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Nuklearmedizin 2015; 54(03): 94-100
DOI: 10.1055/s-0037-1616610
Innovation Schilddrüse
Schattauer GmbH

Molecular genetic markers for thyroid FNAB

Established assays and future perspectiveMolekulare Marker in der Feinnadelpunktion der SchilddrüseWas ist etabliert, was ist die Zukunft?
T. J. Musholt
1   Section of Endocrine Surgery, Dept. of General, Visceral- and Transplantation Surgery, University Medicine Mainz, Germany
,
P. B. Musholt
1   Section of Endocrine Surgery, Dept. of General, Visceral- and Transplantation Surgery, University Medicine Mainz, Germany
2   Translational Medicine & Early Clinical, Diabetes Division, Sanofi Aventis Deutschland GmbH, Industrial Park Hoechst, Frankfurt, Germany
› Author Affiliations
Further Information

Publication History

received: 04 March 2015

accepted: 20 May 2015

Publication Date:
11 January 2018 (online)

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Summary

Aim: Thyroid nodules > 1 cm are observed in about 12% of unselected adult employees aged 18–65 years screened by ultrasound scan (40). While intensive ultrasound screening leads to early detection of thyroid diseases, the determination of benign or malignant behaviour remains uncertain and may trigger anxieties in many patients and their physicians. A considerable number of thyroid resections are consecutively performed due to suspicion of malignancy in the detected nodes. Fine needle aspiration biopsy (FNAB) has been recommended for the assessment of thyroid nodules to facilitate detection of thyroid carcinomas but also to rule out malignancy and thereby avoid unnecessary thyroid resections. However, cytology results are dependent on experience of the respective cytologist and unfortunately inconclusive in many cases. Methods: Molecular genetic markers are already used nowadays to enhance sensitivity and specificity of FNAB cytology in some centers in Germany. The most clinically relevant molecular genetic markers as pre-operative diagnostic tools and the clinical implications for the intraoperative and postoperative management were reviewed. Results: Molecular genetic markers predominantly focus on the preoperative detection of thyroid malignancies rather than the exclusion of thyroid carcinomas. While some centers routinely assess FNABs, other centers concentrate on FNABs with cytology results of follicular neoplasia or suspicion of thyroid carcinoma. Predominantly mutations of BRAF, RET/PTC, RAS, and PAX8/PPARγ or expression of miRNAs are analyzed. However, only the detection of BRAF mutations predicts the presence of (papillary) thyroid malignancy with almost 98% probability, indicating necessity of oncologic thyroid resections irrespective of the cytology result. Other genetic alterations are associated with thyroid malignancy with varying frequency and achieve less impact on the clinical management. Conclusion: Molecular genetic analysis of FNABs is increasingly performed in Germany. Standardization, quality controls, and validation of various methods need to be implemented in the near future to be able to compare the results. With increasing knowledge about the impact of genetic alterations on the prognosis of thyroid carcinomas, recommendations have to be defined that may lead to individually optimized treatment strategies.

Zusammenfassung

Ziele: Schilddrüsenknoten >1 cm Durchmesser werden bei etwa 12% der unselektierten berufstätigen Bevölkerung beobachtet (40). Während intensives Screening mittels Ultraschall zur Früherkennung von Schilddrüsenerkrankungen führt, bleibt die Dignitäts-Festlegung eines Knotens unsicher und löst ggf. Befürchtungen in vielen Patienten und behandelnden ärzten aus. Eine bemerkenswerte Anzahl der Schilddrüsenoperationen wird daher zum Malignitätsausschluss durchgeführt. Die Feinnadelpunktion wurde hingegen zum Nachweis – aber auch Ausschluss – von Schilddrüsenkarzinomen empfohlen, um unnötige Schilddrüsenoperationen zu vermeiden. Eine punktionszytologische Beurteilung ist jedoch von der Erfahrung des Zytologen abhängig und führt in vielen Fällen zu indifferenten Befunden. Methoden: Zur Verbesserung von Sensitivität und Spezifität von Feinnadelpunktionen werden in einigen Zentren in Deutschland bereits molekulargenetische Marker verwendet. Relevante Biomarker zur präoperativen Diagnostik sowie ihre Auswirkungen auf das intra- und postoperative Management wurden analysiert. Ergebnisse: Derzeit eingesetzte molekulargenetische Marker fokussieren in erster Linie auf den Nachweis und weniger auf den Ausschluss von Schilddrüsenkarzinomen. Während einige Zentren routinemäßig Feinnadelpunktionen molekulargenetisch analysieren, begrenzen andere die Analyse auf follikuläre Neoplasien und malignitätsverdächtige zytologische Ergebnisse. überwiegend werden BRAF, RET/PTC, RAS, und PAX8/PPARγ-Mutationen bzw. Expressionen von miRNAs untersucht. Nur der Nachweis einer BRAF-Mutation entspricht in nahezu 98% der Fälle einem (papillären) Schilddrüsenkarzinom, unabhängig vom korrespondierenden zytologischen Befund. Andere genetische Veränderungen sind mit variierender Frequenz mit Schilddrüsenkarzinomen assoziiert und erlangen daher weniger Einfluss auf das klinische Management. Schlussfolgerung: Molekulargenetische Analysen von Feinnadelpunktaten der Schilddrüse werden in Deutschland zunehmend eingesetzt. Eine Standardisierung, Qualitätskontrolle und Validierung der unterschiedlichen Analyse-Verfahren ist in naher Zukunft erforderlich, um vergleichbare Ergebnisse zu erzielen. Mit zunehmendem Wissen über die Assoziation genetischer Veränderungen mit der Prognose von Schilddrüsenkarzinomen müssen Therapieempfehlungen definiert werden, die zu einer optimierten individualisierten Therapie führen.

