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Abstract
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
Objective
To determine the predictability of sonography for detection of calcifications in thyroid nodules by histopathologic examination and to demonstrate the association between calcification pattern and malignancy.
Methods
We prospectively evaluated 81 dominant nodules from 81 patients. Thyroid glands were assessed preoperatively with thyroid ultrasonography, and the presence of sonographic calcification was specified as intranodular coarse and micro calcification. Micro and coarse calcification in surgery specimens were specified postoperatively as present or absent in the histopathological evaluation. The correlation between sonographic and histopathologic calcifications and the relationship between malignancy and calcification patterns were determined.
Results
Calcification was detected histopathologically in 66.7% of the sonographically calcified nodules and in 12.8% of the sonographically noncalcified nodules. The sensitivity and specificity of sonography for detecting histopathologic calcification were 84.8 and 70.8%, respectively, while positive and negative predictive values were 66.7 and 87.2%, respectively. The sonographical and histopathological outcomes for detection of coarse and micro calcification showed 85 and 50% compatibility, respectively. The difference in malignancy rates between sonographic coarse and micro calcified nodules was not significant (p < 0.976). Histopathologic detection of calcification showed no significant difference between malignant and benign nodules (p < 0.129).
Conclusion
Histopathology confirmed a high rate of sonographic macrocalcifications. The micro and macro patterns of sonographic calcification showed no particular association with thyroid malignancy. The preoperative risk of malignancy should be determined in conjunction with other known sonographic risk factors and diagnostic tests.
1. Introduction
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
Ultrasonography (US) is a complete imaging technique for detecting thyroid nodules and is frequently utilized in clinical practice [1]. High-resolution ultrasound has identified thyroid nodules in 19–67% of the general adult population [2], and several ultrasonographic criteria are used to discriminate between benign and malignant nodules. Ultrasonographic features for the prediction of malignancy include hypoechogenicity, irregular margins, microcalcification, increased blood flow in the nodule, local invasion, and regional lymphadenopathy [[3], [4], [5], [6], [7], [8], [9], [10]], with several studies reporting calcification in about 19.8–32.1% of thyroid nodules [[11], [12]]. Thyroid nodular calcifications can be classified into three patterns by US based on their diameter, location, and acoustic shadow features. Microcalcifications are defined as tiny, punctate, echogenic foci of 1 mm or less, either with or without posterior shadowing, whereas macrocalcifications are defined as punctate echogenic foci > 1 mm and rim calcifications are defined as peripheral curvilinear eggshell calcification [[13], [14], [15]]. Microcalcification has a high association with papillary thyroid carcinoma [13], but the importance of the other calcification patterns is uncertain [16]. Recent studies have shown a relationship between macrocalcifications and malignancy, especially in papillary thyroid carcinomas [[17], [18], [19], [20],[21]].
Detection of calcification by US, in conjunction with other ultrasonographic features, can guide the clinician in discriminating between benign and suspicious malignant nodules, but the question remains whether these echogenic foci invariably represent calcifications when examined histopathologically. The aim of this study was to determine the predictability of sonography for the detection of calcifications in thyroid nodules by histopathologic examination and to demonstrate the association between calcification pattern and malignancy.
2. Materials and methods
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
A prospective clinical study was designed. Between January 2013 and March 2014, 117 patients with a solitary thyroid nodule or multiple thyroid nodules who had undergone FNA for suspected malignancy at our institution were considered for the study. Our inclusion criteria required that same ultrasonographic features were observed by two experienced radiologists. Patients with ultrasonographic findings pointing to a possible risk for malignancy with benign FNA results were included, as well as those with nodules with malignant FNA results, based on the ultimate decision of the thyroid committee, which included an ENT surgeon, an endocrinologist, a radiologist, and a nuclear medicine specialist. A total of 81 dominant nodules from 81 patients were included for analysis in the study, and these patients subsequently underwent thyroidectomy for nodular thyroid disease. The study was approved by the Local Ethics Committee of the Istanbul Research and Training Hospital and written informed consent was obtained from all study participants.
