Well Differen*ated Thyroid Microcarcinoma. Robert A. Levine, MD, FACE, ECNU Thyroid Center of New Hampshire Geisel School of Medicine at Dartmouth

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1 Well Differen*ated Thyroid Microcarcinoma Robert A. Levine, MD, FACE, ECNU Thyroid Center of New Hampshire Geisel School of Medicine at Dartmouth

2 Objec*ves (1) Review epidemiology of thyroid microcarcinoma. Consider the changes in thyroid cancer detec*on and management over the past decade. Review recent changes to thyroid nodule and thyroid cancer guidelines, par*cularly regarding micronodules and microcarcinoma. Compare and contrast thyroid microcarcinoma and low risk thyroid cancer. Review prognosis of treated thyroid microcarcinoma and low risk thyroid cancer.

3 Objec*ves (2) Review exis*ng (Japanese) studies concerning observa*on of thyroid microcarcinoma without surgery. Consider whether exis*ng studies regarding observa*on can be applied to prac*ce in the United States. Provide recommenda*ons regarding observa*on of sub- cen*meter nodules and cancer.

4 Davies L, Welch HG 2014 JAMA otolaryngology- - head & neck surgery: Current thyroid cancer trends in the United States.

5 Rising incidence and stable mortality Davies L, Welch HG 2014 JAMA otolaryngology- - head & neck surgery: Current thyroid cancer trends in the United States.

6 Davies L, Welch HG 2014 JAMA otolaryngology- - head & neck surgery: Current thyroid cancer trends in the United States. 39% < 1cm

7 Ahn HS, Kim HJ, Welch HG NEJM 371(19): Korea s Thyroid- Cancer Epidemic Screening and Overdiagnosis.

8 Ahn HS, Kim HJ, Welch HG NEJM 371(19): Korea s Thyroid- Cancer Epidemic Screening and Overdiagnosis.

9 Geographical varia*on in diagnosis of thyroid cancer Brito JP, Hay ID, Morris JC 2014 BMJ (Clinical research ed.): Low risk papillary thyroid cancer. United States

10 Ito Y, Nikiforov YE, Schlumberger M, Vigneri R 2013 Nature reviews. Endocrinology 9(3): Increasing incidence of thyroid cancer: controversies explored.

11 What do the DRAFT guidelines proposed by the ATA recommend for nodules and cancers smaller than 1 cm?

12 DRAFT Guidelines regarding decision to perform biopsy.

13 DRAFT Guidelines regarding decision to NOT perform biopsy in HIGH SUSPICION sub- cen*meter nodules.

14 DRAFT Guidelines regarding decision to observe without biopsy.

15 DRAFT Guidelines regarding decision to observe without biopsy.

16 DRAFT Guidelines regarding decision to perform ac*ve surveillance rather than surgery for papillary microcarcinoma

17 Thyroid Microcarcinoma is not the same as Low Risk Thyroid Carcinoma

18 How is Low Risk Thyroid Cancer Defined? Criteria Include: Age: year old cut off Invasiveness or extra- thyroidal extension Distant metastases or loco- regional metastases Completeness of resec*on Size: 4-5 cm or con*nuous variable Not 1 cm cut- off Brito JP, Hay ID, Morris JC 2014 BMJ (Clinical research ed.): Low risk papillary thyroid cancer.

19 Sugitani I, Fujimoto Y 2010 Surgery today: Management of low- risk papillary thyroid carcinoma: unique conven*onal policy in Japan and our efforts to improve the level of evidence.

20 Sugitani I, Fujimoto Y 2010 Surgery today: Management of low- risk papillary thyroid carcinoma: unique conven*onal policy in Japan and our efforts to improve the level of evidence.

21 What is the outcome of treated low risk thyroid cancer?

22 Survival in low- risk and high- risk PTC Sugitani I, Fujimoto Y 2010 Surgery today: Management of low- risk papillary thyroid carcinoma: unique conven*onal policy in Japan and our efforts to improve the level of evidence.

23 Mortality and recurrence in low- risk and high- risk PTC Sugitani I, Fujimoto Y 2010 Surgery today: Management of low- risk papillary thyroid carcinoma: unique conven*onal policy in Japan and our efforts to improve the level of evidence.

24 Risk factors for poor outcome in pa*ents presen*ng with clinically evident nodes, or RLN palsy Sugitani I, Fujimoto Y 2010 Surgery today: Management of low- risk papillary thyroid carcinoma: unique conven*onal policy in Japan and our efforts to improve the level of evidence.

25 Chow SM, Law SC, Chan JK, Au SK, Yau S, Lau WH 2003 Cancer: 98(1) July 2003 Papillary microcarcinoma of the thyroid- Prognos*c significance of lymph node metastasis and mul*focality.

26 Chow SM, Law SC, Chan JK, Au SK, Yau S, Lau WH 2003 Cancer: 98(1) July 2003 Papillary microcarcinoma of the thyroid- Prognos*c significance of lymph node metastasis and mul*focality.

