1. Clinical Significance of Preoperative 18F-FDG PET Non- Avidity in Papillary Thyroid Carcinoma Do Hoon Koo 1, Ho-Young Lee 2, Kyu Eun Lee 3,4, So Won Oh 2, Hyung Ju Kwon 3,4, Sehyun Pack 3,4, Youngpeck Song 5, June Key Chung 2, Yeo-Kyu Youn 3,4 1 Department of Surgery, Seoul National University Boramae Medical Center, and College of Medicine, Seoul, Korea 2 Department of Nuclear medicine, Seoul National University College of Medicine, Seoul, Korea 3 Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Korea 4 Division of Surgery, Thyroid Center, Seoul National University Cancer Hospital, Seoul, Korea 5 Department of Surgery, Seoul National University Bundang Hospital and College of Medicine, Seongnam, Korea

2. - Introduction (I) - [18 F ] FDG-PET positivity is known to be associated with a tumor aggressiveness and poor prognosis in various types of malignancy. In post-thyroidectomy thyroid cancer patients, RAI negative /FDG- positive recurrences are known to be associated with dedifferentiated tumors and a grave prognosis. [Rivera 2008 Cancer; Chung 1999 J Nucl Med] However, preoperative FDG PET in papillary thyroid carcinoma (PTC) patients had shown limited sensitivity, because majority of them are well differentiated. Nevertheless, a large number of thyroid cancers, including incidentalomas and PTCs, exhibit increased FDG uptake despite their well-differentiated histology. [Kim 2010 Annals Nucl Med; Kang 2003 JCEM]

3. - Introduction (II) - PET avidity could be utilized as a potential risk factor for tumor aggressiveness like extrathyroid extension or lymph node metastasis [Yun 2010 JCEM] SUV max higher than cutoff value was associated with central compartment LN metastasis. [Byun 2012 Annals Nucl Med] Some limitations since ETE or LN metastasis would not be predicted in all PET avid cases [Jeong 2006 Laryngoscope; Choi 2010 ASO] Whether PET non-avid group, as is regarded as better differentiated characteristics, would truly show less aggressive nature needed to be evaluated. We aimed to evaluate the rate of preoperative FDG non-avidity and assess clinical significance in PTC.

4. - Patients and Methods -  Between 2011 Jan and 2012 Apr, from 201 patients who underwent thyroidectomy d/t thyroid cancer in Seoul National University Boramae Medical Center, 81 patients who performed preoperative FDG PET examination and revealed final diagnosis of PTC were included in this study.  12 cases (MTC 1, FTC 2, PTC+SCC 1, recurred 2, diffuse sclerosing variant 1 and fvPTC 5) was excluded.  Preoperative FDG PET results were re-evaluated by the department of nuclear medicine and the clinicopathologic factors were analyzed.

5. - Patients Characteristics - Variables Value (n=81) Age (years)50.0 ± 12.1 (25-79) Sex, M : F 1:4.1 (16:65) Size of tumor (cm)1.06 ± 0.64 (0.3-3.3) PTMC rate 50 (61.7%) Preop. PET non-avidity20 (24.7%) Multifocality30 (37.0%) Extrathyroid extension 51 (62.9%) LN meta37 (45.7%) Retrieved LN number 8.7 ± 8.8 (0-36) Positive LN number4.1 ± 3.4 (1-15)

6. Variables PET non-avid (n=20)PET avid (n=61)p value Age (years) 48.1 ± 11.1 (29-73)50.6 ± 12.4 (25-79)0.198 Sex, M / F 8 (40.0%) / 128 (13.1%) / 53 0.009 Size of tumor (cm) 0.76 ± 0.34 (0.3-1.5)1.20 ± 0.69 (0.3-3.3) 0.001 PTMC rate 16 (80.0%)34 (55.7%) 0.053 Multifocality 4 (20.0%)26 (42.6%) 0.069 Extrathyroid extension 6 (30.0%)45 (73.8%) 0.001 LN meta 4 (20.0%)33 (54.1%) 0.008 Retrieved LN number 4.3 ± 4.4 (0-17)10.2 ± 9.3 (0-36) < 0.001 Positive LN number 3.5 ± 3.0 (1-7)4.1 ± 3.5 (1-15) 0.721 Result 1) Comparison of PET non-avid vs PET–avid groups : classified by visually discernible uptake

7. Patient † T SUV max nlT SUV mean T SUV max / nlT SUV mea n Liver SUV mean T SUV max / Liver SUV mea n 1 3.11.71.822.61.19 2 1.51.41.071.90.79 3 6.41.54.272.32.78 79 15.81.114.361.98.32 80 1.61.31.232.10.76 81 1.51.11.362.50.60 Median (range) 2.4 (1.1-25.8) 1.4 (0.9-2.8) 1.8 (0.52-23.0) 2.1 (1.2-3.0) 1.2 (0.48-9.58) † 2 cases unknown Definition of T SUV max / nlT SUV mean and T SUV max / Liver SUV mean Nilsson et al 2011 World J Surg T SUV max : maximum SUVs of focally increased thyroid FDG uptake at the anatomic location of the tumor nlT SUV mean : mean SUV from the surrounding normal thyroid Liver SUV mean : for normal organ reference

8. Variables (median) PET non-avid (n=20) † PET avid (n=61) † p value T SUV max 1.74 (1.1-4.4)5.19 (1.3-25.8)< 0.001 T SUV max / nlT SUV mean 1.27 (0.52-1.5)3.89 (0.64-23) < 0.001 T SUV max / Liver SUV mean 0.84 (0.48-2.0)2.44 (0.52-9.58) < 0.001 † 1 case unknown Result 2) Comparison of visual PET avidity by using quantitative analysis of SUV T SUV max correlated to tumor size (r=0.686, p<0.001) T SUV max / nlT SUV mean correlated to tumor size (r=0.664, p<0.001) T SUV max / Liver SUV mean correlated to tumor size (r=0.667, p<0.001)