2.1. US examination
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
All patients were evaluated with thorough sonography of the thyroid gland and neck, performed with a 13–18 MHz linear-array volumetric transducer (Toshiba Aplio 500 XG; Toshiba Medical Systems, Tokyo, Japan 2012). The radiologists were blinded to the cytopathological diagnosis. Following the examination of the thyroid tissue, the presence of nodules was assessed. The following sonographic features were assessed by thyroid Doppler ultrasonography (TDU): echogenicity, location, and size of each nodule. The presence of a halo with hypoechogenicity in the periphery of the nodule and the presence of intranodular micro and macrocalcifications were noted. Macrocalcifications were defined as those larger than 1 mm (Fig. 1). Microcalcifications were defined as multiple tiny punctate bright echoes of 1 mm or less, with or without posterior acoustic shadowing (Fig. 2). Rim calcification patterns were not evaluated, as none was detected in any of the patients participated in our study.
Fig. 1
Ultrasonographic image of a hypoechoic solitary nodule with macro (coarse) calcifications.
Fig. 2
Ultrasonographic image of a hypoechoic nodule with microcalcifications seen as punctate echogenic foci.
2.2. Histopathology
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
All nodules with radiological findings of possible malignancy were marked intraoperatively and included in the study. This was done by evaluating the specimen based on the preoperative ultrasonography report and placing a suture by the palpated dominant nodule immediately following the surgery. After the routine tissue follow-up procedures, the samples of the thyroidectomy materials were embedded in paraffin. Sections obtained from these nodules in surgical specimens were stained with hematoxylin-eosin and examined under a light microscope. All specimens were evaluated in a blinded fashion by a pathologist specialized in thyroid pathology. Intranodular micro and dystrophic calcification was specified as present or absent in the postoperative histopathological evaluation. Microcalcifications were defined as 10–100 μm round laminated crystalline calcific deposits, whereas dystrophic calcifications were defined as nonlaminated amorphous calcific deposits (Fig. 3, Fig. 4). The histopathological results of the operated patients were grouped as malignant (papillary carcinoma, follicular carcinoma, Hurthle cell carcinoma, anaplastic carcinoma, and medullary carcinoma) or benign (nodular hyperplasia, colloidal goiter, lymphocytic thyroiditis, Hashimoto thyroiditis, follicular adenoma, and Hurthle cell adenoma).
Fig. 3
Papillary thyroid carcinoma showing small, round, calcified structures with concentric laminations (Psammoma Body) (HE × 400).
Fig. 4
Coarse-dystrophic calcification is seen in the tumor capsule of papillary thyroid carcinoma (HE × 100).
2.3. Statistical analysis
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
Statistical analysis was conducted using the SPSS 15.0 Windows software package. Numerical variables were presented as mean ± standard deviation (SD). Nominal variables were given as the number of cases and percentages. Intergroup differences of nominal variables were evaluated by the Chi-square test. Sensitivity, specificity, positive and negative predictive values were calculated. A value of p < 0.05 was considered statistically significant.
3. Results
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
The subjects were 51 female and 30 male patients (with a female-to-male ratio of 1.7:1). The median age was 49.5 ± 9.3 years, with a range between 19 and 81. Ultrasonographic calcifications were detected in 51.9% (42/81) of all nodules. Ultrasonographic microcalcification pattern was found in 27.2% (22), whereas the macrocalcification pattern was found in 24.7% (20). Histopathology revealed that 45 nodules were benign and 36 nodules were malignant (Table 1).
| Age (years) mean ± SD (min–max) | 49.5 ± 9.3 (19–65) | |
|---|---|---|
| Gender n (%) | Men | 30 (37.0) |
| Women | 51 (63.0) | |
| Ultrasonographic calcification n (%) | No | 39 (48.1) |
| Yes | 42 (51.9) | |
| Ultrasonographic calcification type n (%) | Macro(coarse-dystrophic) | 16 (19.8) |
| Micro | 22 (27.2) | |
| Histopathologic calcification n (%) | No | 45 (55.6) |
| Yes | 36 (44.4) | |
| Histopathological diagnosis n (%) | Benign | 45 (55.6) |
| Malign | 36 (44.4) |
SD: standard deviation data presented as n %.
