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. BRAF(V600E) 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".