Medulläres Schilddrüsenkarzinom

Zusammenfassung

Diagnose und Prognose Calcitonin ist ein sensitiver und spezifischer Tumormarker zur Früherkennung und Verlaufskontrolle des MTC. Daneben kommt dem Ultraschall der Schilddrüse eine entscheidende Rolle zu.

Rolle des RET-Proto-Onkogens Das medulläre Schilddrüsenkarzinom (MTC) nimmt seinen Ursprung aus den parafollikulären calcitoninproduzierenden C-Zellen. Es macht nur ca. 3–8% aller Schilddrüsenkarzinome aus. Aktivierende Mutationen im RET (rearranged during transfection)-Gen liegen bei etwa 25% der Patienten in der Keimbahn vor, werden aber auch beim sporadischen MTC als somatische Mutationen in ca. 60% der Fälle beobachtet. Bei metastasierter Erkrankung findet sich in 90% eine RET-Mutation. RET-Mutationen gelten als Treibermutationen und schließen weitere Treibermutationen weitestgehend aus. Seltener sind somatische Mutationen der RAS-Gene.

Chirurgische Therapie Die chirurgische Resektion ist bis heute der einzige kurative Therapieansatz. Entscheidend für eine frühzeitige Diagnosestellung ist die Bestimmung des Serum-Calcitonins bei Nachweis von Schilddrüsenknoten. Die chirurgische Therapie steht auch bei der Behandlung lokoregionärer Rezidive oder lokal angehbarer Metastasen im Zentrum.

Systemtherapie Bei irresektabel fortgeschrittener und progredienter Erkrankung mit signifikanter Tumorlast kann eine systemische Therapie erforderlich werden. Neuerdings ist die Kenntnis einer RET-Mutation im Tumorgewebe therapeutisch relevant, da mit dem selektiven RET-Inhibitor Selpercatinib eine neue, effektive und gut verträgliche Systemtherapien zur Verfügung steht. Dieser ist inzwischen wie bisher nur die Multityrosinkinaseinhibitoren Cabozantinib und Vandetanib als Erstlinientherapie des fortgeschrittenen MTC zugelassen. Vandetanib darf ebenfalls nur noch bei Patienten mit RET-Mutation angewendet werden.

Abstract

Diagnosis and prognosis Calcitonin is a sensitive and specific tumour marker for early detection and follow-up of MTC. In addition, the ultrasound of the thyroid gland plays a decisive role.

Role of the RET proto-oncogene Medullary thyroid carcinoma (MTC) originates from parafollicular calcitonin-producing C cells. It accounts for only about 3–8% of all thyroid carcinomas. Activating mutations in the RET (rearranged during transfection) gene are present in the germline in about 25% of patients, but are also observed in sporadic MTC as somatic mutations in about 60% of cases. In metastatic disease, a RET mutation is found in 90% of cases. RET mutations are considered driver mutations and largely exclude further driver mutations. Somatic mutations of the RAS genes are rarer.

Surgical therapy Surgical resection is still the only curative therapeutic approach. The measurement of serum calcitonin is crucial for an early diagnosis if thyroid nodules are detected. Surgical therapy is also a cornerstone of treatment in locoregional recurrences or locally approachable metastases.

Systemic therapy Systemic therapy may be required for irresectably advanced and progressive disease with significant tumour burden. Recently, the detection of a RET mutation in the tumour tissue has become therapeutically relevant, since a new, effective, and well-tolerated system therapy is available with the selective RET inhibitor selpercatinib. Like the multityrosine kinase inhibitors cabozantinib and vandetanib, it is now approved as a first-line therapy for advanced MTC. Vandetanib may also only be used in patients with RET mutations.

Schlüsselwörter

Medulläres Schilddrüsenkarzinom - MTC - Calcitonin - RET-Mutation - Selpercatinib

