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Thyroid Cancer: A Unique Neoplasm Discretionary Decisions and Diverse Outcomes

2006 Semon Lecture. Thyroid Cancer: A Unique Neoplasm Discretionary Decisions and Diverse Outcomes. Harrison D. Felix Semon 1849 – 1921 A Victorian Laryngologist. London: Royal Society of Medicine Press Limited, 2000. Sir Felix Semon 1849 - 1921. Medical Studies 1868 – 1873

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Thyroid Cancer: A Unique Neoplasm Discretionary Decisions and Diverse Outcomes

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  1. 2006Semon Lecture Thyroid Cancer:A Unique NeoplasmDiscretionary DecisionsandDiverse Outcomes

  2. Harrison D. Felix Semon 1849 – 1921 A Victorian Laryngologist. London: Royal Society of Medicine Press Limited, 2000.

  3. Sir Felix Semon1849 - 1921 Medical Studies 1868 – 1873 Heidelberg and Berlin Studied Laryngology In Vienna & Paris FRCP 1885 Order of Red Eagle 1888 Royal Prussian Professor 1894 President – Laryngological Society 1894 – 1896 Knighthood 1897 CVC 1902 KCVO 1905 Physician Extraordinary to King Edward VII 1901 Retired 1911

  4. Harrison D. Felix Semon 1849 – 1921 A Victorian Laryngologist. London: Royal Society of Medicine Press Limited, 2000.

  5. Harrison D. Felix Semon 1849 – 1921 A Victorian Laryngologist. London: Royal Society of Medicine Press Limited, 2000.

  6. Vanity Fair, 1902

  7. Harrison D. Felix Semon 1849 – 1921 A Victorian Laryngologist. London: Royal Society of Medicine Press Limited, 2000.

  8. Sir Felix Semon1849 - 1921 First lecture delivered by Dr. P. McBride in 1913 on “Sir Felix Semon, His Work and Its Influence on Laryngology” The Semon Lecture Trust was established with the capital of £1040, through contributions from laryngologists and friends

  9. Thyroid CancerIssues • Risk Group Stratification • Selection of Therapy • Follow up (problems?) • Exploiting Biology • Future Directions • Incidence • Pathology • Natural History • Practice Patterns • Prognostics Factors

  10. Thyroid Cancer – Incidence & Mortality1974 to 2005 Thousands Overall Women Men Mortality

  11. Changes in Thyroid Cancer Over Time 1990 2005 Change Total cases 12,100 25,690 + 112% Deaths 1,025 1,490 + 45% Death rate: Total 8% 6% - 2% Male 37% 42% 5% Female 63% 58% - 5% Relative survival 86% (1970-1973) 96% (1986-1992) Based on SEER Data

  12. Thyroid CancerComparative Incidence

  13. Is this Increasing Incidence Real? • Delayed effect of radioactive fallout? • The peak effect of this should be past • Geographical distribution does not support this • Other environmental influences • Incidence of subclinical disease may be much higher • Autopsy studies show thyroid cancer in as many as 36% of patients • Improved Diagnostic Scrutiny – Sonography and FNA • Increase in incidence is due to an increase in Papillary Ca • 49% of the increase is in cancers < 1 cm; 87% < 2 cm • Does this correspond to an increasing mortality? We may be overdiagnosing and treating cancers that are of no clinical significance? Davies and Welch, JAMA 2006

  14. Differentiated Cancer of the Thyroid Gland A Unique Neoplasm • Multifocal microscopic foci of carcinoma are • common (60 – 80%) • Micrometastases to regional lymph nodes • are common (>50%) Its clinical significance is hardly any, if at all

  15. Cancer of the Thyroid Papillary Poorly differentiated,tall cell, insular, etc. Anaplastic Follicular Good Bad Ugly 80% 15% 5%

  16. Differentiated Cancer of the Thyroid Gland Treatment Paradigm Total or near total thyroidectomy Radioiodine ablation Radioiodine therapy Follow up with TGb and ultrasound • Majority get excessive treatment at great cost with little • or no benefit • Some derive benefit • Some have no impact on prognosis with treatment

  17. Differentiated Carcinoma of the Thyroid Prognostic Factors MSKCC Mayo Lahey Karolinska GAMES AGES MACIS AMES DAMES Grade Age Metastases Age DNA Age Grade Age Age Metastases Completeness Metastases Metastases of resection Extension Extension Invasion Extension Extension Size Size Size Size Size

