1. 갑상선 결절 및 암의 최신 치료지침 2016.2.28 분당서울대학교병원 내과 연수강좌 분당서울대학교병원 내분비내과 문재훈

2. Epidemiology on Thyroid Cancer – In Korea 남자 여자 우리 나라 여성 갑상선암 발생률의 급증 10 만명당 1999 년 11.9 명 → 2013 년 114.4 명 1cm 이하의 미세갑상선유두암 (Papillary Thyroid Microcarcinoma, PTMC) 의 분율 증가 1990 년 이전 9% → 2005 년 이후 54% ( 서울대학교병원, Cho et al., 2013)

3. Crude and age-standardized thyroid cancer morality rates in 1985 to 2010 in Korea for both sexes. Epidemiology on Thyroid Cancer – In Korea

4. Active Surveillance in PTMC Conservative observational management strategy Offered to properly selected patients with prostate cancer, urethral cancer, and some non-Hodgkin lymphomas In patients being followed with active surveillance, definitive therapy (usually preceded by definitive diagnostic procedure) is not recommended until there is evidence of disease progression.

5. 2015 American Thyroid Association (ATA) Guidelines Surgery is generally recommended for biopsy proven thyroid cancer Active surveillance management approach “can be considered” as an alternative to immediate surgery in patients with very low risk tumors. In subcentimeter thyroid nodules with highly suspicious ultrasonographic characteristics and In cytologically confirmed very low risk papillary thyroid cancer. Strongly discourage FNA of asymptomatic sub-centimeter thyroid nodules, even if ultrasonographically suspicious Did not provide specific recommendations with regard to the optimal selection of patients.

6. Active Surveillance vs Intervention Active surveillance in patients with low-risk thyroid cancers Study Tumor Size Cutoff, cm Patients, No. Follow-up Duration Patients, No.(%) Tumor Growth >3mm Development of Lymph Node Metastases Subsequent Need for Surgery Sugitani et al, 2010<1 230 (300 lesions) Mean 5y (range, 1-17y) 22 (7.3)3 (1.3)16 (6.9) Ito et al, 2014<11235 Mean 5y (range, 1.5-19.0y) 58 (4.6)19 (1.5)191 (15.5) Pace et al, 2013<1.571Median 15mo1 (1.4) 6 (8.5) 논문연도대상기간 PTMC 환자수, No.(%) 수술 없이 경과관찰 경과 (5 년 /10 년, %) 전체 ( 수술 포함 ) 초기 경과 관찰 선택 경과 중 수술 시행 3mm 이상 크기 증가 림프절 전이 발생 임상적 암 진행 20031993-2002732162 (22.1)56 (34.6)--- 20101993-20041286340 (26.4)109 (32.1)6.4/15.591.4/3.4 20131993-2012na1235 (na)191 (15.5)4.9/81.7/3.86.8/11.8

7. Indolent nature of PTMC Majority of papillary microcarcinomas either do not progress or progress very slowly. Even patients that demonstrated disease progression while under active surveillance were effectively treated. Delayed surgical management approach in properly selected patients had no impact on disease specific survival. The same risk of locoregional spread, distant metastasis and disease specific mortality Risk stratified clinical decision making is needed.

8. Risk-stratified Approach Tumor/neck ultrasound characteristics The size of the primary tumor The location of the tumor within the thyroid gland Molecular profile Status of the cervical lymph nodes. Patient characteristics Age of the patient Child bearing potential Family history of thyroid cancer The willingness of the patient to defer immediate surgery Compliance with follow-up Medical team characteristics Availability and experience of the multidisciplinary team The quality of neck ultrasonography Experience of the clinician treating thyroid cancer

9. Suitability of an active surveillance management Ideal candidate: Older Well defined margins Not adjacent to the thyroid capsule Confined to the thyroid parenchyma Appropriate candidate: Younger Multifocal disease Adjacent to the thyroid capsule at non-critical locations Potentially more aggressive molecular phenotype Other ultrasonographic findings (thyroiditis, LAP, benign) Inappropriate candidate: Critical subcapsular locations Evidence of spread outside the thyroid (direct extension/meta) Evidence of disease progression

