calcification/halo/irregular margins and also blood flow pattern, presence and aspect of micro-calcification and also the characteristics of the strain elastography, as described by Tan et al. (1995)

Patients
The study is a preliminary stage report.We analyzed cases seen in the Endocrinology Office, Center Dr. D, affiliated with the University of Medicine and Pharmacy "Victor Babes" Timisoara, in the period January 2011-January 2013.We included only cases with solitary thyroid nodules, predominantly solid, with volumes higher than 0.50 mL.All of the patients underwent surgery in the Surgical Department of County Hospital, member of the same University.All patients gave their inform consent to the approach.In the over mentioned time spam, we identified 145 cases that matched to the inclusion criteria: solitary solid thyroid nodule.

Equipment
We performed the ultrasound evaluation of each patient on a Hitachi EUB 7500 HV machine with 6-13 MHz variable frequency linear probe, with Doppler and elastography software, with recording of frames of all lesions prospectively on color elastography color map 1 (red-yellowgreen-blue color map); Hitachi Medical System, Tokyo, Japan.

Conventional, Power Doppler US and Elastography
Preoperative, all patients were examined by the same operator (D.S.), using High Resolution B-mode grey scale ultrasonography (US), Power Doppler ultrasonography (PD) and Real Time ultrasound strain elastography (USE) using the same machine.We analyses at each nodule the following parameters, used also by Thyroid study Group of Korean Society of Radiology (2011): echogenity (hyper-, iso and hyperecoic compared to the normal thyroid parenchyma); halo phenomena (presence or absence); irregular or well defined margins, shape (dominant dimension); intranodular homogeneity; extracapsular extension; presence of calcification: spot micro calcifications: hyperechoic spots less than 2 mm, without acoustic shadowing, macrocalcifications round solitary/eggshell or nonspecific calcification.The paper of Gao et al. (2011) defines different patterns for color flow Doppler: absence of any blood flow, perinodular with no or scare intranodular blood flow, marked intranodular blood flow or unique dominant intranodular vessel.Additional malignant changes in the regional limfnodes were also evaluated, as recommended by the Thyroid study Group of Korean Society of Radiology (2011).
The US elastography was performed during the same US examination, by the same observer.The US elastograme valuated qualitatively, as usual, over de 2B map, with the scale ranging from red -soft tissue to blue -hard lesions with no strain.The compression applied to the neck was always between double-checked by the standardized real-time measurement displayed on the screen.Bamber

FNAB
We performed FNAB guided by the ultrasound in 57 out of the 112 cases.We used 30 -40 mm 23G needles, no anesthetic procedure.The other 55 cases were: to small (diameter under 1 mm -26 cases), pre-carotidian position (11 cases), or noncompliant patients (18 cases).Cytological diagnostic was made according to the Bethesda Classification.

Treatment
All patients with predominant solid nodules (112 cases) were referred to surgery.The surgical protocol was: in cases with no suspicious findings -total lobectomy on the site of the nodule, respectively in cases with suspect lesions, total thyroidectomy was performed as a principle.
All excised pieces were sent to the Histopathological Department.

Histopathological Diagnosis
Each piece extracted from each case was formalin-fixed and paraffin embedded both nodular and apparent healthy thyroid tissue.The histological diagnosis was made by the pathologist on duty, on the day of surgery, according to the World Health Organization Guidelines described in 1974 by Heidinger

Conventional Ultrasound
We described and quantified the same set of parameters in each nodule: conventional ultrasound, Doppler and strain elastography.All data regarding ultrasound characteristics are described for this number of cases.
The numerical parameters values in benign (BN) and malignant (CA) nodules are presented in Table I

Figure 4: ROC CURVE for Grey Scale and Doppler Ultrasound Diagnostic Criteria for Evaluation Solid Nodules
There is to note the low sensitivity of the different types of calcifications but high specificity, especially of eggshell calcifications.
Without being very sensitive, the calcifications are specific to malignancy.
Only intranodular hypervascularisation, diffuse or uni-vascular are predictive for malignancy, but perinodular vascularization is present both in benign and malign thyroid solid nodules.The diagnostic power of each ES value was calculated for the entire group, high ES score having high diagnostic value for cancer, and low ES score having high diagnostic value for benign condition.The results are present in TABLE 3.There is to remark that other diagnostic tools have high specificity but low sensitivity (extracapsular extension, eggshell calcification, microcalcifications) or high sensitivity with low specificity (absent halo sign, hypoecogenicity).We analyzed the quality of qualitative elastography evaluation and we observed that the AUC of the ROC curve was very high, of 0.99108.p=0.00001-Figure 6.The diagnostic quality outreached the other ultrasound evaluation, even the positive combined criteria very much.

When
The false positive results for malignancy were two cases with oncocytic lesions.These benign lesions appeared to be malignant, due to hypoecogenicity, increased intranodular vascularization and a pattern 4 of RTE.They did not show extracapsular extension and did not present any calcifications.Microcarcinoma appeared to be benign because only a portion of the nodule was with increased strain.

