The 25 cases (100%) that were interpreted cytologically as papillary carcinoma were confirmed on histopathological examination (Table 1, Fig. 5). The risk for malignancy in malignant cytological diagnosis was 100%.
Of the 47 cases cytologically diagnosed as negative, 46 (97.9%) were proved to be benign on histopathology (true negative) and one case (2.1%) was papillary carcinoma (false negative). Of the remaining 49 cytologically positive samples, 34 (69.4%) were proved to be malignant (true positive) and 15 (30.6%) were diagnosed as benign on histopathological reports (false positive) (Table 2).
Thus, FNAC achieved a sensitivity of 97.1%, specificity of 75.4%, PPV of 69.4%, NPV of 97.9%, and total diagnostic accuracy of 83.3%. The false-negative rate and false-positive rate were 2.9 and 24.6%, respectively.
Forty-six of 61 cases (75.4%) with a final histopathological diagnosis of being a benign nodule had a negative cytological diagnosis, whereas 34 of 35 cases (97.1%) with a final histopathological diagnosis of carcinoma had a positive cytological diagnosis (P<0.005).
Among the 39 cases with histopathological diagnosis of nodular goiter, 35 (89.7%) were correctly diagnosed by cytology as being negative. The last four cases were overdiagnosed by cytology as being positive – follicular neoplasm in three cases (7.7%) and suspicious for malignancy in one case (2.6%) – achieving 89.7% diagnostic accuracy. With regard to the 22 follicular adenoma cases, 11 (50%) revealed negative cytological result and 11 cases (50%) showed positive results, achieving 50% diagnostic accuracy. Of the 31 nodules with a final histopathological diagnosis of papillary carcinoma, 30 cases (96.8%) were positive on cytology and one case (3.2%) was negative, achieving 96.8% diagnostic accuracy. All the three nodules (100%) with a final diagnosis of invasive follicular carcinoma gave positive cytological reports. The only medullary carcinoma case was positive on cytology (Table 1).
On USE, score 1 was found in six cases (6.3%), score 2 in 51 cases (53.1%), score 3 in five cases (5.2%), score 4 in 15 cases (15.6%), and score 5 in 19 cases (19.8%) (Table 3).
The results of USE were then compared with their corresponding histopathological diagnosis. All cases with a USE score of 1 or 2 (100%) were confirmed as benign on histopathological diagnosis (Figs 6 and 7). Two of the five cases (40%) with score 3 were malignant on histopathology (Fig. 8), whereas three cases (60%) were benign. Among the 15 cases with a score of 4, 14 (93.3%) were malignant and the remaining one case (6.7%) was benign on final histopathology. This case showed incomplete rim-like calcification on conventional ultrasonography. All cases with USE score 5 (100%) were malignant (Table 3).
All the 57 included cases with an elastography score of 1 or 2 (negative) were proved to be benign on histopathology (true negative) and there were no false-negative cases. The remaining 39 cases were referred for surgery because they had scores of 3, 4, or 5. Of these, 35 cases (89.7%) were proved to be malignant on histopathological reports (true positive) and four cases (10.3%) were diagnosed as benign (false positive) (Table 4).
Thus, USE achieved a sensitivity of 100%, specificity of 93.4%, PPV of 89.7%, NPV of 100%, and total accuracy of 95.8%. The false-negative rate and false-positive rate were 0 and 6.6%, respectively.
Fifty-seven of 61 cases (93.4%) with a final histopathological diagnosis of benign nodule had USE scores of 1 and 2, whereas all cases (100%) with a final histopathological diagnosis of malignant nodule had scores 3, 4, or 5 (P<0.0001).
The 39 cases with histopathological diagnosis of nodular goiter correctly showed a negative score (1 and 2), achieving 100% diagnostic accuracy. Among the 22 follicular adenoma cases, 18 were correctly scored 1 or 2, whereas four cases were overscored as 3 or 4, achieving 81.8% diagnostic accuracy. All the 31 nodules with a final hiatopathological diagnosis of papillary carcinoma were correctly scored as 5, 4, or 3, achieving 100% diagnostic accuracy. The three nodules with a final diagnosis of invasive follicular carcinoma were correctly scored as 4 or 5. The only medullary carcinoma case had a score of 5 (Table 3).
