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Thyroid Treatment and Vitamin D Update

A CPMC Regional CME Event. Thyroid Treatment and Vitamin D Update. - An Integrated Approach. Saturday October 27, 2012. THYROID DISORDERS: GENETIC CONSIDERATIONS. Theresa B. Kim, MD San Francisco Otolaryngology Medical Group. Financial disclosures. None. Outline of Discussion.

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Thyroid Treatment and Vitamin D Update

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  1. A CPMC Regional CME Event Thyroid Treatment and Vitamin D Update - An Integrated Approach Saturday October 27, 2012

  2. THYROID DISORDERS:GENETIC CONSIDERATIONS Theresa B. Kim, MD San Francisco Otolaryngology Medical Group

  3. Financial disclosures None

  4. Outline of Discussion • Familial thyroid cancer • Medullary thyroid cancer • Non-medullary thyroid cancer • Molecular genetics in cancer management

  5. POP QUIZ

  6. quiz Specific RET mutations in MEN syndromes are associated with disease prognosis: True False

  7. quiz What percentage of non-medullary thyroid cancers are hereditary? 5% 30% 60% 90%

  8. quiz What is the most common genetic mutation found in thyroid cancer? PAX8/PPARγrearrangement WFS1 point mutation BRAF point mutation IDK translocation

  9. Familial Thyroid Cancer Thyroid Cancer Medullary Thyroid Cancer (5%) Non-medullary Thyroid Cancer (95%) Familial (25%) Sporadic (75%) Familial (5-10%) Sporadic (90-95%)

  10. Medullary Thyroid Cancer • Arises from calcitonin-producing parafollicular C cells • Accounts for 15% of deaths from thyroid cancer • Early metastasis to lymph nodes Medullary Thyroid Cancer (5%)

  11. Medullary Thyroid Cancer • Multiple endocrine neoplasia (MEN) syndrome • Autosomal dominant • MEN2A and MEN 2B • Familial MTC • Least aggressive form • Hereditary MTC usually bilateral and multicentric Medullary Thyroid Cancer (5%) Familial (25%) MEN2A MEN2A fMTC

  12. Medullary Thyroid Cancer • Gene for inherited MTC was localized to chromosome 10 in 1987 Medullary Thyroid Cancer (5%) Familial (25%)

  13. Medullary Thyroid Cancer 1987: Aretha Franklin is the first woman inducted into the Rock and Roll Hall of Fame

  14. Medullary Thyroid Cancer • Gene for inherited MTC was localized to chromosome 10 in 1987 • Germline mutations in RET proto-oncogene identified in 1993 Medullary Thyroid Cancer (5%) Familial (25%)

  15. Medullary Thyroid Cancer 1993: Tennis star Monica Seles is stabbed on-court by a deranged fan

  16. Medullary Thyroid Cancer • Gene for inherited MTC was localized to chromosome 10 in 1987 • Germline mutations in RET proto-oncogene identified in 1993 • Specific mutations are associated with disease phenotype and prognosis Medullary Thyroid Cancer (5%) Familial (25%)

  17. Medullary Thyroid Cancer • Usually solitary • Lymph node metastases present in 50% • Distant metastases present in 10-20% • Somatic mutations in RET occur in 40-50% • 4-10% of presumed sporadic cases have germline RET mutations Medullary Thyroid Cancer (5%) Sporadic (75%)

  18. Pearls: Medullary Thyroid Cancer • All patients with MTC should be tested for genetic mutations • 1st degree relatives should be screened • RET testing • Basal calcitonin (?) Medullary Thyroid Cancer (5%) Familial (25%) Sporadic (75%)

  19. Familial Thyroid Cancer Thyroid Cancer Medullary Thyroid Cancer (5%) Non-medullary Thyroid Cancer (95%)

  20. Non-Medullary Thyroid Cancer • First described in 1955 • Identical 24yo twins Non-medullary Thyroid Cancer (95%) Familial (5-10%)

  21. Non-Medullary Thyroid Cancer 1955: Scrabble makes its commercial debut

  22. Non-Medullary Thyroid Cancer • First described in 1955 • Identical 24yo twins • ≥3 first degree relatives • Compared to sporadic • Younger age • Multifocal disease • Local invasion • Lymph node metastasis • Local and regional recurrence Non-medullary Thyroid Cancer (95%) Familial (5-10%) Syndromic Nonsyndromic

  23. Non-Medullary Thyroid Cancer • Thyroid tumors less common than other associated tumors • Syndromes • Familial adenomatous polyposis (FAP) • Cowden’s syndrome • Werner’s syndrome • Carney’s complex Non-medullary Thyroid Cancer (95%) Familial (5-10%) Syndromic

  24. Non-Medullary Thyroid Cancer • More aggressive than sporadic PTC • Subclassification • fPTC • fPTC with renal papillary tumor • fPTC with multinodular goiter Non-medullary Thyroid Cancer (95%) Familial (5-10%) Nonsyndromic

  25. Non-Medullary Thyroid Cancer • Thought to be autosomal dominant • Putative genes identified, none definitive • 4-10x increase in incidence of PTC in relatives of patients with familial PTC Non-medullary Thyroid Cancer (95%) Familial (5-10%) Nonsyndromic

  26. Pearls: Non-Medullary Thyroid Cancer • Suspect familial NMTC in patients with multifocal, multinodular and bilateral thyroid cancer • May need more aggressive treatment • Prophylactic neck dissection • Postop I131 and thyroid hormone suppression regardless of tumor size Non-medullary Thyroid Cancer (95%) Familial (5-10%)

  27. Molecular genetics • Four main genetic mutations • BRAF point mutation • RAS point mutation • RET/PTC rearrangement • PAX8/PPARγ rearrangement

  28. Molecular genetics • Papillary thyroid cancer • BRAF and RAS point mutations, and RET/PTC rearrangements • Mutations activate mitogen-activated protein kinase (MAPK) pathway • Identified in >70% of papillary cancers • Follicular thyroid cancer • RAS point mutations and PAX8/PPARγrearrangements

  29. Molecular genetics Bhaijee 2011

  30. Molecular genetics Bhaijee 2011

  31. Molecular genetics • Testing methods • PCR: requires careful coordination of specimen acquisition and processing • FISH: can be performed on formalin fixed tissue • VeracyteAfirma • AsuragenmiRInform • Quest Diagnostics

  32. PEARLS: Molecular genetics • ATA class C recommendation for molecular testing for “follicular lesion of unknown significance” (FLUS) • Testing methods not standardized or widely available

  33. Summary • Medullary thyroid cancer • 5% of all thyroid cancers, 25% hereditary • Non-medullary thyroid cancer • 95% of all thyroid cancers, 5-10% hereditary • Somatic mutations in thyroid cancer • BRAF and RAS point mutations • RET/PTC and PAX8/PPARγrearrangements

  34. quiz Specific RET mutations in MEN syndromes are associated with disease prognosis: True False

  35. quiz What percentage of non-medullary thyroid cancers are hereditary? 5% 30% 60% 90%

  36. quiz What is the most common genetic mutation found in thyroid cancer? PAX8/PPARγrearrangement WFS1 point mutation BRAF point mutation IDK translocation

  37. References

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