Nodular thyroid disease is a common disorder of the endocrine system characterized by one or more nodules in the thyroid gland (1). The most common cause is iodine deficiency (2). The incidence of thyroid nodules in the general population is 3%-5% with palpation, 40%-50% by autopsy and 30%-40% by ultrasound (US) respectively (2,3,4). Thyroids’ nodular disease can be neoplastic or non-neoplastic. Independent from the size of the thyroid nodule prevalence of cancer has been found to be 5%-10%, on top of that on autopsy data, the ratio is as high as 6-35% (5,6). Early diagnosis of thyroid cancer is very important due to the indolent nature of the disease and long life expectancy after early treatment.
Today, the basic diagnostic method of thyroid nodule is fine needle aspiration biopsy of the thyroid (FNAB). Being safe with low-cost and accurate results, this method is the first choice in the diagnosis of thyroid nodules. US guidance and the presence of a cytopathologists increases the rate of correct diagnosis (7,8,9) FNAB reveales the character of many nodular thyroid lesions and it is helpful in determining patients who should undergo surgical treatment. However, the sensitivity is low in the evaluation of follicular lesions (9,10,11). Thyroid follicular cell mediated cancers are; papillary thyroid carcinoma, follicular thyroid cancer and Hurthle cell (oncocytic) thyroid cancer. Only 15 to 25% of the FNAB results reported as follicular neoplasm are malignant (12,13,14). Thus, 80% of the cases who were reported as follicular neoplasm and its variants (hurthle cell and oncocytic) are benign lesions according to their histological examination and these patients are undergoing unnecessary surgery (14). In our study, we evaluated patients’ thyroid US findings, age, gender, goiter type, cancer, smoking, history of radiation to neck area, scintigraphic features and post-operative histopathological examination whose FNAB results were reported as follicular neoplasm, oncocytic change and hurthle cell neoplasm and had thyroid surgery.
In this study, we enrolled patients retrospectively whose FNAB results were reported as follicular neoplasms, oncocytic change or Hurthle cell neoplasm, and had surgery after FNAB. These patients were evaluated between 2009-2012 in Düzce University, Medical Faculty Hospital Endocrinology outpatient clinic.
In all patients who got diagnosed with growth or nodule in the thyroid gland by physical examination in outpatient clinics, thyroid US verification and thyroid function tests (thyroid-stimulating hormone “TSH” and free T4) was performed. Thyroid US was performed in the endocrinology department by the same endocrinologist by using 4-10 MHz superficial linear probe (GE LOGIQ 3 10L). During US, the right and left thyroid lobe and isthmus size, nodular structure, echogenicity (hypoechoic, isoechoic, hyperechoic, cystic, mixed), nodule long size-short size (LS / SS), calcification and calcification type (microcalcifications, wall calcification, coarse calcifications) were recorded.
Thyroid scintigraphy was performed in patients who had suppressed TSH. Scintigraphic features of the nodules were recorded as hypoactive (cold), isoactive or overactive (hot). US-guided FNAB was performed on all of the nodules by the same person. Written consent was taken from all patients prior to FNAB and surgery.
US guided FNAB procedure was performed with 10 ml syringe with a 21 gauge needle after cleansing of the skin with patients head slightly extended to back. During the process we did not need to use anesthetic agents. During the aspiration, needle was moved into various positions within the nodule and we vacuumed the nodule while moving the needle back and forth. The material taken from the nodule was spreaded to the slide and it was allowed to air dry and was sent to pathology unit for cytological evaluation purposes. After staining, the preparations were evaluated by the same pathologist. Cytology results were classified as without atypia, malignant, suspicious for malignancy, papillary carcinoma, follicular neoplasm, Hurthle cell neoplasm, oncocytic change and inadequate cytology. In the cases considered as inadequate cytology procedure was repeated. If FNAB cytology results were detected as follicular neoplasm, Hurthle cell neoplasms or oncocytic change; these patients were consulted to the general surgery unit for thyroidectomy. Postoperative histopathological results were compared with the long dimension of nodules, nodules’ long dimension and a short dimension ratio and with the age range. Age groups were classified as under 45, 46-60 age group, 61-75 age group and older than 75 years old group. Nodule size was categorized as above 15mm or equal-under 15mm. Long size-short size ratio were classified as ≤ 1.5, 1.5-2.5 and above 2.5. 123 patients were operated but we could not reach to the postoperative results of 20 of these patients. After the operation, thyroidectomy material was evaluated by the same pathologist. Pathological findings were defined as benign papillary carcinoma, follicular cancer, medullary cancer and anaplastic cancer. FNAB cytology results reported as without atypia, malignant or suspicious for malignancy were excluded from the study.