The USE scores were compared with the results of FNAC. In the 18 nodules with cytological report of follicular neoplasm (indeterminate cytology), score 2, describing high elasticity, was found in 10 of 14 benign nodules on histology and in no malignant nodule and scores 3, 4, and 5, describing low elasticity, were found in the four malignant nodules and in four of the 14 benign nodules (P<0.0005). The elastography scoring was efficient in differentiating benign from malignant nodules in indeterminate cytological results.
For the 31 nodules with suspicious or malignant cytological reports, score 2, describing benignity, was found in one case, which was nodular goiter (papillary hyperplastic nodule) on histopathology, whereas scores 3, 4, and 5, describing malignancy, were scored in the remaining 30 nodules, which were malignant on histopathology (P<0.0005). The elastography scoring was highly efficient in differentiating benign from malignant nodules in suspicious or malignant cytological results. Among the 47 cases with benign cytological reports, 46 nodules had scores 1 and 2 and the only case that was falsely diagnosed on cytology as benign was correctly scored 4 on elastography (P<0.0001). This case was papillary carcinoma on histopathology. The elastography scoring was highly efficient in differentiating benign from malignant nodules in benign cytological results (Table 5).
The utility of any diagnostic procedure mainly depends on three foundations: sensitivity, specificity, and practical success (i.e. ease in carrying out the procedure). A major advancement in the diagnosis of thyroid nodules has been achieved with the perfection and common use of FNAC, which can obviate a lot of unnecessary surgeries in thyroid lesions (Tareq et al., 2010). Before the routine use of thyroid FNA, the percentage of surgically resected thyroid nodules that were malignant was 14%. With current thyroid FNA practice, the percentage of resected nodules that are malignant surpasses 50% (Yassa et al., 2007). Treatment is decided on the basis of whether the cytologic results are benign or malignant, or at least suspicious for malignancy. However, when the cytological diagnosis is reported as atypical or indeterminate, clinicians could be confronted with some difficulties in the management of patients. Thus, the recommended treatment of these lesions remains the diagnostic surgical excision of the nodule (Chung et al., 2011).
This study was undertaken to specifically address whether USE improves the diagnostic accuracy of FNAC in patients with thyroid nodules.
In the statistical estimation of our cytological results, we considered the new category ‘follicular lesion of undetermined significance’ as negative samples because of many reasons; first, the malignancy risk of this category (∼5–15%) is not sufficient to justify immediate surgery, and the recommended treatment is repeated FNAs in the appropriate clinical context within a span of 3–6 months (Ohori et al., 2010). The second reason can be attributed to the subjective cytomorphological diagnostic features of this category. It was reported in the literature that this category may never have good interobserver reproducibility, even after pathologists familiarize themselves with the criteria in the Bethesda atlas (Crippa Mazzucchelli, 2010). Chung et al. (2011) reported that, although the Bethesda system systematized the pre-existing cytological knowledge, the clarification of criteria for this category is worthy of special attention. Some authors reported that a presumptive institutional philosophy has arisen with regard to this diagnosis (Theoharis et al., 2009). Some authors in their series re-evaluated these cases to reclassify them into other groups. Thus, no patient from their final series was included in this category (Merino et al., 2011). Third, in a previous work performed at our institute in 2012, no cases of this category turned out to malignant on histopathological follow-up (Sinna and Ezzat, 2012). This result is comparable to ours. In our unit, there is a tendency to use this category when the smears are suggestive but not conclusive for benignity, and any observed atypical feature in our cases was classified under follicular neoplasm or suspicious categories.
In our series, analysis of data revealed that FANC achieved a sensitivity of 97.1%, specificity of 75.4%, PPV of 69.4%, and NPV of 97.9%. These results were in agreement with the published data in which FNAC of the thyroid is reported to have a sensitivity range from 65 to 98%, a specificity from 72 to 100%, a PPV from 34 to 100%, and an NPV from 83 to 100% (Čáp et al., 1999). The explained factors for such wide range of differences may be related to: (a) the number of studied cases; (b) clinical presentation of the patients in terms of having multiple or solitary thyroid nodules; and (c) the included diagnostic categories and how the cytopathologists classify follicular lesions of undetermined significance. Some authors classify it as a neoplastic suspicious lesion as its risk for malignancy is 5–15%, whereas some do not as its usual management does not include surgery, and others exclude it from the statistics.
