1 Department of Surgery , Seoul National University Bundang Hospital, Seongnam, Korea

1. Papillary Thyroid Microcarcinoma, The Significance Of 5 mm: A Meta-analysis Youngpeck Song,1Do Hoon Koo,2Seung Hyun Ma,3,5 Sue K. Park,3,4,5June Young Choi,6,7 Kyuhyung Kim,1Eunyoung Kim,6,7 Yeo-Kyu Youn,6,7,8Kyu Eun Lee,6,7 1Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea 2Department of Surgery, Seoul National University Boramae Medical Center and College of Medicine, Seoul, Korea 3Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea 4Department of Biomedical Science, Seoul National University Graduate School, Seoul, Korea 5Cancer Research Institute, Seoul National University, Seoul, Korea 6Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Korea 7Division of Surgery, Thyroid Center, Seoul National University Cancer Hospital, Seoul, Korea 8Department of Surgery, National Medical Center, Seoul, Korea

2. Introduction • Most PTMCs are clinically indolent and have a good prognosis. • Aggressive tumor features and recurrence are similar to conventional PTC • Roti et al. Eur J Endocrino. 2008: Meta-analysis on PTMC characteristics for recurrence; age, incidental tumor, multifocality, LN metastasis, distant metastasis • Yu et al. Ann Surg2011;254:653–660 • Ito et al. World J Surg2010;34:1285-1290 • Arora et al. Thyroid 2009;19:473-477 • Kasai et al. Cancer 1987;60:1767-1770 • Han et al. KATES 2006;6:63-67

3. Introduction • ATA and KTA guideline: FNA only the patient with over 5 mm PTMC • NCCN guideline 2012: above 1 cm or high-risk clinical features • No general consensus about relationship between tumor size and aggressiveness of PTMC • No difference is in aggressiveness between patients with PTMC greater than 5 mm and smaller than 5 mm. • Significant difference is exist in the rate of LN metastasis according tumor size • Pelizzo et al. Nucl Med Commun. 2004;25(6):547-552 • Kasai et al. Cancer 1987;60:1767-70

4. Aim • Systemically reviewing the relevant articles and evaluate tumor aggressiveness of PTMC by size: less than 5 mm vs. over 5 mm

5. Methods • Search Strategy • Literature search : PUBMED, MEDLINE, EMBASE, KoMCI and KOREAMED published from May 1976 through April 2012 • Search terms • Papillary thyroid microcarcinoma • To find any additional published studies, a manual search was performed by checking all the references of prior meta-analysis and of all original studies.

6. Publications were identified using search word “Papillary thyroid microcarcinoma” (n = 689) Selection of The Studies Remove duplicated records (n = 184) Titles and abstracts were reviewed (n = 505) Articles described about PTMC characteristics for any tumor size were included (n = 36) 20 articles were excluded (n) Not reported eligible risk factor for tumor size (7) No description about number of patients have risk factors for tumor size (3) Cut off point was not 5 mm (3) Review article (1)  Time sequential recurrence free survival rate (1)  Not pure papillary thyroid cancer (data was mixed with follicular thyroid cancer) (1) Discordance between data of tables (1) Same center and author, duplicated data (1) Different pathologic subtype between over 5 mm and less than 5 mm (1) Unable to assay due to have 0 cell (1) 9 relevant articles of initially selected articles was added by bibliography and full-text assessed for eligibility (n = 45) 25 articles were finally included in meta-analysis

7. Methods • Data Extraction • Authorship, Publication year, Country, Age, Sample size, OR and 95% CI • Outcomes : Lymph node metastasis, Extrathyroidal extension, Multifocality, Bilaterality, Recurrence • Statistical Analysis • Meta-analysisusing STATA 9.2 • Random-effects model • The Cochran Q statistics : Heterogeneity • Egger's regression asymmetry test : Publication bias

8. Methods • Subgroup analysis • Thyroid cancer incidence rate : Globocan 2008 in WHO • Two authors qualified 25 articles independently using RoBANS scale

9. Summary odds ratio (95% CI), incidence rate and quality of study in the present 25 articles

10. Results Summary odds ratio (OR) for outcomes in relation to the cut-off point tumor size (5 mm)

11. Results

12. OR(95% CI) Lymph node metastasis1 2.70 (1.20, 6.40) 1.83 (0.93, 3.62) Lee et al,2008 3.11 (1.63, 5.91) 1.04 (0.16, 3.05) Subtotal (I-squared = 0.0%, p = 0.476) 2.34 (1.58, 3.46) Extrathyroidalextension3 Cho et al,2006 2.98 (1.18, 7.53) • 2.47 (0.54, 11.33) 3.76 (1.64, 8.64) • Subtotal (I-squared = 0.0%, p = 0.630) • 2.34 (1.60, 3.43) 4.05 (1.14, 14.38) Friguglietti et al,2010 1.11 (0.66, 1.89) Kim et al,2008 0.78 (0.23, 2.68) 2.34 (1.08, 5.04) Kim et al,2009 1.68 (0.77, 3.68) Kim et al,2010 1.61 (0.63, 4.14) Lee et al,2010 1.49 (0.88, 2.55) Pakdaman et al,2008 2.34 (1.53, 3.56) 1.23 (0.78, 1.92) 1.40 (0.59, 3.32) Vasileiadis et al,2011 3.09 (1.78, 5.39) • 1.72 (1.39, 2.11) Han et al,2006 4.34 (1.46, 12.89) Kim et al,2008 3.69 (0.46, 29.69) 2.26 (0.88, 5.83) 3.06 (1.56, 6.01) Outcome Author et al J.-C. Riss et al,2012 Kim et al,2009 Lee et al,2010 . Bilateral tumors3 Kim et al,2009 1.53 (0.47, 5.13) Kim et al,2010 1.38 (0.61, 3.12) 1.43 (0.74, 2.75) Lee et al,2010 2.01 (0.79, 5.07) Pakdaman,2008 2.08 (1.23, 3.53) 1.69 (1.19, 2.40) Subtotal (I-squared = 0.0%, p = 0.775) Tae et al,2008 Kim et al,2008 Lee et al,2006 . Summary odds ratio (OR) for outcomes in papillary thyroid microcarcinoma patients without heterogeneity 1.Analysis about study of high quality 2.Analysis about all study 3.Analysis about study in high incidence rate Lee et al,2010 • 1.72 (0.93, 3.18) Multifocaltumors2 Cho et al,2006 • Chow et al,2003 • 1.47 (0.77, 2.81) Kim et al,2008 Pelizzo et al,2007 Tae et al,2008 Park et al,2007 1.92 (1.02, 3.59) • Subtotal (I-squared = 24.8%, p = 0.193) Recurrence2 Pelizzo et al,2006 Subtotal (I-squared = 0.0%, p = 0.663) NOTE: Weights are from random effects analysis .2 .5 1 2 5

13. Results Summary patient ratio for LN metastasis in the group of less than 5 mm and over 5 mm

14. Limitation • Our search was restricted to studies published in indexed journals. • Only four articles provided adjusting odds ratio. Others were calculated crudely. • Heterogeneity was high in each literatures, so subgroup analysis was performed.

15. Conclusion • PTMC over 5 mm has more aggressive character than PTMC less than 5mmin terms of LN metastasis, ETE, multifocality, bilaterality and recurrence. • However even PTMC less than 5 mm do shows aggressiveness in terms of LN metastasis, ETE, bilaterality, multiplicity, and recurrence.  • We need further evidence to justify the avoidance of further study for the PTMC less than 5 mm.