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. Orv Hetil. 2024; 165(44): 1735–1745.
Bevezetés: A medullaris pajzsmirigyrák ritka pajzsmirigydaganat, amely a kalcitonint termelő, parafollicularis C-sejtekből ered. Annak ellenére, hogy egyedi hisztológiai és biokémiai markerekkel rendelkezik, a medullaris pajzsmirigyrák diagnosztizálása és kezelése továbbra is összetett feladat. Célkitűzés és módszer: Tanulmányunkban négy magyar egyetemi központban 2000 és 2023 között diagnosztizált medullaris pajzsmirigyrák eseteket elemeztünk restrospektíven. Vizsgáltuk a demográfiai adatokat, a biokémiai markereket, meghatároztuk a betegség stádiumát, elemeztük a beavatkozás típusait, valamint a szérumkalcitonin kettőződési idejét és a betegség lefolyását. Eredmények: A 171 esetből 156 beteg volt alkalmas a bevonásra. A diagnózis időpontjában nyirokcsomó-érintettség 37,5%-ban volt jelen. Preoperatív kalcitoninmeghatározás az esetek 84,2%-ában, vékonytű-aspirációs biopszia a betegek 72%-ában történt. A preoperatív citológia az esetek 67,4%-ában igazolta a medullaris pajzsmirigyrákot. A betegek közel egyharmadát IV. stádiumban diagnosztizáltuk. Totalis thyreoidectomia és nyirokcsomó-dissectio 53,8%-ban történt, ez az arány nagyobb volt 2015 után, mint korábban (p<0,05). A kalcitoninértékek alapján 44 beteget gyógyultnak tekintettünk a műtét után. Progresszív betegséget az esetek 47,8%-ában észleltünk. A műtét utáni első évben a betegek 75%-ában volt elérhető kalcitoninmérés. A két évnél rövidebb posztoperatív kalcitoninkettőződési idő szignifikánsan rövidebb progressziómentes túléléssel járt, mint a két évnél hosszabb kalcitoninduplázódási idő. Megbeszélés: A genetikai vizsgálatok az esetek 34,2%-ában azonosítottak csíravonali tirozin-kináz-receptor (RET)-mutációkat, főként a 634-es kodonban. Tirozin-kináz-inhibitorokat 35 előrehaladott esetben alkalmaztunk. Szelperkatinibkezelés mellett ritkábban észleltünk betegség progressziót, és kevesebb volt a mellékhatás, mint a multikináz-gátlók adása esetén. Következtetés: A medullaris pajzsmirigyrák kezelése továbbra is kihívást jelent. Bár rutinszerű mérése vitatott, a preoperatív kalcitoninmérés továbbra is kulcsfontosságú a diagnózisban. A vékonytű-aspirációs biopszia önmagában gyakran nem elegendő a pontos preoperatív diagnózishoz; immuncitológia vagy a szívadékból meghatározott kalcitonin növelheti a preoperatív diagnosztika érzékenységét. Lokális betegségek esetén a műtét kuratív lehet, míg az előrehaladott esetek egyedi megközelítést igényelnek. A csírasejtes és szomatikus RET-mutációk elemzése elengedhetetlen a medullaris pajzsmirigyrák célzott kezeléséhez. Orv Hetil 2024; 165(44): 1735–1745.
Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009; 19: 565–612. Erratum in: Thyroid 2009; 19: 1295.
Locati L, Cavalieri S, Dal Maso L, et al. Rare thyroid malignancies in Europe: data from the information network on rare cancers in Europe (RARECAREnet). Oral Oncol. 2020; 108: 104766.
Kitahara CM, Sosa JA. The changing incidence of thyroid cancer. Nat Rev Endocrinol. 2016; 12: 646–653.
Lim H, Devesa SS, Sosa JA, et al. Trends in thyroid cancer incidence and mortality in the United States, 1974–2013. JAMA 2017; 317: 1338–1348.
Miranda-Filho A, Lortet-Tieulent J, Bray F, et al. Thyroid cancer incidence trends by histology in 25 countries: a population-based study. Lancet Diabetes Endocrinol. 2021; 9: 225–234.
Mathiesen JS, Kroustrup JP, Vestergaard P, et al. Incidence and prevalence of sporadic and hereditary MTC in Denmark 1960-2014: a nationwide study. Endocr Connect. 2018; 7: 829–839.
Opsahl EM, Akslen LA, Schlichting E, et al. Trends in diagnostics, surgical treatment, and prognostic factors for outcomes in medullary thyroid carcinoma in Norway: a nationwide population-based study. Eur Thyroid J. 2019; 8: 31–40.