The specificity in our study was low, probably secondary to a relatively high number of indeterminately classified nodules, follicular neoplasms, in which determining malignancy or benignity was not possible with cytology, and all these cases were considered positive and subjected to diagnostic surgery.
In the current study, the overall accuracy of cytological diagnosis was 83.3%. Our result was much lower than that reported in a study carried out at our institute in 2012 (Sinna and Ezzat, 2012) in which the reported accuracy was 93.6%. The determinant factors for such a difference may be related to exclusion of the follicular lesion of undetermined significance from their statistical calculation or because follicular adenoma cases were considered among their positive results. Our diagnostic accuracy was higher than the reported figure of 79.1 and 68.8% in the studies by Mundasad et al. (2005) and Bongiovanni et al. (2012). In the former series, no follicular lesions of undetermined significance were included, and in the latter this category was considered true positive.
In the current series, there is a strong agreement between cytology and histopathological results (P<0.005). This is comparable to that of others (Theoharis et al., 2009; Tareq et al., 2010).
However, a discrepancy between cytological report and histopathological diagnosis was found in 16 of 96 cases (16.7%) (Table 1). One case was initially diagnosed as benign on cytology and turned out to be papillary carcinoma in the histopathological study (the false-negative rate was 2.9%). This may result from sampling error or coexistence of benign and malignant lesions. This case exhibited cystic properties. This may be one explanation for the poor test performance, as these properties can make diagnosis of malignancy difficult and it could explain the only missing case in the current study (Mistry et al., 2011). On secondary review, the cytology aspirate of this case demonstrated no evidence of papillary carcinoma. Multiple aspirations from different parts of the swelling or combined use of ultrasound and FNAC would aid in sampling the solid portions of cystic nodules (Chung et al., 2011). This case is of much importance as it refers to the potential of missing malignant lesions. Typically, the reported rates of false-negative cytologic diagnoses reported in the literature ranged from 1 to 16% (Nggada et al., 2006). Our result was lower than that reported by Sinna and Ezzat (2012), in which the false-negative rate was 5.8%.
In contrast, we reported one case as suspicious for malignancy on FNAC (Fig. 4) that proved to be papillary hyperplastic nodule on histopathology, and 14 of 18 cases that were reported as follicular neoplasm proved to be benign, nodular goiter in three cases and follicular adenoma in 11 cases on histological correlation (false-positive rate was 24.6%). These cases are of great concern because they underwent unnecessary surgery. The papillary hyperplastic nodule has been recently recognized as a potential pitfall in the cytologic diagnosis of papillary carcinoma (Khayyata et al., 2008). Aspiration from the three nodular goiter cases was probably carried out from the hypercellular and hyperplastic areas of nodules, which led to overdiagnosis. Cytological distinction between hyperplastic nodules and follicular neoplasm is sometimes very difficult. A possible remedy is multiple aspirations from different parts of the swelling that could demonstrate hypocellular, polymorphic, and colloid-rich areas. Demonstration of monolayered sheets of epithelial cells representing macrofollicles and degenerative changes would suggest the possibility of non-neoplastic lesions (Sinna and Ezzat, 2012). It is well recognized that certain thyroid lesions have similar cytological features that make diagnosis extremely difficult on cytology. This problem is commonly reported with follicular adenoma and carcinoma and is considered the main pitfalls of thyroid FNAC. The diagnosis of follicular and Hurthle cell carcinoma requires demonstration of capsular and/or vascular invasion, which cannot be evaluated on cytology (Mistry et al., 2011). This pitfall is responsible for most of our incorrect false-positive cytologic diagnoses. The published guidelines of the Papanicolaou Society of Cytopathology (Suen, 1996) suggested that a false-negative and a false-positive rate of less than 2 and 3%, respectively, should be achieved. In other series, the false-positive rate ranged from 0 to 8% (Basharat et al., 2011).
USE is one of the latest technologies that use ultrasound to analyze the stiffness of a nodule by measuring the amount of distortion that occurs when the nodule is subjected to external pressure (Hong et al., 2009). Many previous studies have proved that elastography is useful in differentiating malignant thyroid nodules from benign thyroid nodules (Asteria et al., 2008; Hong et al., 2009). Others have reported that elastography showed inferior performance in comparison with gray-scale ultrasound features (Moon et al., 2012).
