The histologic distinction of follicular patterned lesions of thyroid, that is follicular adenoma, follicular carcinoma, and the follicular variant of papillary thyroid carcinoma can be extremely difficult. The differential diagnostic criteria regarding nuclear features of papillary thyroid carcinoma are subjective, resulting in high interobserver variability. Although papillary thyroid carcinoma metastasizes mainly via lymphatic vessels, whereas follicular carcinoma spreads mostly hematogenously, there are no data regarding utility of objective quantitative criteria such as lymphatic and general blood vessel density for the differential diagnosis of these lesions. In this study, 35 follicular patterned lesions of thyroid (14 follicular adenomas, 10 follicular carcinomas, and 11 of the follicular variant of papillary thyroid carcinomas) were evaluated immunohistochemically. An assessment of intra- and peritumoral lymphatic vessel density was performed using novel lymphatic endothelium-specific marker D2-40, and the intra- and peritumoral general vessel density was determined by the panendothelial marker CD31. There were no significant differences in the intra- and/or peritumoral general vessel densities, and peritumoral lymphatic vessel densities among follicular adenoma, follicular carcinoma and the follicular variant of papillary thyroid carcinoma. In contrast, the intratumoral lymphatic vessel density was significantly higher in the follicular variant of papillary thyroid carcinoma than in either follicular adenoma or follicular carcinoma (34.63, 15.04, and 0.11 respectively; P<0.0001). The results of the study show that intratumoral lymphatic vessel density may serve as a useful tool in the differential diagnosis of follicular patterned lesions of thyroid. © 2005 USCAP, Inc All rights reserved.