Calcification was detected histopathologically in 28 (66.7%) of the ultrasonographically (US) calcified nodules and in 5 (12.8%) of US noncalcified nodules. The rate of histopathological calcification was significantly higher in the US calcified nodules than US noncalcified nodules (p < 0.001). Histopathologic hyalinization was detected in 81% (n = 34) of US calcified nodules but only in 30.8% (n = 12) of the US noncalcified nodules. The rate of histopathological hyalinization was significantly higher in US calcified nodules than US noncalcified nodules (p < 0.001). The malignancy rate for US calcified and US noncalcified nodules were 54.8 (n = 23) and 33.3% (n = 13), respectively. Malignancy was not significantly different in US calcified nodules compared to nodules without calcification (p = 0.052) (Table 2).
| Ultrasonographic calcification | ||||
|---|---|---|---|---|
| Positive n(%) | Negative n(%) | p | ||
| Histopathologic calcification | Positive | 28 (66.7%) | 5 (12.8%) | χ2 = 24.286 p < 0.001* |
| Negative | 14 (33.3%) | 34 (87.2%) | ||
| Histopathologic hyalinization | Positive | 34 (81%) | 12 (30.8%) | χ2 = 20.753 p < 0.001* |
| Negative | 8 (19%) | 27 (69.2%) | ||
| Histopathological diagnosis | Benign | 19 (45.2%) | 26 (66.7%) | χ2 = 3.761 p = 0.052 |
| Malignant | 23 (54.8%) | 13 (33.3%) | ||
p < 0.05 was statistically significant.
Sensitivity and specificity of US for predicting histopathologic calcification were 84.8 and 70.8% respectively while positive and negative predictive values were 66.7 and 87.2%respectively. For predicting malignancy US showed lower ratios; 63.9 and 57.8% for sensitivity and specificity and 54.8 and 66.7% for positive and negative predictive values respectively.
Calcification was detected by histopathologic examination in 33.3% (15/45) and 50% (18/36) of benign and malign nodules, respectively, and the difference was not statistically significant (p < 0.129). The rates of hyalinization for benign and malign nodules were 42.2 (19/54) and 61.1% (22/36), respectively, which also showed no statistically significant difference (p < 0.109) (Table 3).
| Histopathological diagnosis | ||||
|---|---|---|---|---|
| Benign n(%) | Malign n(%) | p | ||
| Histopathologic calcification | Positive | 15 (33.3%) | 18 (50%) | χ2 = 2.301 p = 0.129 |
| Negative | 30 (66.7%) | 18 (50%) | ||
| Histopathologic hyalinization | Positive | 22 (48.9%) | 24 (66.7%) | χ2 = 2.576 p = 0.109 |
| Negative | 23 (51.1%) | 12 (33.3%) | ||
p < 0.05 was statistically significant.
For detection of macro calcification, ultrasonographic and histopathological outcomes showed 85% (17/20) compatibility. However, the outcomes for microcalcifications were only 50% (11/22) compatible. The rate of histopathological calcification was significantly higher in US macrocalcified nodules than US positive microcalcified nodules (p < 0.016). Malignancy rate was not significantly different between US positive micro or macrocalcified nodules, with 54.5% (12/22) and 55% (11/20) rates, respectively (p < 0.976). Hyalinization was detected in 72.7 (16/22) of US microcalcified nodules whereas in 90% (18/20) of US macrocalcified nodules and the rate of histopathological hyalinization showed no statistical significance (p < 0.011) (Table 4).