Statistical analyzes were performed with the SPSS computer software (ver. 18.0 for Windows, SPSS Inc, Chicago, IL, USA). Nominal data were compared with Pearson’s chi-square test or Fisher’s Exact chi-square test using 2x2 tables between independent groups and the results was expressed as frequency and percentage (%). Bonferroni correction was used when multiple comparisons were made and p<0.05 / 3=0.017 was considered as significant limit. Numeric data showing normal distribution was compared in two groups. When comparing independent samples t test was used and the mean ± standard deviation were used as descriptive values. Numerical data which do not show normal distribution was compared in more than two groups with the Kruskal-Wallis analysis and median (minimum-maximum) values were used as descriptive values. While investigating independent predictive factors for malignancy, binary logistic regression analysis was used. Forward Variable Screening Method was used as a method. Goodness of fit was assessed by Hosmer-Lemeshow Test. For the evaluation of coefficients of the model, Omnibus Test was used and significance of the model was evaluated. Statistically, p-values less than 0.05 was considered as significant.
Among patients who had their FNAB cytology results reported as follicular neoplasm, oncocytic change or Hurthle cell neoplasm and had surgery, 103 patients were eligible for the study. (81 women and 22 men between the ages of 26-78). 20 patients with unattainable postoperative results were not included in the study.
The mean age of the 103 patients enrolled in the study were 48.6±11.1; 47.5±11.1 for women, men 52.9±10.3, respectively (p=0.67). None of the patients included in the study had radiation therapy or history of cancer. 16.5% of the patients had a history of cigarette smoking. 33 (32%) patients had solitary nodular goiter and 70 (68%) patients were diagnosed as multinodular goiter after thyroid US examination. In the FNAB cytologic evaluation results were interpreted as, 68.9% (n=71) follicular neoplasm (56 female, 15 male), 9.7% (n=10) hurthle cell neoplasms (6 women and 4 men) and 21.4% (n=22) oncocytic change (19 female, 3 male). There was no significant correlation between FNAB cytologic evaluation and gender, smoking history or nodule type (Table 1).
We did not detect a statistically significant difference between FNAB cytology results, nodule echogenicity or features of nodular calcification. And there was no statistically significant difference between FNAB cytologic evaluation and the scintigraphic features of nodules (Table 2). In addition, in the statistical analysis, there were no significant differences between FNAB results and the median values of long size of the nodules (follicular: 21 (9-50); hurthle: 22 (10-34); oncocytic: 23 (10-75), p=0.908), nodules’ long size-short size ratio (follicular: 1.5 (1-3.3); hurthle: 1.1 (1.08-2.1); oncocytic: 1.4 (1.1-2.5), p=0.171), and patient age (follicular: 48 (26-78); hurthle: 53 (35-62), oncocytic: 48 (29-73), p=0.670).
When we compare FNAB cytological results and post-operative histopathological results: among the group of patient whose results were interpreted as follicular neoplasm, 8 patients had (11.3%) papillary carcinomas, 6 patients had (8.5%) follicular carcinoma and 57 (80.3%) had benign histopathology. Among the group of patient whose results were interpreted as Hurthle cell neoplasms; 1 patient (10%) had papillary carcinoma, 9 patients (90%) had benign histopathology. And among patients with oncocytic change result; 6 patients had (27.3%) papillary carcinomas and 16 patients’ (82.7%) results were interpreted as benign histopathology. All patients were evaluated for the post-operative histopathology results, 15 patients (14.6%) had papillary carcinomas, 6 patients (5.8%) had follicular carcinoma and 82 patients (79.6%) had benign histopathology (Figure 1). There was no significant difference between FNAB and postoperative histopathology results for malignancy (p=0.193).
There was no history of neck radiation or cancer in patients who got diagnosed with carcinoma. There were no significant differences between postoperative histopathology results (papillary carcinoma, follicular carcinoma and benign histopathology) and gender, type of goiter, thyroid history or smoking history. We compared postoperative histopathology results and FNAB cytology with US features (echogenicity, long size, calcification) of nodules which were reported as follicular, hurthle cell neoplasms or oncocytic change. Mostly, malignant nodules was found to be hypoechoic on ultrasonography. In terms of calcification no significant difference was found (Table 3).