  18. Thyroid Carcinoma with Extrathyroid Extension Treatment Failure p<0.0001 Percent

  19. Differentiated Carcinoma of the Thyroid Risk Groups Prognostic Factors Low Intermediate High Risk Groups >45 <45 >45 <45 FactorHigh Low Age Gender Size Extent Grade Dist. Mets. Age >45 <45 Gender Male Female Extent Extraglandular Intraglandular Grade High Low Distant mets Present Absent Female < 4 cms. Intraglandular Low Absent Male > 4 cms. Extraglandular High Present

  20. Risk Groups Prognostic Factors Age Gender Size Extent Grade Dist. Mets. Low Intermediate High <45 >45 <45 >45 Female < 4 cms. Intraglandular Low Absent Male > 4 cms. Extraglandular High Present

  21. Selection of Therapy Be Aggressive at Extremes of Age • Children (< 16 yrs). Total thyroidectomy and RAI therapy • Older patients (> 60 yrs). Appropriate aggressive • surgery followed by RAI and/or RT Adults High risk Aggressive surgery Low Risk Unifocal Intraglandular nodule Lobectomy Older pt Low risk Intraglandular tumor Lobectomy Young pt High risk tumor Aggressive surgery

  22. Lobectomy vs Total Thyroidectomy Tumor Recurrence Thyroid Lobectomy Total Thyroidectomy Local 5 7% 5 7% Regional 9 12% 15 21% Distant 17 23% 22 30% MSKCC, 1930-1980 match pair analysis

  23. Total Thyroidectomy • Diffuse bilobar tumor • Bilateral nodules regardless of the size of primary • Major extrathyroid extension • Massive bilateral nodal metastases • Distant metastases • History of radiation exposure

  24. Extrathyroidal Extension from Differentiated Carcinoma of the Thyroid Minor: T3 • Strap muscles • Soft tissues Major: T4A • Trachea • Larynx • Esophagus • Recurrent laryngeal nerve

  25. Thyroid Carcinoma with Extrathyroid Extension Treatment Failure Percent p<0.0001

  26. Thyroid Carcinoma with Extrathyroid Extension Survival Survival 1.0 .9 .8 .7 .6 p=0.0001 .5 .4 .3 No ETE, N=933 .2 All patients, N=1012 .1 ETE, N=79 0.0 0 60 120 180 240 300 360 Time (months)

  27. Thyroid Carcinoma with Extrathyroid Extension Young Patients with Complete Excision Survival 1.0 .9 .8 p=0.46 .7 .6 .5 p=0.005 .4 .3 .2 <=45, ETE, Complete excision .1 <=45, No ETE <=45, ETE, Incomplete excision 0.0 0 60 120 180 240 300 360 Time (months)

  28. Tumor Excision • Group I - complete excision • Group II - “shave” excision • Group III - incomplete excision • Overall survival was: 79% at 5 yrs 63% at 10 yrs 54% at 15 yrs • No statistical difference in “complete excision” • and “shave excision” group • Gross residual group - 50% 5 yr survival McCaffrey T V et al. Head & Neck 1994;16:165-172

  29. Surgery for Extrathyroid Extension Principles • All gross tumor should be removed • Preserve functioning structures • Preserve vital structures • Balance between tumor control and best • functional results • Use adjuvant treatments - RAI, and/or RT

  30. Extrathyroid Extension Trachea • Shaving tumor off the trachea • Partial/window resection and reconstruction • Sleeve resection with primary anastomosis • Resection of trachea with cricoid

  31. Limited anterior tracheal invasion by thyroid carcinoma. Insert on right shows resection with a tracheal window: a “shave” excision in this case would leave behind intraluminal tumor. McCaffrey T V et al. Head & Neck 1994;16:165-172

  32. AJCC/UICC 2003 Staging Nodal Staging for Thyroid Cancer Nx – regional lymph nodes cannot be assessed N0 – No regional lymph node metastasis N1 – Regional lymph node metastasis N1b Metastasis to unilateral, bilateral or contralateral cervical or superior mediastinal lymph nodes N1a Metastasis to Level VI pretracheal, paratracheal, prelaryngeal, delphian Risk of Metastatic Spread Central Compartment Node Dissection Modified Radical Neck Dissection – Type III

