Encapsulated follicular thyroid tumor with equivocal nuclear changes, so‐called well‐differentiated tumor of uncertain malignant potential: a morphological, immunohistochemical, and molecular appraisal

There is a continuous debate regarding the classification of thyroid follicular lesions and the term “well‐differentiated tumor of uncertain malignant potential (WDT‐UMP)” was recently introduced to cover this problematic spectrum of tumors. The objective of this study was to reappraise WDT‐UMP using morphological, immunochemical, and molecular analysis and to shed more light on encapsulated thyroid follicular‐patterned tumors. A total of 30 cases of WDT‐UMP with equivocal papillary thyroid carcinoma‐type nuclear changes (PTC‐N) or focal unequivocal PTC‐N were examined. As a control, follicular adenoma (n = 29), follicular carcinoma (n = 8), hyalinizing trabecular adenoma (n = 5), and PTC (n = 48) were included. HBME‐1, cytokeratin 19, and galectin‐3 were positive in 12 (40.0%), 10 (33.3%) and 11 (36.7%) cases of WDT‐UMP, respectively. According to the positivity of those markers, significant differences were obtained between WDT‐UMP and PTC encapsulated common type (P = 0.028, 0.010, and 0.004, respectively), infiltrative follicular variant (P = 0.020, 0.026, and 0.008, respectively), and infiltrative common type (P = 0.004, 0.001, and 0.005, respectively), but not between WDT‐UMP and follicular adenoma or follicular carcinoma. BRAFV600E mutation was absent but RET/PTC1 rearrangement was found in only two (6.7%) cases of WDT‐UMP. None of the 20 patients with WDT‐UMP developed recurrence, with an average follow‐up of 80 months. These findings indicate that WDT‐UMP has a favorable outcome and is distinct from PTC in morphological, immunohistochemical, and molecular characteristics. We propose that WDT‐UMP should be classified as “well‐differentiated tumor with uncertain behavior”. (Cancer Sci 2011; 102: 288–294)