In our study, tissue stiffness was scored from 1 to 5 on the basis of subjective analysis of the elastograms. Using this score classification, the predictivity of USE was highly rewarding. Scores 3, 4, and 5 identified 100% of thyroid cancers (Fig. 8) and scores 1 and 2 excluded malignancy (Figs 6 and 7) with a sensitivity, specificity, PPV, and NPV of 100, 93.4, 89, and 100%, respectively. Sensitivity was very high in this study with no false negatives found; hence, all nodules with high elasticity (score 1 and 2) in our study were benign on pathological results. Our results are comparable to another similar study in which scores 1 and 2 were detected in 49 cases; all were benign. Scores 4 and 5 were detected in 30 cases, and all were malignant. Score 3 was recorded in 13 cases: one was a carcinoma and 12 were benign. They considered score 3 as negative with an overall sensitivity of 97%, specificity of 100%, PPV of 100%, and NPV of 98% (Rago et al., 2007).
Most publications referring to USE in the evaluation of thyroid nodules revealed sensitivity ranges from 82 to 100%, specificity from 81 to 100%, PPV from 55 to 100%, and NPV from 93 to 100%. The explanations for these ranges were: (a) different machines used, which were either based on gray-scale patterns or color-scale patterns; (b) different score classifications of tissue stiffness – either four-point scores (Friedrich-Rust et al., 2010), five-point scores (Rago et al., 2007; Rago and Vitti, 2009), or six-point scores (Hong et al., 2009); (c) whether score 3, the indeterminate score, is considered negative or positive (Rago and Vitti, 2009); (d) the sample size; (e) the method of case selection.
In the current study, the overall diagnostic accuracy of USE was 95.8%, which agrees with the 94.3% reported by others (Fukunari, 2007). Our result was higher than that reported in other studies (Asteria et al., 2008; Rubaltelli et al., 2009).
However, in the group of nodules that scored 3, 4, and 5, four cases (10.3%) were false positive (score 3 in three cases and score 4 in one case). The score 4 case showed incomplete rim-like calcification on conventional ultrasonography. It is reported in the literature that the USE is not valuable in the presence of calcific shell or coarse calcifications because the US beam does not cross the calcifications, and no tissue strain is obtained by the probe pressure. It is reported that conventional US maintains a pivotal importance in defining which nodules are suitable for USE scoring (Rago et al., 2007). Thus, if this case had been excluded from the beginning of the work, the incorrect scoring would have been minimized. The remaining three benign nodules revealed microfollicular pattern with crowdening of the cells on histopathological examination. Fukunari (2007) reported that the blue zone recorded at the periphery of his studied follicular tumor in the elastography images more or less matches with the hypercellularity of the small irregular follicular structure formed under the capsules on pathological examination. Another previous report concluded that USE is not suitable for the diagnosis of follicular carcinoma, and four of nine follicular carcinomas in the meta-analysis published by Bojunga et al. (2010) were missed on USE. We had three cases of follicular carcinoma in our series that were correctly scored. However, statistically, these nine and three cases are considered unrepresentative.
On comparing the cytological results with the elastography scores, the sensitivity, specificity, PPV, NPV, and accuracy of USE are higher than that of FNAC. To our knowledge, only few reports had studied the relation between the thyroid cytology and elastography score (Rago and Vitti, 2009; Merino et al., 2011). In these works, FNAC was used as the reference standard for the diagnosis of benign nodules, but histopathological evaluations were performed when results suspicious for malignancy or malignant results were obtained on FNAC as well as in indeterminate lesions. Some works were focused mainly on the relation of elastography and indeterminate and nondiagnostic cytological results with the usage of histopathological diagnosis as a reference (Rago et al., 2010).
