Background: RET alterations are found in 60% of sporadic medullary thyroid cancers (MTCs). RET specific tyrosine kinase inhibitors (TKI), selpercatinib and praseltinib, have improved progression free survival in metastatic patients with tolerable adverse effects. Langerhans cell histiocytosis (LCH), an unrelated clonal neoplasm of myeloid dendritic cells, is usually driven by alterations in the MAPK pathway. We report an MTC patient who developed LCH whilst being treated with selpercatinib and postulate that inhibition of RET may have led to paradoxical activation of its downstream pathway and driven the progression of LCH.
Clinical Case: A 22 year old female non smoker presented with widely metastatic MTC with serum calcitonin of 25,600ng/L. After debulking surgery a somatic RETM918T alteration was identified and she was commenced on selpercatinib. She had a partial response with minimal adverse effects. 24 months after treatment, 3-4mm lung nodules were identified on imaging. Although asymptomatic, the nodules doubled in size in 8 weeks. 18FDG-PET scan showed low avidity. Core biopsy revealed an inflammatory infiltrate rich in eosinophils with lesser numbers of histiocytes including neoplastic Langerhans cells. Molecular testing identified a complex BRAF mutation BRAF p.(V600_K601>D) at a variant allele frequency of 4.76% in keeping with expected neoplastic cellularity and confirming the diagnosis of pulmonary LCH. Although this BRAF alteration has not previously been reported in LCH, it has been reported in melanoma where it is responsive to BRAF/MEK inhibition. As the patient is asymptomatic, she was commenced on inhaled steroids and close monitoring.
Conclusion: This is the first case report of RET kinase inhibition and concurrent LCH. We speculate treatment with a RET specific TKI may activate dormant LCH driven by a BRAF mutation. We recommend continued vigilance for the possibility that RET inhibition may activate other underlying neoplasms with mutations in the MAPK pathway.