The distinction of benign from malignant follicular thyroid neoplasms remains a difficult task in diagnostic fine-needle aspiration cytology, and some discrepant results have been reported for the individual immunocytochemical markers of malignancy proposed so far. The aim of this study was to test if the combined use of a panel of markers could improve the diagnostic accuracy in the preoperative cytological evaluation of 'follicular neoplasms' in an attempt to reduce the number of thyroidectomies performed for benign lesions. The immunocytochemical expression of galectin-3, HBME-1, thyroperoxidase, cytokeratin-19 and keratan-sulfate was retrospectively analyzed in 125 consecutive fine-needle aspiration samples (cell blocks) of indeterminate diagnoses of 'follicular thyroid neoplasm', and compared with their corresponding surgical specimens, including 33 follicular carcinomas, 42 papillary carcinomas and 50 follicular adenomas. Statistical analysis on each marker confirmed that galectin-3 and HBME-1 were the most sensitive (92% and 80% respectively) and specific (94% and 96% respectively) molecules. The use of these two markers sequentially in non-oncocytic lesions (testing HBME-1 as a second marker whenever galectin-3 proved negative) increased the sensitivity and specificity up to 97% and 95% respectively. In oncocytic lesions, HBME-1 proved to be less sensitive, and the sequential combination of galectin-3 and cytokeratin-19 reached 100% of both specificity and sensitivity. Our data showed that, as compared with the use of single markers, the sequential combination of two markers represents the most accurate immunohistochemical panel in managing patients with a fine-needle aspiration biopsy diagnosis of 'follicular neoplasms', especially in otherwise controversial categories such as oncocytic tumours. The combination of three or more markers did not substantially improve the diagnostic accuracy of the test.

Well-differentiated encapsulated tumors of the thyroid gland with a follicular architecture may cause diagnostic difficulties. Questionable vascular or capsular penetration may raise the possibility of a follicular carcinoma, while focal nuclear clearing and grooves may suggest a diagnosis of papillary carcinoma. A proposal has recently been made to designate cases showing suggestive but not conclusive morphological evidence of malignancy along these lines as well-differentiated or follicular tumors of uncertain malignant potential. The aim of the present study was to investigate the expression and diagnostic role in well-differentiated or follicular tumors of uncertain malignant potential of Galectin-3 and HBME-1, two malignancy-related markers. A total of 21 tumors fulfilling the criteria of well-differentiated or follicular tumors of uncertain malignant potential were collected from two institutions, including eight cases with questionable vascular and/or capsular invasion and 13 cases with some degree of nuclear changes in the form of clearing, grooves, and/or pseudoinclusions. Tumors in the first group expressed HBME-1 and Galectin-3 focally (less than 25% of tumor cells) in 5/8 and 3/8 cases, respectively, with 62.5% of cases reacting for at least one marker. Cases in the second category expressed HBME-1 and Galectin-3 in 9/13 and 10/13 cases, respectively, with 92.3% of cases having at least one marker expressed. These findings indicate that HBME-1 and Galectin-3 are heterogeneously distributed in these borderline tumors, but that a strong and diffuse expression of HBME-1 and to a lower extent of Galectin-3 was preferentially observed in the group characterized by nuclear changes which were similar but less developed than those of conventional papillary carcinoma. The relationship found between the markers investigated and these nuclear changes suggests that the tumors containing them are pathogenetically linked to papillary carcinomas.

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