Konrády A. Differentiated thyroid cancer – 2009. [Differenciált pajzsmirigyrák – 2009.] Orv Hetil. 2011; 152: 163–170. Hungarian]
Kovács GL, Hella Z, Vass L, et al. Retrospective analysis of low-risk differentiated thyroid tumours: is lobectomy the adequate approach? [Kis rizikójú differenciált pajzsmirigydaganatok retrospektív analízise: lobectomia a megfelelo választás?] Orv Hetil. 2022; 163: 1074–1081. [Hungarian]
Lévay B, Tóth E, Péter I, et al. Results of surgical treatment of papillary thyroid cancer with lymph node metastasis – review of our data in a 5-year period. [Nyaki áttétet adó papillaris pajzsmirigyrák sebészi kezelésének eredményei – 5 éves anyagunk feldolgozása.] Orv Hetil. 2024; 165: 83–88. [Hungarian]
Patocs A, Klein I, Szilvasi A, et al. Genotype-phenotype correlations in Hungarian patients with hereditary medullary thyroid cancer. Wien Klin Wochenschr. 2006; 118: 417–421.
Réti Z, Tabák ÁG, Garami M, et al. Spontaneous and treatment-related changes of serum calcitonin in medullary thyroid cancer: long-term experience in a patient with multiple endocrine neoplasia type 2B. JCO Precis Oncol. 2024; 8: e2300675.
Sira L, Balogh Z, Vitális E, et al. Medullary thyroid cancer workup initiated by unexpectedly high procalcitonin level-endocrine training saves life in the COVID-19 unit. Front Endocrinol (Lausanne) 2021; 12: 727320.
Raue F, Frank-Raue K. Genotype-phenotype correlation in multiple endocrine neoplasia type 2. Clinics (Sao Paulo) 2012; 67(Suppl 1): 69–75.
Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association Guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25: 567–610.
Gild ML, Clifton-Bligh RJ, Wirth LJ, et al. Medullary thyroid cancer: updates and challenges. Endocr Rev. 2023; 44: 934–946.
Kesby NL, Papachristos AJ, Gild M, et al. Outcomes of advanced medullary thyroid carcinoma in the era of targeted therapy. Ann Surg Oncol. 2022; 29: 64–71.
Meijer JA, le Cessie S, van den Hout WB, et al. Calcitonin and carcinoembryonic antigen doubling times as prognostic factors in medullary thyroid carcinoma: a structured meta-analysis. Clin Endocrinol (Oxf.) 2010; 72: 534–542.
Miyauchi A, Kudo T, Kihara M, et al. Spontaneous deceleration and acceleration of growth rate in medullary thyroid carcinomas suggested by changes in calcitonin doubling times over long-term surveillance. World J Surg. 2019; 43: 504–512.
Miyauchi A, Onishi T, Morimoto S, et al. Relation of doubling time of plasma calcitonin levels to prognosis and recurrence of medullary thyroid carcinoma. Ann Surg. 1984; 199: 461–466.
Amin MB, Greene FL, Edge SB, et al. (eds.) AJCC Cancer staging manual. 8th edition. Springer, Cham, 2016.
Essig GF Jr, Porter K, Schneider D, et al. Fine needle aspiration and medullary thyroid carcinoma: the risk of inadequate preoperative evaluation and initial surgery when relying upon FNAB cytology alone. Endocr Pract. 2013; 19: 920–927.
Trimboli P, Giannelli J, Marques B, et al. Head-to-head comparison of FNA cytology vs. calcitonin measurement in FNA washout fluids (FNA-CT) to diagnose medullary thyroid carcinoma. A systematic review and meta-analysis. Endocrine 2022; 75: 33–39.
Trimboli P, Treglia G, Guidobaldi L, et al. Detection rate of FNA cytology in medullary thyroid carcinoma: a meta-analysis. Clin Endocrinol (Oxf.) 2015; 82: 280–285.
Liu CY, Bychkov A, Agarwal S, et al. Cytologic diagnosis of medullary thyroid carcinoma in the Asia-Pacific region. Diagn Cytopathol. 2021; 49: 60–69.
Gharib H, Papini E, Paschke R, et al. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association Medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. Endocr Pract. 2010; 16: 468–475.
Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2016; 26: 1–133.
Cheung K, Roman SA, Wang TS, et al. Calcitonin measurement in the evaluation of thyroid nodules in the United States: a cost-effectiveness and decision analysis. J Clin Endocrinol Metab. 2008; 93: 2173–2180.
