The preoperative diagnosis of thyroid lesions is not the only challenge faced by pathologists. Very often, establishing the differential diagnosis between benignancy and malignancy of a thyroid nodule, based only on the histopathological exam, can be quite difficult.
One of the greatest research challenges involving well-differentiated thyroid carcinoma is to develop a method to enable the correct differential diagnosis between benign and malignant lesions, trying to avoid a diagnostic surgery. To really reach this objective a test would need to have an especially high sensitivity rate,
 but it has not yet been achieved in the literature even when genomic classifiers are employed
. Thus, the search for a “marker” that enhances this diagnostic capability is ongoing
Cytokeratin-19 (CK-19) expression in thyroid nodules is in general intense and diffuse in papillary carcinoma and heterogeneous labeling in carcinoma and in follicular adenoma, with nil or low expression in other benign lesions
[30, 82]. Galectins, especially galectin-3, are suggested to play a role in the pathogenesis of well-differentiated thyroid carcinoma, particularly in papillary carcinoma
 and, therefore, it is one of the markers most commonly used to assist in distinguishing thyroid lesions. Hector Battifora mesothelial-1 (HBME-1) has been demonstrated to be important as a thyroid marker of follicular origin, with greater affinity to malignant lesions when compared to benign lesions
. Because of that, they are the three most used immunomarkers in pathology practice and each of them had different rates of false-negatives and false-positive results and some authors advocate that a panel of the three markers might be more helpful than the use of a single immunomarker, improving the specificity, positive and negative predictive value and thus diagnostic accuracy
The main contribution of this meta-analysis was to precisely quantify the accuracy of values of these three important markers employed in clinical practice. Several literature reviews have already been published but the present study is the first to analyze cumulative data and is worthy for this reason.
As demonstrated, the association of positivity for CK-19, Gal-3 and HBME-1 in IHC assays and the preoperative expression of galectin-3 in ICC samples proved to be highly accurate tests in the distinction between benign and well-differentiated thyroid carcinoma. This is further noted when heterogeneity factors were disregarded; the SROC analysis showed a global accuracy of more than 90% in this situation.
However, these results must be analyzed with great care. Despite the fact that the accuracy rates are, in general, high there is a considerable percentage of false-results. When a diagnostic test could potentially produce a false-negative result this is not a good reason to take a watchful waiting approach, especially when a malignant neoplasm is the object of the study, and many patients are subjected to a theoretically unnecessary diagnostic surgery, with associated morbidity and mortality rates.
Another important point of this study was the determination of heterogeneity variables involved in the analysis of tumors markers employed in thyroid nodule diagnosis. Thus, the combination of markers, the exclusion of Hürthle cells and the review of what must be considered positive immunostaining were the main heterogeneity factors identified. Another possible heterogeneity factor that might be considered and that was not possible to evaluate in this research has to do with the technical methodology applied in the immunohistochemical reactions like specimen fixation, monoclonal or polyclonal antibodies, biotin-free detection method, etc. These parameters should be standardized in future works in order to achieve uniformity in the studies and improvement in diagnostic accuracy of the immunocytochemistry and immunohistochemistry methods.
Nevertheless, this study has some limitations. The present review might have been influenced by publication bias since it was limited to articles in English and included only published articles. However, the wide search criteria applied and the rigorous exclusion criteria have helped to ensure the inclusion of the most relevant studies.
In summary, this meta-analysis demonstrated that the three studied immunomarkers are accurate in making a pre- and postoperative distinction between benign and malignant thyroid lesions with accuracy of around 90% for both immunocytochemistry and immunohistochemistry assays, despite avoiding variables responsible for heterogeneity in the analysis. Although, the search for other molecular markers must continue in order to enhance this diagnostic accuracy since the results found still show persistency of false-negative and false-positive tests.