There were no differences between scintigraphy features and postoperative histopathology results (Table 3). Rate of malignancy in hypoactive nodules was calculated as 21.9%.
We classified FNAB results as (follicular neoplasm-Hurthle / oncocytic cell neoplasms) and when comparison is made again between these two groups in terms of general characteristics of the patients and post-operative malignancy, no difference was found (Table 4).
There was no significant difference between postoperative histopathology results with age (papillary: 46 (26-78); follicular: 43 (37-65); benign: 50 (29-74), p=0.806), nodular long size (papillary: 18 (11-42); follicular: 30 (15-38); benign: 21 (9-75), p=0.186), and nodule long size / short size (LS / SS) median ratio (papillary: 1.4 (1.1-2); follicular: 1:25 (1:08 to 1:55); benign: 1.4 (1-3.3), p=0.404).
We did logistic regression analysis (Hosmer Lemeshow fit test: p=1.000 and model: p=0.005) to find the factors to predict malignancy in nodules whose results were reported as follicular, Hurthle cell neoplasm or oncocytic changes after FNAB. It was found that Ultrasound echo findings were an independent predictor for malignancy (p=0.017).
With reference to eco mixed hypoechoic nodules odds ratio 6.064 were found to be (95% Confidence Interval: 1878-19584, p=0.003). Age, gender, calcification, nodule size and scintigraphic features were not identified as independent predictors.
Eighty-nine patients had total thyroidectomy, one case had subtotal thyroidectomy, 11 patients underwent lobectomy and near-total thyroidectomy was performed in 2 cases. Among the cases of malignancy, 19 patients had total thyroidectomy, one case had subtotal thyroidectomy and one case had lobectomy. In post-operative histopathological examination, none of the patients with malignancy had adjacent tissue metastasis, lymph node metastasis or distant metastasis. In cases diagnosed with malignancy, post-operative histopathological examination results were as following; 8 cases had microcarcinoma (6 papillary carcinoma, 2 follicular carcinoma) and 13 cases had macrocarsinoma (9 papillary carcinoma, 4 follicular carcinoma).
Cancer type (micro/macro carcinoma) compared with postoperative pathology showed no statistically significant difference (p>0.05).
In patients enrolled in this study whose FNAB results were reported as follicular lesion, oncocytic change or hurthle cell lesion, 20.4% of them were diagnosed with thyroid cancer according to post-operative examinations. 14.6% of these patients had papillary carcinoma and 5.8% had follicular carcinoma. When we evaulate malignancy predictors in terms of the regression analysis; In patients whose FNAB results were reported as follicular lesion, oncocytic change or hurthle cell lesion, nodules which appeared hypoechoic in ultrasonography were identified as independent predictor factor. In the differentiation of malignant and benign thyroid nodules, there is no precise criteria determined by scintigraphy or ultrasonography. But for more accurate and reliable results in the light of the criterias set for ultrasound and scintigraphy, the most important and widely used method in differentiating benign from malignant is FNAB (15,16).
Hawkins have been reported that, with the application of FNAB in thyroid diseases surgical procedures ratio fell from 61% to 14% and preoperative diagnosis of thyroid carcinoma raised from 8.3% to 37.3%. These results are very important in terms of benefits of clinical application of FNAB (17).
‘Follicular neoplasm’ expression includes follicular development of groups of benign and malignant lesions originated from thyroid follicular epithelium. Despite the low rate of malignancy of these nodules, differential diagnosis should be made. In follicular, hurthle / oncocytic cell lesions, it is difficult to distinguish benign neoplasms from cancer with FNAB. Malignancy decision is made by the evaluation of capsular and / or vascular invasion in the post-operative histopathological examination. Such neoplasms constitutes a major portion of cases which can not be judged to be malignant for certain and put in a doubtful category and had surgery (7,9,18).
In the literature, postoperative rate of malignancy in patients with follicular neoplasm after cytological evaluation is noted as 20%-30%. In our study we found postoperative cancer rate as 20.4%. According to our results, it is noteworthy that in cases whose FNAB results were reported as hurthle cell neoplasms or oncocytic change, postoperative pathology did not report cancer. As with nodular thyroid disease, thyroid cancer is 3-4 times more common in women than men (20). In our study, among patients with postoperative cancer 16 of them were female, and 5 were male (F / M = 3.2 / 1).
