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Maria Chiara Zatelli

Ferrara, 20 gennaio 2012. Analisi genetica del nodulo tiroideo: implicazioni per l’esecuzione del linfonodo sentinella. Maria Chiara Zatelli. Sezione di Endocrinologia Dip. di Scienze Biomediche e Terapie Avanzate Università di Ferrara Direttore: Prof. Ettore degli Uberti.

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Maria Chiara Zatelli

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  1. Ferrara, 20 gennaio 2012 Analisi genetica del nodulo tiroideo: implicazioni per l’esecuzione del linfonodo sentinella Maria Chiara Zatelli Sezione di Endocrinologia Dip. di Scienze Biomediche e Terapie Avanzate Università di Ferrara Direttore: Prof. Ettore degli Uberti

  2. Thyroid molecular markers & sentinel lymphnode EFE 2012 …molecularmarker…? …a molecular marker (genetic marker) is a DNA sequence associated to a part of the genome, used in molecular biology and biotechnology experiments to identify a very highly specific DNA sequence… What relevance in thyroid nodules?

  3. Thyroid molecular markers & sentinel lymphnode EFE 2012 Fine-needle aspiration biopsy (FNAB) is currently the most sensitive and specific tool for the presurgical differential diagnosis of thyroid malignancy but has also substantial limitations Eszlinger et al. Mol Cell Endocrinol 2010;322:29 75% benign lesions 5% malignant lesions 20% follicular proliferation FA FTC fvPTC thyroid surgery

  4. Thyroid molecular markers & sentinel lymphnode pathology Does it improve cytological fine needle aspiration diagnosis of thyroid nodules? EFE 2012 MOLECULAR BIOLOGY study of biology at molecular level

  5. Thyroid molecular markers & sentinel lymphnode cytology DNA RNA EFE 2012 Highlyfeasible in clinicalsettings rearrangement studies somatic mutation analysis RET/PTC1 RET/PTC3 PPARg/PAX8 BRAF N-RAS H-RAS K-RAS

  6. Thyroid molecular markers & sentinel lymphnode • BRAF V600E point mutation • [K601E and V599Ins] • 45-80% of PTC, mainly tall cell and classic hystology •  extrathyroidal invasion • higher stage • recurrence (with reduced I up-take) • de-differentiation resticted to PTC Lupi et al. J Clin Endocrinol Metab. 2007;92:4085 EFE 2012 Nikiforova et al. Exp Rev Mol Diagn 2008, 8: 83 PAPILLARY CARCINOMA DNA

  7. Thyroid molecular markers & sentinel lymphnode EFE 2012 genetictests • do theyimprovediagnosis? Kim et al. J Clin Endocrinol Metab, 2011, 96:658 Zatelli et al . Eur J Endocrinol 2009, 161:467

  8. Thyroid molecular markers & sentinel lymphnode EFE 2012 genetictests • do theyimprovediagnosis? BRAFV600E molecular test Kim et al. J Clin Endocrinol Metab, 2011, 96:658 BRAF mutation analysis may help especially in small nodules

  9. Thyroid molecular markers & sentinel lymphnode EFE 2012 BRAFV600E molecular test Section of Endocrinology University of Ferrara 1856 pz (1436 ♀; 420♂) age 52 ± 0,32 (12-73) Biomolecular analysis suspected: 829 2421 FNAs US & clinical evaluation NON suspected: 1529 Pathology

  10. Thyroid molecular markers & sentinel lymphnode EFE 2012 FNAB per se detects a high percentage of malignant lesions in unsuspected nodules Martina Rossi et al. submitted All nodules should undergo FNAB

  11. Thyroid molecular markers & sentinel lymphnode EFE 2012 BRAF testing significantly increases FNAB sensitivity also in nodules clinically non suspected Martina Rossi et al . submitted 15 PTC patients “rescued” by BRAF analysis BRAFV600E molecular test increasesdiagnosticsensitivityfor PTC

  12. Thyroid molecular markers & sentinel lymphnode EFE 2012 BRAF testing identifies as malignant 10% of FN Martina Rossi et al . submitted Indication to total thyroidectomy

