Medullary thyroid cancer (MTC) is a rare thyroid cancer arising from the parafollicular cells. It is predominantly caused by mutations in the RET proto-oncogene. Cabozantinib and vandetanib are non-selective multi-kinase inhibitors licensed to treat MTC, but they have significant side effects (diarrhoea, hypertension and palmar–plantar erythrodysaesthesia syndrome). Selpercatinib is a selective RET kinase inhibitor, currently in phase III trials.

Langerhans cell histiocytosis (LCH) is a rare clonal neoplasm of myeloid dendritic cells not associated with MTC. However, LCH is caused by mutations in the BRAF gene downstream of RET.

Wu et al. report a case of a 22-year-old woman with metastatic MTC who developed LCH while being treated with selpercatinib. She presented with six months of diarrhoea, night sweats, weight loss and hot flushes. Imaging and biopsies confirmed MTC, and she underwent a thyroidectomy followed by selpercatinib treatment, leading to significant symptom improvement and reduced serum calcitonin levels (25,600 to 56ng/l, reference <20 ng/l). After two years of stable disease, bilateral pulmonary nodules were found that rapidly increased in size (4 to 8mm). Lung biopsy was consistent with LCH due to a rare BRAF mutation (p.V600_K601>D). She was treated with inhaled steroids, resulting in the improvement of the lung nodules and her symptoms.

This case highlights that tyrosine kinase inhibitors, such as selpercatinib, may paradoxically increase MAPK signalling, potentially leading to secondary neoplasms.

Read the full article in Endocrinology, Diabetes & Metabolism Case Reports 23-0079 https://doi.org/10.1530/EDM-23-0079