| Ultrasonographic calcification type | ||||
|---|---|---|---|---|
| Micro n(%) | Macro n(%) | p | ||
| Histopathologic calcification | Positive | 11 (%50) | 17 (%85) | χ2:5775 p:0,016* |
| Negative | 11 (%50) | 3 (%15) | ||
| Histopathologic hyalinization | Positive | 16 (%72,7) | 18 (%90) | χ2:2027 p:0,243 |
| Negative | 6 (%27,3) | 2 (%10) | ||
| Histopathological diagnosis | Benign | 10 (%45,5) | 9 (%45) | χ2:0,001 p = 0,976 |
| Malign | 12 (%54,5) | 11 (%55) | ||
4. Discussion
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
Ultrasonography is currently used as the first line of investigation for determination of thyroid nodules [22]. Calcification of a thyroid nodule is one of the most important US findings for differentiating malignant from benign nodules; however, the calcifications described in sonography can be seen in both benign and malignant thyroid nodules [[13], [23]]. Microcalcification, coarse or macrocalcification, and rim calcification patterns have all been defined based on their sonographic features [13]. Histopathologically, calcifications are classified as psammoma bodies and dystrophic calcifications. Psammoma bodies are characteristic for papillary thyroid carcinoma and are laminated basophilic, spherical concretions [24]. They are found in papillary thyroid carcinoma, as well as in malignant and benign thyroid diseases, such as follicular adenoma, follicular carcinoma, multinodular goiter, and Hashimoto thyroiditis [25]. These bodies have been theorized to occur secondary to deposition of calcium in necrotic tissues, to calcification of intravascular tumor thrombi, or to infarcted tips of malign papillae [[26], [27], [28]]. Similarly, dystrophic calcifications occur as a result of tissue necrosis but are described as irregular concretions without laminations [24]. They occur in benign or malignant conditions and are thought to match macrocalcifications detected by US [6]. By contrast, sonographic microcalcifications mostly represent psammoma bodies and are accepted as highly suggestive of malignancy [[13], [29]]. Various studies have focused on the relationship between calcification pattern and malignancy, but the correlation between histopathology and radiology of calcifications has not been researched sufficiently.
To our knowledge, this is one of the few studies that have evaluated the presence of sonographic calcifications by histopathological examination. Our results revealed that 66.7% of the nodules with sonographic calcifications actually contain calcifications. Despite a high rate of macrocalcifications (85%), only half of the microcalcifications were verified histopathologically. Moreover, calcification was detected in 12.8% of the nodules without sonographic calcification. All nodules with pathological calcification also had pathological hyalinization. However, six nodules with pathological hyalinization had no pathological calcification. This finding might be associated with early stages of calcification in these nodules, as hyalin globules are suggested as precursors of psammoma bodies [30].
A recent study by Tahvildari et al. reported that >50% of the punctate echogenic foci detected in papillary thyroid carcinoma patients by thyroid sonography showed no correlation with psammomatous calcifications on pathologic examination, and it was proposed that the term punctate echogenic foci would be more accurate than microcalcifications to define these imaging findings [31]. Takashima et al. reported a higher calcification detection rate, as microcalcification was determined by histopathology in 89% of sonographic microcalcifications. For macrocalcification, they reported a 71% rate, which is similar to our results [29]. We believe that the most important reason why sonography overestimated the real extent of true calcifications might be the echogenic hyalinized foci or colloid material, which misled the examiner. Nevertheless, five nodules without sonographic calcifications actually had pathological calcification. This false negative result can be explained by the lack of posterior shadowing in these calcifications because they were much smaller than 1 mm. Some reverberation artifacts on some colloid nodules could give rise to a false negative result.
The sensitivity, specificity, and positive and negative predictive values of sonographic calcification for the presence of histopathologic calcification were 84.8, 70.8, 66.7, and 87.2%, respectively. Tahvildari et al. reported lower ratios; the presence of punctate echogenic foci on sonography was 74% sensitive and 46–53% specific for the presence of psammomatous calcification for two different radiologists [31]. Moreover, the positive and negative predictive values were 45–48% and 75–77% respectively. The interpretation of our findings, in conjunction with the results offered by Tahvildari et al., supports the fact that sonography is an operator-dependent modality that frequently lacks identical description of calcification patterns, which affects the outcome.
