Marginal vacuoles (fire-flare appearance) in fine needle aspiration smears of thyroid lesions: does it represent diffusing out of thyroid hormones at the base of follicular cells?

Marginal vacuoles (MVs) or fire-flare appearance in May-Grünwald Giemsa stained fine needle aspiration (FNA) smears was initially described as a distinctive feature of thyrotoxic goiter in hyperthyroidism, but was subsequently found in various nontoxic thyroid lesions, both non-neoplastic and neoplastic. Although these MVs have been characterized as dilated endoplasmic reticulum, and manifestation of active pinocytosis/vacuoles containing colloid, their exact nature is not so far resolved. In this connection, FNA smears of 82 hyperplasia cases, consisting of 71 colloid goiters and 11 hyperplastic nodules (HN), and 76 thyroid neoplasms of follicular epithelium origin were reviewed to detect the MVs and grade them on a sliding scale of + (scanty), ++ (moderate), and +++ (abundant). A hypothesis was put forth regarding the nature of MVs based on their cytomorphological features as observed by us and the physiological/pathophysiological mechanisms related to synthesis, storage and secretion of thyroid hormones described in the literature. The frequency of MVs in neoplastic goiters (50.0%) was significantly lower than that in HN (90.9%, P = 0.0196) but higher than that in colloid goiters (29.6%, P = 0.0124). MVs were present in a significantly higher number of follicular neoplasm (FN; 85.7%) than in papillary thyroid carcinoma (44.4%, P = 0.0069) and Hurthle cell neoplasm (25.0%, P = 0.0083). Among the variants of papillary thyroid carcinoma (PTC), follicular variant showed MVs in 94.1% cases, which was higher than those in usual variant (23.5%, P < 0.0001), tall cell variant (16.7%, P = 0.001), and PTC with a significant tall cell component (25.0%, P = 0.001). It was possible to demonstrate pinocytic vesicles on one side (luminal aspect) and MVs on the other side (basal aspect) of follicular cells in colloid goiters. In the aspirates from follicular lesions such as HN, FNs, and follicular variant of PTC, numerous MVs were found to be radiating from the basal aspect of follicular cells in the intact follicles with or without colloid in the central lumen. Since MVs in literature have been linked to thyrotoxicity in Graves' disease and neoplasms with a follicular pattern, our findings suggest that MVs represent the diffusing out of thyroid hormones (T(3) and T(4)) from the basal aspect of follicular cells on their way to interfollicular capillaries.