The Thyroid Pathologist Meets Therapeutic Pharmacology

Abstract

The effects of many pharmacological agents on thyroid function are well known. Direct influences on measurements of thyroid function tests are also described. However, certain classes of drugs produce morphological changes in the gland. This review focuses on the significance of the following drug classes for the thyroid pathologist: iodine, antithyroid drugs, psychotropic drugs, antibiotics, cardiotropic drugs, antidiabetic drugs, and immunomodulatory agents. Radioactive iodine initially induces mild histologic changes; however, the long-term effects include marked follicular atrophy, fibrosis, and nuclear atypia-changes that vary depending on the pre-therapy condition of the gland. Some psychotropic drugs have been associated with a spectrum of inflammatory changes throughout the gland. The tetracycline class of antibiotics, namely minocycline, can lead to a grossly black thyroid gland with pigment seen in both colloid and follicular epithelial cells while variably present within thyroid nodules. The surgical pathologist most commonly sees an amiodarone-affected gland removed for hyperthyroidism, and the histologic findings again depend on the pre-therapy condition of the gland. While GLP-1 receptor agonists carry an FDA black box warning for patients with a personal or family history of multiple endocrine neoplasia or medullary thyroid carcinoma, the C cell hyperplasia originally noted in rats has not borne out in human studies. Finally, thyroiditis and hypothyroidism are well known complications of checkpoint inhibitor therapy, and rare cases of severe thyroiditis requiring urgent thyroidectomy have been reported with unique histologic findings. In this review, we describe the histologic findings for these drugs and more, in many cases including their functional consequences.

Keywords: Antithyroid drugs; Checkpoint inhibitors; GLP-1 receptor agonists; Iodine; Lithium; Minocycline; Thyroid histology.

Fig. 1

Atrophic thyroid from patient with history of radioiodine treatment for Graves disease 15 years before and had developed a new nodule (not shown). The background thyroid shows extensive fibrosis follicular atrophy and clusters of stromal lymphocytes (a, H&E, original 20 × magnification) and high-power magnification of the follicles shows oncocytic cytoplasm and enlarged, atypical nuclei (b, H&E, original 400 × magnification)

Fig. 2

Lithium effects on the thyroid can manifest histologically as chronic lymphocytic thyroiditis (H&E, original 100 × magnification)

Fig. 3

Minocycline use can result in the accumulation of black pigment, which can be observed grossly as a black thyroid as seen in this autopsy (a). Histologically, black pigment is seen predominantly accumulating within the colloid but also within thyroid follicular cells. In this example, increased pigment accumulation is present within a hyperplastic nodule compared to the surrounding parenchyma (b, H&E, original 40 × magnification). On high power, the pigment is fine and granular, forming loose but distinct aggregates in colloid. Within follicular cells, an apical distribution can be seen (c, H&E, original 200 × magnification). In this example, essentially no pigment is seen within an encapsulated papillary thyroid carcinoma while robust pigmentation is present in the surrounding parenchyma (d, H&E, original 100 × magnification)

Fig. 4

This thyroid is from a 78-year-old patient with severe hyperthyroidism who had been treated with amiodarone for cardiac arrythmias. Part a shows a follicle with prominent histiocytic reaction to colloid (H&E, 100 × original magnification). Part b is higher power to show follicular epithelium replaced by histiocytes, which also are present in the colloid (H&E, 400 × original magnification)

Fig. 5

Histologically, pembrolizumab-associated thyroiditis shows diffuse involvement of the gland with a vaguely nodular appearance on low power (a, H&E, original 40 × magnification). At higher magnification, a robust histiocytic infiltrate fills most follicles, replacing most of the follicular cells with only rare intact follicle remaining (b, H&E, original 200 × magnification). The intervening inflammatory infiltrate is predominantly B and T lymphocytes. PD-L1 staining predominantly highlights the membranes of histiocytes (c, original 200 × magnification), which are confirmed by a CD68 immunohistochemical stain (d, original 200 × magnification)