Remission of Ectopic Cushing Syndrome Secondary to Medullary Thyroid Cancer With Vandetanib and Selpercatinib

Abstract

Medullary thyroid cancer (MTC) is a neuroendocrine tumor associated with activating mutations of the rearranged during transfection (RET) proto-oncogene. These tumors may rarely secrete adrenocorticotropin or corticotropin-releasing hormone, resulting in a paraneoplastic ectopic Cushing syndrome (ECS). Paraneoplastic ECS carries a high risk of mortality, and management is difficult due to the lack of response to antiadrenal therapies. We report on a 37-year-old man who was diagnosed with metastatic MTC and reported symptoms of cortisol excess with laboratory testing in keeping with ECS. He began treatment with vandetanib, a multitargeted tyrosine kinase inhibitor, which resulted in decreased tumor burden as well as clinical and biochemical resolution of ECS. Due to progressive structural disease 10 months later, he was switched to the selective RET inhibitor selpercatinib, which was followed by a rapid reduction of cortisol nearing the threshold of adrenal insufficiency. Tumor markers were also improved, and repeat imaging showed decreased tumor burden. Our case highlights the efficacy of tyrosine kinase inhibitors in the management of paraneoplastic ECS. Selective RET inhibitors may emerge as preferred targeted treatment options due to better efficacy and toxicity profiles compared to multitargeted inhibitors. Clinicians should monitor for adrenal insufficiency with the use of selective RET inhibitors.

Keywords: MTC; RET inhibitors; ectopic Cushing syndrome; medullary thyroid cancer; treatment; tyrosine kinase inhibitors; vandetanib.

Figure 1.

A, Thyroid ultrasound revealing a large 50 × 38 mm mass in the left lobe of the thyroid with calcifications, Thyroid Imaging Reporting and Data System 4; and B, fine-needle biopsy of the left neck mass demonstrating metastatic medullary thyroid carcinoma: Papanicolaou stain demonstrating clusters of cells with polygonal and spindle cell morphology associated with polarized nuclei and dispersed chromatic pattern with granular cytoplasm (magnification 1000×).

Figure 2.

Computed tomography images demonstrating A, axial and B, coronal views of left neck mass.

Figure 3.

Histopathologic analysis of hepatic metastases consistent with metastatic medullary thyroid carcinoma (magnification 200×).

Figure 4.

Rapid resolution of 24-hour urine cortisol and calcitonin levels following initiation of vandetanib and selpercatinib.

Figure 5.

Decrease in tumor burden following initiation of selpercatinib. A, Computed tomography (CT) imaging demonstrating metastases to the left upper prevascular nodes prior to selpercatinib initiation (2.24 cm) and 3 months following selpercatinib initiation (0.99 cm). B, CT imaging demonstrating metastases to subcarinal lymph nodes prior to selpercatinib initiation (1.50 cm) and 3 months following selpercatinib initiation (0.92 cm).