Discussion
The paper of Ophir et al. (1999) explains the principle of elastography, as an extended ultrasound dynamic technique that uses tissue rigidity/elasticity modulus = Young modulus for differentiating elasticity/anelasticity of the nodules.The strain ration technique, that our group used, evaluates, as recommended in the literature, Yourong et al. ( 2009), the degree of distortion of a tissue under the application of a controlled external force, measuring differences between different tissue elasticity.We used the monitoring of the freehand applied compression by the standardized real-time measurement on a numerical scale, provided by the US machine, which a moderate pressure of 3-4 on the selfevaluation pressure scale of the Hitachi device.This technique is easy to perform, in real time, in the same session, and minimized the artifacts generated by the applied external pressure as described Asteria et al. (20108) and in the opinion of some authors, by the EFSMUB Guidleines (2013) might substitute FNAB in the future, especially in small or difficult to punction lesions, as we saw in a previous study (2012).
Almost all high ES score we observed, 4 and 5, were described in cancer cases.The false negative results were 1 case with big nodule and microcarcinoma, that was assigned to score 3 lesions, because, with o portion of nodule with hard density, and a carcinoma presented in a big nodule, that also was assessed as ES =3

Conclusions
Real time elastography is a useful tool in differentiating the solitary thyroid nodules.In cases with intermediate cytological results, small lesions and difficult nodules or in noncompliant patients, the information obtained, form the real time elastography should be used.Regardless, conventional US results and Doppler findings, a very high ES score (4 or 5) has to be considered suggestive for malignancy.
et al. (2013) recommend the use of moderate pressure with the scale 3 to 4 for the analysis.This is required because the extent of tissue compression influences both the tissue response and the elasticity score.The images were classified by the UENO 5 point scale (19): ES 1 = soft, elasticity (green color) within whole lesion, ES 2 = soft, elasticity (green color) in more than 50% of the lesion, especially in the center, ES 3 = intermediate, blue in circa 50% of the area predominant in the center of the lesion (elasticity only at the periphery of the nodule), ES 4 = hard, no elasticity, predominant blue color, ES 5 = no elasticity in the nodule and surrounding area.Examples are presented in the following images: Fig.1 and Fig.2 and Fig. 3. _______________ Stoian Dana, Mihaela Crăciunescu, Lazar Fulger, Diana Anastasiu and Marius Craina (2014), Advances in Cancer Research & Treatment, DOI: 10.5171/2014.515011

Figure 1 :
Figure 1: Images from a 65-Year-Old Women, with A 11.2 Ml Solitary Thyroid Nodule, with Hypoechogenicity, Oval, Well Defined Margins, No Calcifications, No Extracapsular Invasion, Scare Intranodular Vascular Signal, with RTE 3 Scale.The Patient Had FNAB, with Benign (Bethesda 2) Result.Histopathological Results Showed a Papillary Microcarcinoma with a 5 Mm Diameter.

Figure 2 :
Figure 2:A Case of a 41 Year Old Woman, with a Small Solid Nodule, Round, Solid, Intense Hypoecogenicity, Irregular Margins, No Calcifications, Important Intravascular Signal RTE 4 Scale.No FNAB.Histopathological Report: Papillary Carcinoma.

Figure 3 :
Figure 3: Images in a 67-Year-Old Woman with an Old Goiter, with Compressive Symptoms.Ultrasound Revealed a 6.79 Ml Solitary Right Solid Thyroid Nodule, Oval, Well Margins, with Discrete Hypoecogenicity, Incomplete Halo Sign, No Capsular Involvement, Intranodular Calcification, Intravascular Vascularization RTE Score 5 FNAB showed Bethesda 3. Total thyroidectomy was performed and classic papillary thyroid carcinoma was confirmed after the surgery.
we assessed the clinical elastography: score 1 was found in 31 cases, all benign lesions and score 2 in 38 cases, also all of the benign lesions.The majority of the score 3 lesions were benign (22/23), only 1 was found microcarcinoma at the histopathological exam.The majority of ES 4 lesions were cancers (15/17), with two anelastic nonmalignant lesions, oncitomas.All ES 5 scale lesions were thyroid cancers.The results are presented in Figure 5. _______________ Stoian Dana, Mihaela Crăciunescu, Lazar Fulger, Diana Anastasiu and Marius Craina (2014), Advances in Cancer Research & Treatment, DOI: 10.5171/2014.515011

Table 3 : Predictive Value of Us Elastography in Patients with Histopathological Diagnostic
_______________ Stoian Dana, Mihaela Crăciunescu, Lazar Fulger, Diana Anastasiu and Marius Craina (2014), Advances in Cancer Research & Treatment, DOI: 10.5171/2014.515011 We observed that there is a difference between ES in hyperplastic and oxyphilic adenoma compared with follicular or anisofollicular benign lesions, but further studies, with high number of cases, are needed for a precise conclusion.US elastography should be used in differentiating cases with solitary thyroid nodules.Total thyroidectomy in cases with high elastography score (4 and 5) should be performed because the number of false positive cases is very low.Cantisaniet al. (2012) suggest that elastography, helps deciding when and what to operate, in cases with solitary nodule.The threshold of strain ratio remains the great problem of elastography.There is no consensus of which value should be used to correct identify benign versus malignant nodules.Proposed values are, by Park (2008) between 2 and 3 are used (28), mean of 2.9±0.8, with good diagnostic _______________ Stoian Dana, Mihaela Crăciunescu, Lazar Fulger, Diana Anastasiu and Marius Craina (2014), Advances in Cancer Research & Treatment, DOI: 10.5171/2014.515011values: sensitivity = 70.6%,specificity = 85.2%.Cutoff values of 3-4are recommended by Itoh's group (2006), with a sensitivity of 91 %, specificity of 89 %, PPV 94 % and NPV 85 % (29).But, conversely, the same cutoff values Lipollos's paper shows, in selected population, with intermediate cellularity, low PPV, of 34% with low NPV< of 50%.These data come in great controversy with other studies, with good results: Park (2008), Ioth et al. (2006), Ning et al. (2012), and Wang et al. (2010),where values higher than 2 where used.It is clear that more data are needed to clarify this matter.