Fig. 23.3 Graves' disease. (A) Clusters of follicular cells with fine granular cytoplasm, anisonucleosis, and marginal vacuoles (May-Grunwald-Giemsa x MP).
(B) Follicular cells with dark-blue lysosome granules bound to vacuoles (paravacuolar granules) (May-Grunwald-Giemsa x HP). (C) Group of follicular cells with
marginal vacuoles close to a group of Hurthle cells with ample bluish cytoplasm and pleomorphic nuclei (May-Grunwald-Giemsa x HP).
cuboidal cells, the largest ones showing papillary projections,
pale colloid, and numerous resorption vacuoles. Lymphoid infil-
trates, Hurthle cells, and granulomas are seen occasionally.24,64
The reported incidence of carcinoma in Graves' disease is 5% of
cases, of which papillary carcinoma is the most common.99
Key features of Graves' disease
• Blood-stained smear with little or no colloid;
• Numerous pale follicular cells dispersed or arrayed in
• Discrete to moderate anisonucleosis; and
• Marginal cytoplasmic vacuoles.
The usefulness of FNA in Graves' disease is limited because
the diagnosis is generally made on the basis of clinical fea-
tures and laboratory data. The marginal vacuoles are irregularly
shaped, situated peripherally in the groups of follicular cells,
and show an optically clear unstained center with a more dense
periphery ranging from pink to deeply eosinophilic in MGG-
stained smears (Fig. 23.3A).100 Cells with this type of vacuole are
also called "flare cells" or "flame cells" because of their irregular
and radiating appearance. In routine histologic section, the mar-
ginal vacuoles cannot be identified with certainty, and they do
not correspond to the pinocytosis or resorption of colloid (scal-
loping appearance) frequently observed in hyperactive follicles;
they are due to expansion of endoplasmic reticulum caused by
the low pressure in the syringe during FNA and the flattening of
individual cells in dry-fixed smears stained by MGG.100 Recently,
Das has postulated that marginal vacuoles, rather than pinocy-
totic vesicles or dilated cisternae of endoplasmic reticulum, rep-
resent the diffusing out of thyroid hormones at the basal aspect
of follicular cells on their way to interfollicular capillaries.101 Mar-
ginal cytoplasmic vacuoles, although suggestive of a diagnosis of
thyrotoxicosis, are nonspecific because they are also encountered
in nontoxic goiter, Hashimoto's thyroiditis, and follicular neo-
plasms and a follicular variant of papillary carcinoma.100-102
Anisokaryosis is particularly marked in patients treated for long
periods with antithyroid drugs or radioactive iodine.84,103 Other,
less constant cytologic findings are lymphocytes, Hurthle cells,
and paravacuolar cytoplasmic granules in the follicular cells
(Figs 23.3B and 22.3C). The existence of multinucleate cells and
epithelioid granulomas has also been reported.104,105
To evaluate the smear, clinical and physical findings must
be considered because the cytologic picture is not specific; it
is common to all hyperfunctional thyroid states (hot nodular
goiter, toxic adenoma, and primary hyperthyroidism).84,100
The differential diagnosis of hyperthyroidism includes other
entities that may yield highly cellular, colloid-poor aspirates,
such as follicular neoplasms and papillary carcinoma. Hashi-
moto's thyroiditis also should be considered when Hurthle cells
and lymphoid infiltrates are found. A diagnosis of follicular car-
cinoma based on marked cellular pleomorphism in a patient
with treated toxic goiter should be made with caution.
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