Vardarli I, Weber M, Weidemann F, et al. Diagnostic accuracy of routine calcitonin measurement for the detection of medullary thyroid carcinoma in the management of patients with nodular thyroid disease: a meta-analysis. Endocr Connect. 2021; 10: 358–370.
Verbeek HH, de Groot JW, Sluiter WJ, et al. Calcitonin testing for detection of medullary thyroid cancer in people with thyroid nodules. Cochrane Database Syst Rev. 2020; 3: CD010159.
Durante C, Hegedüs L, Czarniecka A, et al. 2023 European Thyroid Association clinical practice guidelines for thyroid nodule management. Eur Thyroid J. 2023; 12: e230067.
Trimboli P, Mian C, Piccardo A, et al. Diagnostic tests for medullary thyroid carcinoma: an umbrella review. Endocrine 2023; 81: 183–193.
Trimboli P, Valderrabano P, Pitoia F, et al. Appropriate and mindful measurement of serum calcitonin in patients with thyroid nodules. A white paper. Endocrine 2024; 83: 60–64.
Piticchio T, Frasca F, Trimboli P. Prevalence and significance of indeterminate calcitonin values in patients with thyroid nodules: a systematic review and meta-analysis. Rev Endocr Metab Disord. 2023; 24: 685–694.
Censi S, Manso J, Mian C. Other markers of medullary thyroid cancer, not only calcitonin. Eur J Endocri. 2023; 188: R1–R13.
Kebebew E, Greenspan FS, Clark OH, et al. Extent of disease and practice patterns for medullary thyroid cancer. J Am Coll Surg. 2005; 200: 890–896.
Van Beek DJ, Almquist M, Bergenfelz AO, et al. Complications after medullary thyroid carcinoma surgery: multicentre study of the SQRTPA and EUROCRINE® databases. Br J Surg. 2021; 108: 691–701.
Papachristos AJ, Nicholls LE, Mechera R, et al. Management of medullary thyroid cancer: patterns of recurrence and outcomes of reoperative surgery. Oncologist 2023; 28: 1064–1071.
Ferreira CV, Marmitt L, Dora JM, et al. An undetectable postoperative calcitonin level is associated with long-term disease-free survival in medullary thyroid carcinoma: results of a retrospective cohort study. Thyroid 2023; 33: 82–90.
Jung KY, Kim SM, Yoo WS, et al. Postoperative biochemical remission of serum calcitonin is the best predictive factor for recurrence-free survival of medullary thyroid cancer: a large-scale retrospective analysis over 30 years. Clin Endocrinol (Oxf.) 2016; 84: 587–597.
Cohen R, Campos JM, Salaün C, et al. Preoperative calcitonin levels are predictive of tumor size and postoperative calcitonin normalization in medullary thyroid carcinoma. J Clin Endocrinol Metab. 2000; 85: 919–922.
Machens A, Lorenz K, Dralle H. Time to calcitonin normalization after surgery for node-negative and node-positive medullary thyroid cancer. Br J Surg. 2019; 106: 412–418.
Kihara M, Miyauchi A, Masuoka H, et al. Kinetic analysis of the growth rate of sporadic and hereditary medullary thyroid carcinoma: comparing the postoperative calcitonin-doubling rate with the hypothetical preoperative tumor volume-doubling rate. Thyroid Res. 2020; 13: 13: 13.
Yang JH, Lindsey SC, Camacho CP, et al. Integration of a postoperative calcitonin measurement into an anatomical staging system improves initial risk stratification in medullary thyroid cancer. Clin Endocrinol (Oxf.) 2015; 83: 938–942.
Call JA, Caudill JS, McIver B, et al. A role for radiotherapy in the management of advanced medullary thyroid carcinoma: the mayo clinic experience. Rare Tumors 2013; 5: e37.
Efstathiadou ZA, Tsentidis C, Bargiota A, et al. Benefits and limitations of TKIs in patients with medullary thyroid cancer: a systematic review and meta-analysis. Eur Thyroid J. 2021; 10: 125–139.
Jozaghi Y, Zafereo M, Williams MD, et al. Neoadjuvant selpercatinib for advanced medullary thyroid cancer. Head Neck. 2021; 43: e7–e12.
Saltiki K, Simeakis G, Karapanou O, et al. Metastatic medullary thyroid carcinoma (MTC): disease course, treatment modalities and factors predisposing for drug resistance. Endocrine 2023; 80: 570–579.
Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020; 383: 825–835.