In the series of 103 patients who have been studied with elastography (gray-scale patterns) for the evaluation of 106 thyroid nodules, all patients included had been referred for the FNA procedure. They concluded that there was a significant statistical association between elasticity score and cytological results, and malignant nodules could be excluded by elastography (Merino et al., 2011). Some authors published an analysis of elastography for the differentiation of benign from malignant thyroid nodules, concluding that USE can be used with high sensitivity and might be a useful method in addition to or even instead of FNAC to select patients for surgery (Bojunga et al., 2010). However others reported that the use of USE alone could miss many malignant nodules. They recommended combined use of BRAF mutation analysis in FNAC and USE (Burger, 2012). Others concluded that USE can be employed in selecting thyroid nodules for FNAC as the clinicians rely more on the FNA procedure because it is easy, simple, acceptable to the patients, gives documented reports, and the only equipment needed is an ordinary plastic syringe. In their series, score 4 or 5 was found in 86.5% of the studied thyroid malignancy and in only 3% of benign nodules (Gietka-Czernel et al., 2010).
In the current study, it was found that, in the case that was incorrectly diagnosed as benign on cytology but turned out to be papillary carcinoma on histopathological study, the elastography examination revealed a correct score (score 4). The case was predominantly cystic. Our elastography result is inconsistent with some publications that concluded that USE of thyroid nodules with cystic components is not reliable and these nodules should be excluded from the study (Rago et al., 2007; Bhatia et al., 2011). The explanation is that the main determinant of nodule stiffness is the fluid content and not the solid areas. The second cytologically incorrect suspicious case, which was diagnosed as papillary hyperplastic nodule on histopathology, was correctly scored on elastographic examination (score 2). It was reported that adenomatous nodules are correctly scored on elastography and their findings differ from that of malignancy (Fukunari, 2007).
Among the 18 cases with a fine-needle aspiration result of follicular neoplasm, 14 had a benign histopathological result and four had malignancy. Elastography scores 3, 4, and 5 were observed in 100% of the four malignant cases and elastography score 2 in 10 of 14 (71.4%) cases who had benign lesions (Table 5). Thus, among the 18 cytological diagnoses of follicular neoplasm (which should be referred for surgical diagnosis), USE may restrict the indications of surgical interference in 10 (55.6%), whereas four cases (22.2%) would be still unnecessarily referred for surgery and four cases (22.2%) would be necessarily referred for surgery. In the series of Rago et al. (2010) on 142 nodules with indeterminate cytological results, only one of 103 nodules classified as negative on elastography had malignancy on histopathological correlation, whereas nine out of 39 nodules with positive elastography were benign. They concluded that USE is an important tool in the presurgical stratification of thyroid cancer in nodules with indeterminate cytology. In another study on 32 nodules with indeterminate cytology, 25 had a benign follicular adenoma on histology and seven had carcinoma. Positive scores were observed in six of seven (86%) patients with carcinoma and negative scores in all 25 patients with benign lesions (Rago et al., 2007). They reported that USE seems to have great potential for the diagnosis of thyroid cancer, especially with indeterminate cytology. However, they recommended larger prospective studies to confirm their results.
In contrast, previous reports concluded that USE, similar to FNAC, is not suitable for the diagnosis of follicular carcinoma (Merino et al., 2011). A lower diagnostic accuracy was reported for the detection of follicular thyroid carcinoma by elastography (Asteria et al., 2008; Dighe et al., 2008).
FNAC is safe, easy, fast, and highly useful in differentiating benign from malignant thyroid nodules with 97.1% sensitivity, 75.4% specificity, and 83.3% diagnostic accuracy. The cytodiagnostic error of some cases can be minimized or avoided by giving greater consideration to the inherent diagnostic difficulties associated with cytological interpretation.
USE is a promising imaging technique that can assist in the differential diagnosis of thyroid nodules with higher sensitivity, specificity, PPV, NPV, and diagnostic accuracy compared with FNAC. USE is helpful in the identification of nodules that should be left alone and for which follow-up would be sufficient and has led to proper planning of surgery in malignant cases. Therefore, it is recommended in the workup of all thyroid nodules in association with FNAC as a multidisciplinary approach that can ensure the best results.
There are some limitations in this study that need to be addressed. The studied cases were selected to be candidates for thyroid surgery, and in principle this could have influenced the sample size. Future studies based on a totally blinded selection will be necessary to provide conclusive evidence on the role of USE in the management of thyroid nodules. Another limitation is that only three follicular carcinoma cases and one medullary carcinoma case were included in the study group. Statistically, the numbers are considered unrepresentative. Further studies are required to evaluate the USE score for different types of thyroid cancer with a special interest in follicular carcinoma.
Conflicts of interest
There are no conflicts of interest.
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