Previous studies have demonstrated a relationship between calcification and thyroid malignancy. The incidence of calcification in the literature is reported as 26–54% in malignant and 8–32% in benign lesions (15). Kakkos et al. detected calcification in 54% of patients with thyroid cancer [23]. Similarly, Shi et al. reported a 53.1% malignancy rate in nodules with calcification [32], while Taki et al. found calcification in malignant and benign nodules at rates of 47% and 31%, respectively [15]. Both research groups found a statistically significant relationship between nodular calcification and malignancy. In present study, we detected sonographic calcification in 54% of the malignant nodules, which is consistent with the literature; however, the rate of sonographic calcification was 45.2% in benign nodules, which was higher than reported in the previous studies. As a result, although rate of malignancy was higher in sonographically calcified nodules, the calcification status showed no statistically significant difference (p = 0.052).
The current literature includes studies that reveal the usefulness of the patterns of calcifications for predicting malignancy. For example, Shi et al. reported that the incidence of malignancy was significantly higher in patients with microcalcifications (96.5%) than in patients with macrocalcifications (41.1%), and they implied that the presence of microcalcifications may be a confident premise for thyroid carcinoma. They also indicated that a sonographic finding of microcalcifications is more important than sonographic macrocalcifications for the diagnosis of micropapillary carcinoma and detection of microcalcifications has a greater clinical significance in the diagnosis of micropapillary carcinoma than of macropapillary carcinoma [32]. By contrast, Kim et al. showed that microcalcification and coarse dystrophic calcification patterns had a significant relationship with malignancy [16]. Another study suggested that a reduced internal echogenicity of the nodule, including peripheral calcifications, may also be related to findings of thyroid nodule malignancy [33]. Arpacı et al. reported that ultrasonographic parenchymal macrocalcifications in particular were more prevalent in malignant nodules than in benign nodules [34]. Our data showed that the malignancy rate did not differ significantly between sonographic micro or macrocalcified nodules, with rates of 54.5% (12/22) and 55% (11/20), respectively.
Our study had several limitations. Although this was a prospective study, our sample size was small. Our study design also precluded an investigation of the association between other sonographic features and malignancy. We also only evaluated the sonographically dominant nodules with calcifications, as marking these for histopathological examination was easy and reliable during surgery.
5. Conclusion
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
In conclusion, ultrasonographic macrocalcifications in the thyroid were confirmed at a high rate by histopathology. The micro or macro subtypes of calcification showed no association with thyroid malignancy, and this might explain why sonographic calcification is not a precise indicator of malignancy in thyroid nodules. However, this opinion needs to be verified by further studies.
Compliance with ethical standards
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
Informed consent
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
Additional informed consent was obtained from all individual participants for whom identifying information is included in this article.
Ethical approval
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
All procedures performed in studies involving human participants were in accordance with the ethical standards of the Local Ethics Committee of the Istanbul Research and Training Hospital and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Funding
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
This study was not supported by any fundings.
Conflict of interest
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
The authors declare that they have no conflict of interest.
References
Jump to Section1. Introduction2. Materials and methods 2.1. US examination 2.2. Histopathology 2.3. Statistical analysis3. Results4. Discussion5. ConclusionCompliance with ethical standards Informed consent Ethical approval Funding Conflict of interestReferences
- Ozel, A., Erturk, S.M., Ercan, A. et al. The diagnostic efficiency of ultrasound in characterization for thyroid nodules: how many criteria are required to predict malignancy?. Med Ultrason. 2012; 14: 24–28
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☆Note: This study was conducted as an oral presentation at the 35th Turkish National Congress of Otorhinolaryngology and Head-Neck Surgery, November 5, 2013; Antalya, Turkey.
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