Keywords

Thyroid - fine needle aspiration biopsy - molecular genetics

Schlüsselwörter

Schilddrüse - Feinnadelaspirationsbiopsie - Molekular genetik
 

  • References

  • 1 Alexander EK, Kennedy GC, Baloch ZW. et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med 2012; 367: 705-715.
    CrossrefPubMedGoogle Scholar
  • 2 Alexander EK, Schorr M, Klopper J. et al. Multicenter clinical experience with the Afirma gene expression classifier. J Clin Endocrinol Metab 2014; 99: 119-125.
    CrossrefPubMedGoogle Scholar
  • 3 Baloch ZW, LiVolsi VA, Asa SL. et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions. Diagn Cytopathol 2008; 36: 425-437.
    CrossrefPubMedGoogle Scholar
  • 4 Cancer Genome Atlas Research N. Integrated genomic characterization of papillary thyroid carcinoma. Cell 2014; 159: 676-690.
    CrossrefPubMedGoogle Scholar
  • 5 Cantara S, Capezzone M, Marchisotta S. et al. Impact of proto-oncogene mutation detection in cytological specimens from thyroid nodules improves the diagnostic accuracy of cytology. J Clin Endocrinol Metab 2010; 95: 1365-1369.
    CrossrefPubMedGoogle Scholar
  • 6 Caria P, Dettori T, Frau DV. et al. Assessing RET/PTC in thyroid nodule fine-needle aspirates. Endocr Relat Cancer 2013; 20: 527-536.
    CrossrefPubMedGoogle Scholar
  • 7 Chudova D, Wilde JI, Wang ET. et al. Molecular classification of thyroid nodules using high-dimensionality genomic data. J Clin Endocrinol Metab 2010; 95: 5296-5304.
    CrossrefPubMedGoogle Scholar
  • 8 Ciampi R, Knauf JA, Rabes HM. et al. BRAF kinase activation via chromosomal rearrangement in radiation-induced and sporadic thyroid cancer. Cell Cycle 2005; 4: 547-548.
    CrossrefPubMedGoogle Scholar
  • 9 Cibas ES, Ali SZ. Conference NCITFSotS. The Bethesda system for reporting thyroid cytopathology. Am J Clin Pathol 2009; 132: 658-665.
    CrossrefPubMedGoogle Scholar
  • 10 Corvi R, Berger N, Balczon R. et al. RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma. Oncogene 2000; 19: 4236-4242.
    CrossrefPubMedGoogle Scholar
  • 11 Dettmer MS, Perren A, Moch H. et al. MicroRNA profile of poorly differentiated thyroid carcinomas: new diagnostic and prognostic insights. J Mol Endocrinol 2014; 52: 181-189.
    CrossrefPubMedGoogle Scholar
  • 12 Dralle H, Musholt TJ, Schabram J. et al. German Association of Endocrine Surgeons practice guideline for the surgical management of malignant thyroid tumors. Langenbecks Arch Surg 2013; 398: 347-375.
    CrossrefPubMedGoogle Scholar
  • 13 Dyhdalo K, Macnamara S, Brainard J. et al. Assessment of cellularity, genomic DNA yields, and technical platforms for BRAF mutational testing in thyroid fine-needle aspirate samples. Cancer Cytopathol 2014; 122: 114-122.
    CrossrefPubMedGoogle Scholar
  • 14 Fugazzola L, Puxeddu E, Avenia N. et al. Correlation between B-RAFV600E mutation and clinico-pathologic parameters in papillary thyroid carcinoma. Endocrine-related cancer 2006; 13: 455-464.
    PubMedGoogle Scholar
  • 15 Fuziwara CS, Kimura ET. MicroRNA deregulation in anaplastic thyroid cancer biology. Int J Endocrinol 2014; 2014: 743450.
    PubMedGoogle Scholar
  • 16 Greco A, Miranda C, Pierotti MA. Rearrangements of NTRK1 gene in papillary thyroid carcinoma. Mol Cell Endocrinol 2010; 321: 44-49.
    CrossrefPubMedGoogle Scholar
  • 17 Greco A, Pierotti MA, Bongarzone I. et al. TRK-T1 is a novel oncogene formed by the fusion of TPR and TRK genes in human papillary thyroid carcinomas. Oncogene 1992; 7: 237-242.
    PubMedGoogle Scholar
  • 18 Harrell RM, Bimston DN. Surgical utility of Afirma: effects of high cancer prevalence and oncocytic cell types in patients with indeterminate thyroid cytology. Endocr Pract 2014; 20: 364-369.
