Abstract
Primary thyroid lymphoma is rare, accounting for less than 5% of all thyroid malignancies. It typically develops in patients with Hashimoto thyroiditis who have approximately a 70 fold higher risk than other patients. The mechanisms underlying the development of thyroid lymphoma remain unclear, and no mouse model has been described. For our studies of papillary thyroid cancer and lymphocytic thyroiditis, we crossed TPO-Cre-ER transgenic mice and hBRAF(V600E) knock-in mice onto the NOD.H2(h4) background to establish TPO-Cre-ER_ hBRAF(V600E) NOD.H2(h4) strain where papillary thyroid cancer is induced by the injection of tamoxifen and thyroiditis by the administration of iodine in the drinking water. Mice injected with corn oil or drinking regular water served as control. In 3 of 121 mice, TPO-Cre-ER_ hBRAF(V600E) NOD.H2(h4) mice injected with corn oil and drinking iodinated water we observed the development of thyroid lymphoma. At about 6 months after the injection of corn oil, these mice developed a marked increase in the size of the thyroid gland, which appeared hypoechoic on thyroid ultrasound. Fine needle aspiration on the thyroid gland under ultrasound was performed, along with measurement of TPO antibodies, H&E thyroid histology, immunohistochemistry, and flow cytometry at the time of sacrifice. Histology established a diagnosis of Hodgkin lymphoma with the typical Reed Sternberg cells. Flow cytometry identified an increased frequency of CD8(+) effector memory T cells in the thyroid lymphoma. TPO antibodies were significantly higher in mice with thyroid lymphoma than in those without, perhaps suggesting their utility as predictive biomarkers. In summary, we report a mouse model of thyroid lymphoma that evolves from a background of lymphocytic thyroiditis with a predictable natural course that can be monitored by thyroid ultrasound and TPO antibodies. This model can be used to study the mechanisms and development of thyroid lymphoma in patients.