  13. Thyroidmolecularmarkers & sentinellymphnode EFE 2012 CONCLUSION -1 Thyroidmolecularmarkersincreasediagnosticsensitivityofcytologyfor PTC and influencesurgicalapproach

  14. Thyroid molecular markers & sentinel lymphnode EFE 2012 genetictests • anyprognosticvalue?

  15. Thyroid molecular markers & sentinel lymphnode EFE 2012 BRAFV600E molecular test Xing et al. J Clin Oncol. 2009;27:2977-82

  16. Thyroid molecular markers & sentinel lymphnode EFE 2012 Xing et al. J Clin Oncol 2009; 27:2977-82 BRAF mutation–positivepatientsare significantly more likely to have PTC persistence/recurrence

  17. Thyroid molecular markers & sentinel lymphnode EFE 2012 BRAF V600E genetic test significantly reduced disease-free probability in BRAF+ patients Xing et al. J ClinOncol. 2009;27:2977-82

  18. Thyroid molecular markers & sentinel lymphnode EFE 2012 BRAF V600E genetic test significantlyincreasedmortality in BRAF+patients Elisei et al. J Clin Endocrinol Metab. 2008;93:3943

  19. Thyroidmolecularmarkers & sentinellymphnode EFE 2012 CONCLUSION -2 Thyroidmolecularmarkersmaypredictpatientsoutcome

  20. Thyroid molecular markers & sentinel lymphnode EFE 2012 genetictests • anysurgicalrelevance ?

  21. Thyroid molecular markers & sentinel lymphnode LN met (+) LN met (-) EFE 2012 BRAF mutation 103 PTC lymph node metastases may show de novo mutations 60 50  is not necessary for locoregional lymph node metastasis 40 30 n. of PTC  is a significant risk factor for locoregional lymph node metastasis 20 10 Vasko et al. J Clin Endocrinol Metab 2005; 90: 5265 0 !! also in microPTC !! BRAF (-) 69 BRAF (+) 34 20/26 BRAF+ LN Lin et al. Ann Surg Oncol 2010;17:3294 Kim et al. Ann Surg 2006;244: 799

  22. Thyroid molecular markers & sentinel lymphnode EFE 2012 lobectomy BRAF mutation  surgical strategy total thyroidectomy lymph node dissection no dissection better staging what lymphnode dissection? High prognostic impact extrathyroidal invasion lymph node metastasis local neck recurrence PTC recurrence complications Xing Endocrine Reviews 2007; 28: 742

  23. Thyroid molecular markers & sentinel lymphnode Indication for sentinel lymphnode Yip et al Surgery 2009; 146: 1215 EFE 2012 BRAF mutation PREDICTOR OF LYMPHNODE METASTASES

  24. Thyroid molecular markers & sentinel lymphnode + - EFE 2012 BRAFV600E molecular test less aggressive surgery more aggressive surgery neck lymph node dissection BRAF mutation-based risk stratification decision making PTC management Xing et al. J ClinOncol. 2009;27:2977-82

  25. Thyroidmolecularmarkers & sentinellymphnode EFE 2012 CONCLUSION -3 Positivityofthyroidmolecularmarkersasindicationforsentinellymphnode procedure

  26. Thyroid molecular markers & sentinel lymphnode EFE 2012 BRAF V600E genetic test May address patients with persistent/recurrent disease to therapy with BRAF-specific inhibitors Cantwell-Dorris et al. Mol Cancer Ther 2011, 10: 385

  27. Thyroid molecular markers & sentinel lymphnode EFE 2012 CONCLUSIONS Thyroidmolecularmarkers • increase cytology diagnostic sensitivity for PTC • may predict patients outcome • influence surgical approach • their positivity is an indication for sentinel lymphnode procedure

  28. THANKS Section of Endocrinology Dept. of Biomedical Sciences and Advanced Therapies University of Ferrara Ettore degli Uberti Personale Medico Tecnico Infermieristico Assegnisti di ricerca Dottorandi Studenti Degenza Day Hospital Ambulatori Ambulatorio Ecografia/ Agoaspirati Laboratorio di Fisiopatologia Endocrina

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