    CrossrefPubMedGoogle Scholar
  • 19 Hsiao SJ, Nikiforov YE. Molecular approaches to thyroid cancer diagnosis. Endocr Relat Cancer 2014; 21: T301-313.
    CrossrefPubMedGoogle Scholar
  • 20 Imkamp F, von Wasielewski R, Musholt TJ. et al. Rearrangement analysis in archival thyroid tissues. J Surg Res 2007; 143: 350-363.
    CrossrefPubMedGoogle Scholar
  • 21 Ito Y, Yoshida H, Maruo R. et al. BRAF mutation in papillary thyroid carcinoma in a Japanese population. Endocr J 2009; 56: 89-97.
    CrossrefPubMedGoogle Scholar
  • 22 Kebebew E, Weng J, Bauer J. et al. The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann Surg 2007; 246: 466-470.
    CrossrefPubMedGoogle Scholar
  • 23 Kim KH, Kang DW, Kim SH. et al. Mutations of the BRAF gene in papillary thyroid carcinoma in a Korean population. Yonsei Med J 2004; 45: 818-821.
    CrossrefPubMedGoogle Scholar
  • 24 Kim TH, Park YJ, Lim JA. et al. The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer. Cancer 2012; 118: 1764-1773.
    CrossrefPubMedGoogle Scholar
  • 25 Kimura ET, Nikiforova MN, Zhu Z. et al. High prevalence of BRAF mutations in thyroid cancer. Cancer Res 2003; 63: 1454-1457.
    PubMedGoogle Scholar
  • 26 Klugbauer S, Demidchik EP, Lengfelder E. et al. Molecular analysis of new subtypes of ELE/RET rearrangements, their reciprocal transcripts and breakpoints in papillary thyroid carcinomas of children after Chernobyl. Oncogene 1998; 16: 671-675.
    CrossrefPubMedGoogle Scholar
  • 27 Klugbauer S, Jauch A, Lengfelder E. et al. A novel type of RET rearrangement (PTC8) in childhood papillary thyroid carcinomas and characterization of the involved gene (RFG8). Cancer Res 2000; 60: 7028-7032.
    PubMedGoogle Scholar
  • 28 Kozma SC, Redmond SM, Fu XC. et al. Activation of the receptor kinase domain of the trk oncogene by recombination with two different cellular sequences. EMBO J 1988; 7: 147-154.
    PubMedGoogle Scholar
  • 29 Lee ST, Kim SW, Ki CS. et al. Clinical implication of highly sensitive detection of the BRAF V600E mutation in fine-needle aspirations of thyroid nodules: a comparative analysis of three molecular assays in 4585 consecutive cases in a BRAF V600E mutation-prevalent area. J Clin Endocrinol Metab 2012; 97: 2299-2306.
    CrossrefPubMedGoogle Scholar
  • 30 Lupi C, Giannini R, Ugolini C. et al. Association of BRAF V600E mutation with poor clinico-pathological outcomes in 500 consecutive cases of papillary thyroid carcinoma. J Clin Endocrinol Metab 2007; 92: 4085-4090.
    CrossrefPubMedGoogle Scholar
  • 31 McIver B, Castro MR, Morris JC. et al. An independent study of a gene expression classifier (Afirma) in the evaluation of cytologically indeterminate thyroid nodules. J Clin Endocrinol Metab. 2014: jc20133584.
    Google Scholar
  • 32 Moses W, Weng J, Sansano I. et al. Molecular testing for somatic mutations improves the accuracy of thyroid fine-needle aspiration biopsy. World J Surg 2010; 34: 2589-2594.
    CrossrefPubMedGoogle Scholar
  • 33 Musholt TJ, Clerici T, Dralle H. et al. German Association of Endocrine Surgeons practice guidelines for the surgical treatment of benign thyroid disease. Langenbecks Arch Surg 2011; 396: 639-649.
    CrossrefPubMedGoogle Scholar
  • 34 Musholt TJ, Musholt PB. Präoperative Molekularzytologie zur Stratifizierung des chirurgischen Vorgehens bei suspekten Schilddrüsenknoten. In: Dralle H. (Hrsg) Endokrine Chirurgie Evidenz und Erfahrung. Stuttgart: Schattauer; 2014: 154-173.
    Google Scholar
  • 35 Musholt TJ, Musholt PB, Khaladj N. et al. Prognostic significance of RET and NTRK1 rearrangements in sporadic papillary thyroid carcinoma. Surgery 2000; 128: 984-993.
    CrossrefPubMedGoogle Scholar