9. ▷ T SUV max / nlT SUV mean Cut-off value 1.5) Sensitivity 0.717, Specificity 0.895 # ROC curve by T SUV max, T SUV max / nlT SUV mean and T SUV max / Liver SUV mean ▷ T SUV max / Liver SUV mean Cut-off value 1.13) Sensitivity 0.700, Specificity 0.895 ▷ T SUV max Cut-off value 2.0) Sensitivity 0.750, Specificity 0.842 Area = 0.797Area = 0.845Area = 0.857

10. Variables PET non-avid (n=31) : T SUV max <2 PET avid (n=48) : T SUV max ≥2 p value Age (years) 47.5 ± 9.9 (26-67)52.1 ± 13.0 (25-79)0.093 Sex, M / F 9 (29.0%) / 226 (12.5%) / 42 0.067 PTMC rate 27 (87.1%)22 (45.8%)< 0.001 Multifocality 13 (41.9%)17 (35.4%) 0.560 ETE 16 (51.6%)34 (70.8%) 0.084 LN meta 9 (29.0%)27 (56.2%) 0.018 Retrieved LNs 5.8 ± 5.7 (1-20)10.2 ± 9.7 (0-36) 0.001 Positive LNs 2.8 ± 2.0 (1-7)4.3 ± 3.7 (1-15) 0.243 Result 3-1) Comparison of PET non-avid vs avid groups : classified by cut-off value 2 of T SUV max † 2 cases unknown

11. Variables PET non-avid (n=34) : T SUV max / nlT SUV mean <1.5 PET avid (n=45) : T SUV max / nlT SUV mean ≥1.5 p value Age (years) 50.1 ± 8.6 (29-67)50.5 ± 14.2 (25-79)0.861 Sex, M / F 8 (23.5%) / 267 (15.6%) / 380.371 PTMC rate 31 (91.2%)18 (40.0%)<0.001 Multifocality 14 (41.2%)16 (35.6%)0.610 ETE 17 (50.0%)33 (73.3%)0.033 LN meta 9 (26.5%)27 (60.0%)0.003 Retrieved LNs 5.5 ± 5.3 (1-24)11.2 ± 10.1 (0-36) 0.002 Positive LNs 2.2 ± 1.9 (1-7)4.5 ± 3.6 (1-15) 0.023 Result 3-2) Comparison of PET non-avid vs PET–avid groups : classified by cut-off value 1.5 of T SUV max / nlT SUV mean † 2 cases unknown

12. Variables PET non-avid (n=35) : T SUV max / Liver SUV mean <1.13 PET avid (n=44) : T SUV max / Liver SUV mean ≥1.13 p value Age (years) 48.6 ± 10.2 (25-67)51.7 ± 13.3 (25-79)0.253 Sex, M / F 10 (28.6%) / 255 (11.4%) / 390.053 PTMC rate 30 (85.7%)19 (43.2%)<0.001 Multifocality 13 (37.1%)17 (38.6%)0.892 ETE 19 (54.3%)31 (70.5%)0.139 LN meta 11 (31.4%)25 (56.8%)0.024 Retrieved LNs 6.3 ± 5.8 (1-24)10.7 ± 10.3 (0-36) 0.041 Positive LNs 2.7 ± 1.8 (1-7)4.5 ± 3.8 (1-15) 0.073 Result 3-3) Comparison of PET non-avid vs PET–avid groups : classified by cut-off value 1.13 of T SUV max / Liver SUV mean † 2 cases unknown

13. - Summary & Conclusion (I) - Preoperative FDG PET was non-avid in 20 out of 81 cases (24.7%) and mean tumor size was 1.06 ± 0.64 cm (0.3-3.3). When classified by visually discernible uptake, Preoperative PET non-avid cases showed lower significant ETE (30.0% vs 73.8%, p=0.001) and LN metastasis rate (20.0% vs 54.1%, p=0.008) than PET avid cases with less number of retrieved LNs (4.3 vs 10.2, p<0.001) and greater proportion of male (40.0% vs 13.1%, p=0.009). There was significant difference in T SUV max (1.74 vs 5.19, p<0.001), T SUV max / nlT SUV mean (1.27 vs 3.89, p=0.001) and T SUV max / Liver SUV mean (0.84 vs 2.44, p<0.001) between PET avid and non-avid groups, which of all showed correlation with tumor size (p<0.001).

14. - Summary & Conclusion (II) - In terms of quantitative analysis ( T SUV max / nlT SUV mean <1.5 vs T SUV max / nlT SUV mean ≥1.5), T SUV max / nlT SUV mean <1.5 (PET non-avid) group showed lower ETE (50.0% vs 73.3%, p=0.033) and LN meta. (26.5% vs 60.0%, p=0.003) rate with less number of retrieved (5.5 vs 11.2, p=0.002) and positive LN (2.2 vs 4.5, p=0.023). In terms of quantitative analysis ( T SUV max / liver SUV mean <1.13 vs T SUV max / Liver SUV mean ≥ 1.13), T SUV max / Liver SUV mean <1.13 (PET non- avid) group showed lower LN meta. rate (31.4% vs 56.8%, p=0.024) with less number of retrieved LNs (6.3 vs 10.7, p=0.041). Preoperative PET avidity in PTC in terms of visual discernible uptake and quantitative analysis could be evaluable. Further large-cohort prospective trial would be needed.

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