  33. New Avenues in Thyroid Cancer Management Clinical Indications for 18FDG PET • FDG – PET scan • Elevated TG, RAI negative • Patient with distant mets • Tumors that poorly concentrate RAI • rhTSH (Thyrogen) • VEGF expression • cMET expression • MUC1 alterations

  34. If thyroid cancer is present, how often will the test detect disease? Is rhTSH an acceptable alternative to standard hypothyroid withdrawal protocols for the detection of recurrent thyroid cancer? Sensitivity Analysis How many patients with a negative test will actually have disease? Levothyroxine Withdrawal Traditional thyroid hormone withdrawal (Prior to 1999) RAI 0 4 wks 6 wks Levothyroxine Suppression False Negatives rhTSH Stimulation (1999-2000) MSKCC Experience Mon Tue Wed Thu Fri

  35. Differentiated Cancer of the Thyroid Gland Follow Up Aggressive Surgery Total Thyroidectomy Lobectomy T4 Suppression RAI RAI +/- RT TGb Ultrasound TGb Ultrasound TGb Ultrasound PET

  36. A Consensus Report of the Role of Serum Thyroglobulin as a Monitoring Method for Low-Risk Patients with Papillary Thyroid CarcinomaE. L. Mazzaferri, R. J. Robbins, C. A. Spencer, L. E. Braverman, F. Pacini, L. Wartofsky, B. R. Haugen, S. I. Sherman, D. S. Cooper, G. D. Braunstein, S. Lee, T. F. Davies, B. M. Arafah, P. W. Ladenson and A. Pinchera • Meta analysis of 1028 patients. • 6.5% found to have metastases outside of the thyroid bed. • 784 patients (76.3%) with suppressed Tg < 1 ng/ml • 168 patients (21.4%) with rhTSH stimulated Tg > 2 • 53 found to have metastases (Local/regional – 60%, Distant – 36%, Uncertain – 4%) • Dx WBS identified only 11 patients with metastases Recommendations • TSH stimulated Tg is sufficient for the follow-up of low risk patients with no clinical evidence of disease. • If TSH stimulated Tg is > 2 ng/ml further evaluation is necessary. • If the initial TSH stimulated Tg is < 0.6 further follow-up can be limited to T4 suppressed Tg and physical exam. J Clin Endocrinol Metab , 2003

  37. Who Dies of Thyroid CancerNational Cancer Data Base (1985 – 1995) 53,856 NCDB patients extrapolated to current incidence Anaplastic (2%) 85% mortality 510 deaths Medullary (4%) 25% mortality 300 deaths WDTC Stage 4 (1%) 50% mortality 150 deaths Aggressive Histologic Subtypes ??? Other High Risk Patients ??? How many patients with apparently curable disease die of thyroid cancer? Most patients who ultimately die of thyroid cancer can be identified at the the time of initial treatment and followed aggressively and appropriately Hundahl et al, Cancer 1998

  38. Low Risk Thyroid CancerSurvival and Recurrence – Mayo Clinic 2305 pts with Papillary Thyroid Cancer treated 1940 – 1999 • All patients had complete cancer resection and disease confined to neck • Median follow-up – 15 years, longest 60 years • CANCER SPECIFIC MORTALITY – 4% (All deaths occurred within 15 years of initial treatment) • Recurrences – 13% (1950 – 1999 cohort) (While recurrences continue to increase over at least 25 years, most occur in the first 5 years) Low Risk Patients • 81% pTNM I or II • 84% MACIS < 6 • CANCER SPECIFIC 10 YEAR MORTALITY – 0% • 10 year recurrence rate – 7.1%-8.8% Hay et al, 2002

  39. Well Differentiated Thyroid CancerKeith S. Heller MD 1979 – 2005809 Previously Untreated Patients • Less than 45 years old – 360 patients • 356 currently alive (99%) • 1 cancer related death • 45 years or older – 449 patients • 409 currently alive (91%) • 8 cancer related deaths Median Follow-up – 67 months Average Follow-up – 82 months

  40. Well Differentiated Thyroid CancerKeith S. Heller MD 1979 – 2005Cancer Related Deaths 1 Pt may have died of lung ca

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