27 Hay ID, Hutchinson ME, Gonzalez- Losada T, McIver B, Reinalda ME, Grant CS, Thompson GB, Sebo TJ, Goe 2008 Surgery: Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60- year period.

28 Hay ID, Hutchinson ME, Gonzalez- Losada T, McIver B, Reinalda ME, Grant CS, Thompson GB, Sebo TJ, Goe 2008 Surgery: Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60- year period.

29 Hay ID, Hutchinson ME, Gonzalez- Losada T, McIver B, Reinalda ME, Grant CS, Thompson GB, Sebo TJ, Goe 2008 Surgery: Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60- year period.

30 Hay ID, Hutchinson ME, Gonzalez- Losada T, McIver B, Reinalda ME, Grant CS, Thompson GB, Sebo TJ, Goe 2008 Surgery: Papillary thyroid microcarcinoma: a study of 900 cases observed in a 60- year period.

31 Disease specific mortality 49/18,445 = 0.26% Yu XM, Wan Y, Sippel RS, Chen H 2011 Annals of surgery: Should all papillary thyroid microcarcinomas be aggressively treated? An analysis of 18,445 cases.

32 Studies of Ac*ve Surveillance of Papillary Microcarcinoma.

33 Ito Y, Miyauchi A, Kobayashi K, Miya A 2014 Endocrine journal: Prognosis and growth ac*vity depend on pa*ent age in clinical and subclinical papillary thyroid carcinoma.

34 Ito Observa*on 1055 Surgical treatment Enlargement of 3mm or more: 6.4% at 5 years and 15.9% at 10 years Novel Nodal Metastasis: 1.4% at 5 years and 3.4% at 10 years 109/340 (32%) underwent surgical treatment Ito Y, Miyauchi A, Inoue H et al 2010, World J Surg: An observa*onal trial for papillary micro carcinoma in Japanese pa*ents.

35 Ito Y, Miyauchi A, Inoue H et al 2010, World J Surg: An observa*onal trial for papillary micro carcinoma in Japaneses pa*ents.

36 Ito Y, Miyauchi A, Inoue H et al 2010, World J Surg: An observa*onal trial for papillary micro carcinoma in Japaneses pa*ents.

37 Ito Y, Miyauchi A, Inoue H et al 2010, World J Surg: An observa*onal trial for papillary micro carcinoma in Japaneses pa*ents.

38 Ito Observa*on Enlargement of 3mm or more: 58/1235 (4.6%) Novel Nodal Metastasis: 19/1235 (1.5%) 191/1235 (19%) underwent surgical treatment Ito Y, Miyauchi A, Kihara M, Higashiyama T, Kobayashi K, Miya A 2014 Thyroid : official journal of the American Thyroid Associa*on: Pa*ent age is significantly related to the progression of papillary microcarcinoma of the thyroid under observa*on.

39 Ito Y, Miyauchi A, Kihara M, Higashiyama T, Kobayashi K, Miya A 2014 Thyroid : official journal of the American Thyroid Associa*on: Pa*ent age is significantly related to the progression of papillary microcarcinoma of the thyroid under observa*on.

40 43/1235 (3.5%) (Nodes or size >12 mm) Ito Y, Miyauchi A, Kihara M, Higashiyama T, Kobayashi K, Miya A 2014 Thyroid : official journal of the American Thyroid Associa*on: Pa*ent age is significantly related to the progression of papillary microcarcinoma of the thyroid under observa*on.

41 Ito Y, Miyauchi A, Kihara M, Higashiyama T, Kobayashi K, Miya A 2014 Thyroid : official journal of the American Thyroid Associa*on: Pa*ent age is significantly related to the progression of papillary microcarcinoma of the thyroid under observa*on.

42 Sugitani I, Toda K, Yamada K, Yamamoto N, Ikenaga M, Fujimoto Y 2010 World journal of surgery: Three dis*nctly different kinds of papillary thyroid microcarcinoma should be recognized: our treatment strategies and outcomes.

43 Sugitani I, Fujimoto Y, Yamada K 2013 World journal of surgery: Associa*on between serum thyrotropin concentra*on and growth of asymptoma*c papillary thyroid microcarcinoma.

44 Ito Y, Miyauchi A, Kihara M, Higashiyama T, Kobayashi K, Miya A 2014 Thyroid : official journal of the American Thyroid Associa*on: Pa*ent age is significantly related to the progression of papillary microcarcinoma of the thyroid under observa*on.

45 Why the discrepancy between growth, (nodal) recurrence, and death? Ito Y, Miyauchi A, Kobayashi K, Miya A 2014 Endocrine journal: Prognosis and growth ac*vity depend on pa*ent age in clinical and subclinical papillary thyroid carcinoma.

46 Applicability of Japanese studies to American popula*on Sugitani I, Fujimoto Y 2010 Surgery today: Management of low- risk papillary thyroid carcinoma: unique conven*onal policy in Japan and our efforts to improve the level of evidence.