  • 36 Musholt TJ, Schonefeld S, Schwarz CH. et al. Impact of pathognomonic genetic alterations on the prognosis of papillary thyroid carcinoma ESES vienna presentation. Langenbecks Arch Surg 2010; 395: 877-883.
    CrossrefPubMedGoogle Scholar
  • 37 Oler G, Cerutti JM. High prevalence of BRAF mutation in a Brazilian cohort of patients with sporadic papillary thyroid carcinomas: correlation with more aggressive phenotype and decreased expression of iodide-metabolizing genes. Cancer 2009; 115: 972-980.
    CrossrefPubMedGoogle Scholar
  • 38 Pak K, Suh S, Kim SJ. et al. Prognostic value of genetic mutations in thyroid cance. Thyroid. 2014
    PubMedGoogle Scholar
  • 39 Pfeifer A, Wojtas B, Oczko-Wojciechowska M. et al. Molecular differential diagnosis of follicular thyroid carcinoma and adenoma based on gene expression profiling by using formalin-fixed paraffin-embedded tissues. BMC Med Genomics 2013; 6: 38.
    CrossrefPubMedGoogle Scholar
  • 40 Reiners C, Wegscheider K, Schicha H. et al. Prevalence of thyroid disorders in the working population of Germany. Thyroid 2004; 14: 926-932.
    CrossrefPubMedGoogle Scholar
  • 41 Romei C, Elisei R. RET/PTC translocations and clinico-pathological features in human papillary thyroid carcinoma. Front Endocrinol (Lausanne) 2012; 3: 54.
    PubMedGoogle Scholar
  • 42 Rossi ED, Schmitt F. Pre-analytic steps for molecular testing on thyroid fine-needle aspirations. Cytojournal 2013; 10: 24.
    CrossrefPubMedGoogle Scholar
  • 43 Santoro M, Dathan NA, Berlingieri MT. et al. Molecular characterization of RET/PTC3. Oncogene 1994; 9: 509-516.
    PubMedGoogle Scholar
  • 44 Schwertheim S, Sheu SY, Worm K. et al. Analysis of deregulated miRNAs is helpful to distinguish poorly differentiated thyroid carcinoma from papillary thyroid carcinoma. Horm Metab Res 2009; 41: 475-481.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Shen R, Liyanarachchi S, Li W. et al. MicroRNA signature in thyroid fine needle aspiration cytology applied to “atypia of undetermined significance” cases. Thyroid 2012; 22: 9-16.
    CrossrefPubMedGoogle Scholar
  • 46 Sheu SY, Grabellus F, Schwertheim S. et al. Lack of correlation between BRAF V600E mutational status and the expression profile of a distinct set of miRNAs in papillary thyroid carcinoma. Horm Metab Res 2009; 41: 482-487.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Sheu SY, Grabellus F, Schwertheim S. et al. Differential miRNA expression profiles in variants of papillary thyroid carcinoma and encapsulated follicular thyroid tumours. Br J Cancer 2010; 102: 376-382.
    CrossrefPubMedGoogle Scholar
  • 48 Statistisches Bundesamt. Gesundheit: Grunddaten der Krankenhäuser. Statistisches Bundesamt. Wiesbaden; 2014
    Google Scholar
  • 49 Tang KT, Lee CH. BRAF mutation in papillary thyroid carcinoma: pathogenic role and clinical implications. J Chin Med Assoc 2010; 73: 113-128.
    CrossrefPubMedGoogle Scholar
  • 50 Trovisco V, Soares P, Soares R. et al. A new BRAF gene mutation detected in a case of a solid variant of papillary thyroid carcinoma. Hum Pathol 2005; 36: 694-697.
    CrossrefPubMedGoogle Scholar
  • 51 Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nature reviews Cancer 2013; 13: 184-199.
    CrossrefPubMedGoogle Scholar
  • 52 Xing M, Haugen BR, Schlumberger M. Progress in molecular-based management of differentiated thyroid cancer. Lancet 2013; 381: 1058-1069.
    CrossrefPubMedGoogle Scholar
  • 53 Xing M, Westra WH, Tufano RP. et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 2005; 90: 6373-6379.
    CrossrefPubMedGoogle Scholar
  • 54 Yip L. Molecular diagnostic testing and the indeterminate thyroid nodule. Curr Opin Oncol 2014; 26: 8-13.
    CrossrefPubMedGoogle Scholar