10. Classification as an IDEAL candidate Less than 1-2% rate of disease progression Very effective salvage therapy No significant morbidity or mortality associated with a delayed management Tumor/neck US characteristics Patient characteristics Medical team characteristics Solitary thyroid nodule Well defined margins Surrounded by ≥ 2 mm normal thyroid parenchyma No evidence of extrathyroidal extension Previous US documenting stability cN0 cM0 Older patients (>60 yrs) Willing to accept an active surveillance approach Understands that a surgical intervention may be necessary in the future Expected to be compliant with follow-up plans Supportive significant others (including other members of their health care team) Life-threatening co-morbidities Experienced multidisciplinary management team  High quality neck ultrasonography  Prospective data collection Tracking/reminder program to ensure proper follow-up

11. Classification as an APPROPRIATE candidate Disease progression rate of approximately 10% Tumor/neck US characteristics Patient characteristics Medical team characteristics Multifocal papillary microcarcinomas  Subcapsular locations not adjacent to RLN without evidence of extrathyroidal extension  Ill defined margins Background USG findings that will make follow up difficult (thyroiditis, non-specific lymphadenopathy, multiple other benign appearing thyroid nodules)  FDG avid PMC Middle aged patients (18-59 yrs) Strong family history of papillary thyroid cancer  Child bearing potential Experienced endocrinologist or thyroid surgeon  Neck ultrasonography routinely available

12. Classification as an INAPPROPRIATE candidate Thyroid surgery (± radioactive iodine ablation) has been demonstrated to be beneficial. Minor disease progression could lead to significant morbidity High rate of disease progression is expected Tumor/neck US characteristics Patient characteristics Medical team characteristics Evidence of aggressive cytology on FNA (rare)  Subcapsular locations adjacent to RLN  Evidence of extrathyroidal extension  Clinical evidence of invasion of RLN or trachea (rare)  N1 disease at initial evaluation or identified during follow-up  M1 disease (rare)  Documented increase in size of ≥ 3 mm in a confirmed papillary thyroid cancer tumor Young patients (< 18 yrs)  Unlikely to be compliant with follow-up plans  Not willing to accept an observation approach Reliable neck ultrasonography not available  Little experience with thyroid cancer management

13. Molecular profile Risk for disease progression? V600E BRAF positive papillary microcarcinoma FDG positive papillary microcarcinoma Other potentially aggressive molecular profile Not required molecular characterization of the tumors prior to an active surveillance management approach

14. A Practical Approach to Active Surveillance Excluded from observation Locoregional or distal metastasis (very rare) Signs of recurrent laryngeal nerve or tracheal invasion Aggressive histologies (very rare in papillary microcarcinoma), Evidence of disease progression. Subcapsular location adjacent to the expected course of the recurrent laryngeal nerve. Tumor multifocality, family history of thyroid cancer, sex and age did not exclude patients from an observation approach.

15. A Practical Approach to Active Surveillance FNA cytology Not necessary in patients that appear to be either ideal or appropriate candidates for an active surveillance management approach Establishing a definitive diagnosis in a subcentimeter thyroid cancer with a high suspicious sonographic pattern may be appropriate. (inappropriate candidate)

16. A Practical Approach to Active Surveillance Neck US check up interval every 6 months until stability of is documented (usually 2 years) stability is documented, every 1-2 years or less frequently. Thyroid function tests, annually

17. Conclusion An active surveillance management approach appears to be a viable management option in properly selected patients, due to the relative indolent nature of sub-clinical PTMC It should decrease the perceived need for immediate fine needle aspiration in the majority of subcentimeter thyroid nodules. For successful AS, clinicians will be required to critically assess the tumor/ultrasonographic characteristics, the experience of the medical team, and the patient/family.