47 Likely differences in Observa*on trials in United States and Japan 1. Pa*ent acceptance may not be equivalent. 2. Ultrasound in Japanese study performed by single surgeon at single center. 3. Pa*ent adherence to follow up may have large cultural discrepancy 4. Possible disease specific differences. Sugitani I, Fujimoto Y 2010 Surgery today: Management of low- risk papillary thyroid carcinoma: unique conven*onal policy in Japan and our efforts to improve the level of evidence.

48 Ac*ve Surveillance of Micro- carcinoma Ac3ve Surveillance Delayed versus Immediate Surgery (Turle) Absolute need for LOW RISK micro- carcinoma No Lymph node metastases No Extra- thyroidal extension Not Mul*focal Favorable Loca*on Not adjacent to trachea or RLN

49 Ultrasound factors in ac*ve surveillance Requires advanced ultrasound skills Lymph node involvement Extrathyroidal extension is difficult to detect 1 High risk loca*ons. Ultrasound in exis*ng studies performed by single inves*gator at single site. 1 Michigishi T, Yokoyama K, Kobayashi E, et al., Poster 80, 84 th annual mee*ng of the ATA. October 2014

50 Extra- thyroidal extension is difficult to detect women underwent ultrasound screening for thyroid cancer. 99 cancers detected (2.3%) 90% <1cm 80 underwent surgery 32/70 (46%) papillary micro- cancer showed extra- thyroidal extension. pex1 - pt3 1 Michigishi T, Yokoyama K, Kobayashi E, et al., Poster 80, 84 th annual mee*ng of the ATA. October 2014

51 Selec*on of Pa*ents for Observa*on Lesion factors Nodes, ETE, loca*on (Adjacent to RLN or trachea) Signs or symptoms of invasion of RLN or trachea FNAB findings of high grade malignancy Pa*ent factors Familial cancer, radia*on, consent, reliability for follow- up (and understanding that will be >>20 yr f/u) Ins*tu*on factors Ultrasound skill (lymph nodes and ETE) Follow up rate approach to lost to follow- up Portability mobility of pa*ents

52 Unanswered Ques*ons Will trend in progressive development of clinical disease con*nue? Will late recurrences have a different degree of aggressiveness? What is the cost effec*veness of delayed versus immediate surgery? What is appropriate follow up? Frequency of US Addi*onal predic*ve factors. Molecular, Sonographic, Clinical Clear need for comprehensive ongoing clinical trials prior to universal acceptance

53 DRAFT Guidelines unanswered ques*ons regarding ac*ve surveillance.

54 Should Ac*ve Surveillance be considered Accepted Clinical Prac*ce or Clinical Research? Need for informed consent? Approval by an IRB? Clear need for data collec*on and analysis. Ins*tu*onal studies v. Clinical prac*ces Poten*al role of the Thyroid Cancer Care Collabora*ve (TCCC) for centers not performing clinical study.

55 What is the TCCC? HIPAA compliant internet based program with centralized data on all aspects of a thyroid cancer pa*ent s care. Sponsored by the Thyroid Head and Neck Cancer Founda*on. Resource for pa*ent educa*on. Resource for disease management decision making. Invaluable resource for clinical research. Endorsed by the AACE Thyroid Scien*fic Commiree Approved by Western IRB

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57 Informed Consent for Ac*ve Surveillance What should discussed? Explana*on of low risk micro- carcinoma Varie*es of thyroid cancer and the prognosis of papillary cancer Incidence of PMC in autopsy studies and popula*on screening compared with clinical disease prevalence. Current standard of care is surgery. Pros and cons of both Surgery and Ac*ve Surveillance. Pa*ents need to be informed that current understanding is based on small numbers followed for rela*vely short intervals. (<600 followed >5 years and < 200 followed > 10 years) Clear explana*on of need for follow- up for >> 20 years.

58 Conclusions The rise in incidence of PTMC may reflect screening and suggests a role for ac*ve surveillance. ATA guidelines suggest ac*ve surveillance may be appropriate for unifocal low risk tumors with no evidence of ETE, lymph node metastasis, or high grade aggressive subtypes. Selec*on of candidates for ac*ve surveillance requires advanced ultrasound skills and the ability to assess nodes and ETE to exclude high risk. Other predic*ve factors need to be determined. Delay in surgery has not been associated with adverse outcome, but the numbers of pa*ents, and the dura*on of follow- up are limited. Ac*ve surveillance will require long term observa*on and the cost analysis remains unclear. Observa*on of suspicious nodules <1 cm without biopsy carries many of the same considera*ons as observa*on of PTMC. Me*culous evalua*on for evidence of ETE, lymph node metastasis, and loca*on of the nodule, along with considera*on of clinical risks is essen*al if planning to not biopsy a suspicious sub- cen*meter nodule. The pa*ent must be informed of the suspicious nature of the lesion and join in the decision making process. It is essen*al that pa*ents enrolled in ac*ve surveillance be tracked for clinical status and long term data analysis.