In a study by Tyler and his colleagues it has been determined that, cytology results of follicular / Hurthle cell neoplasm increases malignancy risk by 40% in patients over 50 years old compared to patients under 50 years old (21). In our study, the age of patients ranged from 26 to 78. Although we observed an increased risk of malignancy with age, no
significant correlation was found between age and gender and malignancy. Likewise, no statistically significant difference was observed when patients who got diagnosed with cancer postoperatively were evaluated according to goiter history, goiter type (solitary nodule / multinodular) and smoking history.
It is specified that, when the echogenicity of the nodule is hypoechoic according to the normal thyroid parenchyma echogenicity, malignancy probability raises compared to iso-or hyperechoic nodules (22,23,24). In our study, consistent with the literature, hypoechogenicity has been found to be statistically related with malignancy. In our study, hypoechoic monitoring of the nodule has been found as an independent predictive factor for malignancy (OR: 6.064, 95% Confidence Interval: 1.878-19.584, p=0.003). In our study, nodules were seen in hypoechoic character in 53.3% of patients with papillary thyroid cancer and 50% of patients with follicular cancer. Overall malignancy rate for nodules which were evaluated as hypoechoic was 45.8%. No cancer was found in hyperechoic nodules.
In the literature, the presence of microcalcifications in nodules has been reported as the highest positive predictive value to detect malignancy (25,26,27). Among the sonographic criteria, it has the highest specificity (93%) but a low sensitivity (36%) (28). The risk of malignancy was found to be 2 to 3 times higher in solid nodules containing microcalcifications than nodules without microcalcifications (22,29,30). In our study, microcalcifications was observed in 20% of papillary thyroid cancer patients, yet no microcalcifications was detected in patients with follicular cancer. However, the presence of microcalcifications in nodules was not found to be significant in terms of malignancy.
In different surveys, carcinoma was reported in about 10%-25% of the nodules which were found to be hypoactive in scintigraphy (22,31). That rate reaches up to 35% in some other studies (32,33). Greenspan et al. gave the rate as 15%-20% (34). In our study, the rate of malignancy in hypoactive nodules was found to be 21.9%, but no significant difference was observed between scintigraphic features of the nodules and malignancy.
Hamming et al. found the rate of malignancy as 27% in their study in cases with MNG who has solitary nodules and a dominant nodule with a diameter of at least 40 mm long, and solid components over 75% (35). Also, Bildik et al. have found the malignancy rate as 14.9%, in nodules 3 cm and above; as 3.2% in nodules smaller than 3 cm. This indicates that the malignancy rate of 3 cm and above nodules are about 4.6 times more than that of the nodules smaller than 3 cm (36). Unlike Hamming et al. and Bildik et al, however, no significant association was found between the nodule size and the malignancy in our study (35,36). Bayrak et al. have concluded that in patients with MNG, no difference was detected between the FNAB results of dominant nodule and the nonspecific nodules (37). Similarly, no significant correlation was found between the nodule size and the malignancy in the study done by Sengoz et al (38).
According to Papini et al, parameters like the existence of single or multiple nodules in the thyroid gland, dominant nodules, or nodules that are larger than 1 centimeter, are not directly related to malignancy (29). In their study published in 2004, Ceresini et al. found no statistically significant correlation between malignancy and the nodules’ diameter (39). There was no correlation between nodule size and malignancy in Berl et al.’s study either (15). Similar to the results from all these studies, our study found no statistically significant correlation between nodule size and malignancy.
In our study, preoperative FNAB results and postoperative histopathologic findings of these nodules have been compared to each other. A large portion of patients were MNG, because of this, malignancy result may have been obtained from another nodule. As a result, 1/5 of cases reported follicular neoplasms, oncocytic change and Hurthle cell neoplasm based on FNAB results, have revealed malignancy and these nodules are independent risk factors in predicting the hypoechoic appearance of malignancy in thyroid US. Especially the ultrasonographic evaluations of the cases with follicular neoplasm and Hurthle cell neoplasm based on FNAB results should be reevaluated and it should be kept in mind that those which have hypoechoic character could be malignant. Moreover, in such patients, the size of nodules are not significant in the prediction of malignancy, it should be known that small nodules can have malignant characteristics as well.
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