Keywords

Medullary thyroid cancer - MTC - calcitonin - RET mutation - Selpercatinib

Publication History

Article published online:
28 August 2023

• Literatur

• 1 Randle RW, Balentine CJ, Leverson GE. et al. Trends in the presentation, treatment, and survival of patients with medullary thyroid cancer over the past 30 years. Surgery 2017; 161: 137-146 DOI: 10.1016/j.surg.2016.04.053.
• 2 Mathiesen JS, Kroustrup JP, Vestergaard P. et al. Survival and Long-Term Biochemical Cure in Medullary Thyroid Carcinoma in Denmark 1997–2014: A Nationwide Study. Thyroid 2019; 29: 368-377 DOI: 10.1089/thy.2018.0564. (PMID: 30618340)
• 3 Kim SH, Kim BS, Jung SL. et al. Ultrasonographic findings of medullary thyroid carcinoma: a comparison with papillary thyroid carcinoma. Korean J Radiol 2009; 10: 101-105 DOI: 10.3348/kjr.2009.10.2.101.
• 4 Lee S, Shin JH, Han BK. et al. Medullary thyroid carcinoma: comparison with papillary thyroid carcinoma and application of current sonographic criteria. Am J Roentgenol 2010; 194: 1090-1094 DOI: 10.2214/ajr.09.3276.
• 5 Woliński K, Rewaj-Łosyk M, Ruchała M. Sonographic features of medullary thyroid carcinomas-a systematic review and meta-analysis. Endokrynol Pol 2014; 65: 314-318 DOI: 10.5603/ep.2014.0043. (PMID: 25185855)
• 6 Allelein S, Ehlers M, Morneau C. et al. Measurement of Basal Serum Calcitonin for the Diagnosis of Medullary Thyroid Cancer. Horm Metab Res 2018; 50: 23-28 DOI: 10.1055/s-0043-122237. (PMID: 29169190)
• 7 Frank-Raue K, Schott M, Raue F. Recommendation for Calcitonin Screening in Nodular Goiter. Dtsch Med Wochenschr 2018; 143: 1065-1069 DOI: 10.1055/a-0585-8097. (PMID: 30060274)
• 8 Machens A, Dralle H. Biomarker-based risk stratification for previously untreated medullary thyroid cancer. The Journal of clinical endocrinology and metabolism 2010; 95: 2655-2663 DOI: 10.1210/jc.2009-2368. (PMID: 20339026)
• 9 Torresan F, Mian C, Cavedon E. et al. Cure and survival of sporadic medullary thyroid carcinoma following systematic preoperative calcitonin screening. Langenbeck’s archives of surgery 2019; 404: 411-419 DOI: 10.1007/s00423-019-01764-3. (PMID: 30903267)
• 10 Machens A, Dralle H. Surgical cure rates of sporadic medullary thyroid cancer in the era of calcitonin screening. Eur J Endocrinol 2016; 175: 219-228 DOI: 10.1530/eje-16-0325. (PMID: 27334331)
• 11 Wells Jr SA, Asa SL, Dralle H. et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25: 567-610 DOI: 10.1089/thy.2014.0335. (PMID: 25810047)
• 12 ARUP Laboratories. Mutation Databases – Multiple Endocrine Neoplasia type 2 (MEN2) and RET. Accessed October 14, 2021 at: http://arup.utah.edu/database/MEN2 /MEN2_welcome.php
• 13 Ciampi R, Romei C, Ramone T. et al. Genetic Landscape of Somatic Mutations in a Large Cohort of Sporadic Medullary Thyroid Carcinomas Studied by Next-Generation Targeted Sequencing. iScience 2019; 20: 324-336 DOI: 10.1016/j.isci.2019.09.030. (PMID: 31605946)
• 14 Romei C, Ciampi R, Casella F. et al. RET mutation heterogeneity in primary advanced medullary thyroid cancers and their metastases. Oncotarget 2018; 9: 9875-9884 DOI: 10.18632/oncotarget.23986.
• 15 Raue F, Frank-Raue K. Long-Term Follow-up in Medullary Thyroid Carcinoma. Recent results in cancer research Fortschritte der Krebsforschung Progres dans les recherches sur le cancer 2015; 204: 207-225 DOI: 10.1007/978-3-319-22542-5_10. (PMID: 26494391)
• 16 Margraf RL, Crockett DK, Krautscheid PM. et al. Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Hum Mutat 2009; 30: 548-556 DOI: 10.1002/humu.20928. (PMID: 19177457)
• 17 Kwon H, Kim WG, Jeon MJ. et al. Dynamic risk stratification for medullary thyroid cancer according to the response to initial therapy. Endocrine 2016; 53: 174-181 DOI: 10.1007/s12020-015-0849-6. (PMID: 26754662)
• 18 Machens A, Hofmann C, Hauptmann S. et al. Locoregional recurrence and death from medullary thyroid carcinoma in a contemporaneous series: 5-year results. Eur J Endocrinol 2007; 157: 85-93 DOI: 10.1530/eje-07-0095.
• 19 Machens A, Lorenz K, Dralle H. Prediction of biochemical cure in patients with medullary thyroid cancer. Br J Surg 2020; 107: 695-704 DOI: 10.1002/bjs.11444. (PMID: 32108330)
• 20 Machens A, Dralle H. Benefit-risk balance of reoperation for persistent medullary thyroid cancer. Ann Surg 2013; 257: 751-757 DOI: 10.1097/SLA.0b013e31826bc239. (PMID: 23023200)
• 21 Schlumberger M, Bastholt L, Dralle H. et al. 2012 European thyroid association guidelines for metastatic medullary thyroid cancer. Eur Thyroid J 2012; 1: 5-14 DOI: 10.1159/000336977. (PMID: 24782992)
• 22 Elisei R, Schlumberger MJ, Müller SP. et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 2013; 31: 3639-3646 DOI: 10.1200/jco.2012.48.4659. (PMID: 24002501)
• 23 Wells Jr SA, Robinson BG, Gagel RF. et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 2012; 30: 134-141 DOI: 10.1200/JCO.2011.35.5040. (PMID: 22025146)
• 24 Elisei Rossella, Schlumberger Martin J, Müller Stefan P. et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 2013; 31: 3639-3646 DOI: 10.1200/JCO.2012.48.4659.
• 25 Koehler VF, Berg E, Adam P. et al. Real world efficacy and safety of multi-tyrosine kinase inhibitors in radioiodine refractory thyroid cancer. Thyroid 2021; 31: 1531-1541 DOI: 10.1089/thy.2021.0091. (PMID: 34405734)
• 26 Wirth LJ, Sherman E, Robinson B. et al. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med 2020; 383: 825-835 DOI: 10.1056/NEJMoa2005651.
• 27 Kroiss M, Sherman EJ, Wirth LJ. et al. Durable efficacy of selpercatinib in patients (pts) with medullary thyroid cancer (MTC): Update of the LIBRETTO-001 trial. Annals of Oncology 2022; 33: S750-S757 DOI: 10.1016/annonc/annonc1077.
• 28 Subbiah V, Hu MI, Wirth LJ. et al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer (ARROW): a multi-cohort, open-label, registrational, phase 1/2 study. Lancet Diabetes Endocrinol 2021; 9: 491-501 DOI: 10.1016/s2213-8587(21)00120-0.