Diagnosis and treatment of medullary thyroid cancer in four Hungarian university centers (2000-2023)

Introduction: Medullary thyroid carcinoma is a rare malignancy originating from the calcitonin-secreting parafollicular C-cells. Despite distinct histological and biochemical markers, diagnosing and managing of medullary thyroid carcinoma remain complex. Objective and method: Our study retrospectively analyzed medullary thyroid carcinoma cases from four Hungarian university centers diagnosed between 2000 and 2023. Demographic data, serum calcitonin and calcitonin doubling time, disease stage, therapeutic interventions and disease progression were investigated. Results: Out of 171 cases, 156 patients were eligible for inclusion. Lymph node involvement was seen in 37.5% of cases at diagnosis. Preoperative calcitonin levels were recorded in 84.2% of cases, and fine-needle aspiration biopsy was performed in 72%. Preoperative cytology confirmed medullary thyroid carcinoma in 67.4% of cases. Nearly one-third of the patients were diagnosed with stage IV. Total thyroidectomy with lymph node dissection was performed in 53.8% of cases, with a higher rate after 2015 (p<0.05). Based on postoperative serum calcitonin measurements, 44 patients were considered cured. Disease progression occurred in 47.8% of patients. In the first postoperative year, calcitonin measurements were available for 75% of patients. A postoperative calcitonin doubling time (Ct-DT) of less than two years was associated with significantly lower progression-free survival than a Ct-DT of more than two years (p<0.05). Discussion: Genetic testing identified germline receptor tyrosine kinase (RET) mutations in 34.2% of patients, predominantly at codon 634. Tyrosine kinase inhibitors were used in 35 advanced cases. Treatment with selpercatinib was associated with less frequent disease progression and fewer adverse events than with the use of multi-kinase inhibitors (p<0.05). Conclusion: Despite recent advances, medullary thyroid carcinoma management remains challenging. Although the routine screening is debated, calcitonin measurement remains crucial for preoperative diagnosis. Fine-needle aspiration biopsy alone often fails to provide an accurate preoperative diagnosis; immunohistology or calcitonin measurement from washout fluid enhances sensitivity. Surgery can cure localized diseases, while advanced cases require personalized approaches. Germline and somatic RET mutation analyses are essential for selecting targeted therapies for medullary thyroid carcinoma.