www.nature.com/scientificreports OPEN Diagnostic Performance of F- FDG PET/CT in Papillary Thyroid Carcinoma with Negative I-WBS Received: 19 January 2017 at first Postablation, Negative Tg Accepted: 20 April 2017 Published: xx xx xxxx and Progressively Increased TgAb Level Zhong-Ling Qiu, Wei-Jun Wei, Chen-Tian Shen, Hong-Jun Song, Xin-Yun Zhang, Zhen-Kui Sun & Quan-Yong Luo Differentiated thyroid cancer (DTC) patients with negative serum thyroglobulin (Tg), negative I whole–body scintigraphy ( I-WBS) at first post-ablation and progressively increased TgAb level are a relatively rare entity in the follow-up after total thyroidectomy and radioactive iodine therapy. The value of F-FDG PET/CT in detecting the recurrence of disease in these patients has only been reported in a small case series. The goal of this study was to investigate the diagnostic accuracy of F-FDG PET/ CT in detecting recurrent disease in these specific PTC patients and to identify risk factors for patients 18 18 with positive F-FDG PET/CT results. Eighty-two PTC patients who had F-FDG PET/CT scans with negative Tg, negative I-WBS at first post-ablation and progressively increased TgAb levels were included. We found that the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of F-FDG PET/CT in this patient group were determined as 84%, 72%, 92%, 57% and 82%, respectively. F-FDG PET/CT scan had a good diagnostic performance and should be performed routinely in PTC patients with negative Tg, negative I-WBS at first postablation and progressively increased TgAb level, especially when span for progressively increased TgAb level ≥ 3 years and/or progressively increased TgAb value up to 150 IU/mL. Differentiated thyroid cancer (DTC) is becoming more and more common in the United States between 1975 and 2012, with an estimated 62,450 new cases in 2015 . Despite the high overall survival rate and good prognosis, 2, 3 the recurrence rate of DTC is not negligible and ranges from 14% to 23% . er Th efore, detection of persistent or 131 131 recurrent disease is very important in DTC management and follow-up. I whole–body scintigraphy ( I-WBS), measurement of serum thyroglobulin (Tg) level and neck ultrasonography are mainstream approaches for detect- ing persistent or recurrent disease after total or near-total thyroidectomy and radioiodine remnant ablation . Serum Tg level is the most sensitive and reliable marker indicating persistent or recurrent disease in the follow-up of DTC because serum Tg only originated from differentiated thyroid cancer cells . According to the current American y Th roid Association (ATA) guideline, negative serum Tg, defined as the low serum Tg levels during TSH suppression (Tg < 0.2 ng/mL) or ae ft r stimulation (Tg < 1 ng/mL) ae ft r total or near-total thyroidectomy and radioiodine remnant ablation, suggests the disease-free status for DTC patients in the follow-up . However, antithyroglobulin antibody (TgAb) can interfere with the measurement of Tg and reduce the accuracy of Tg as a predictor of DTC activity. In a previous study, TgAb was present in 10–25% of 7, 8 patients with PTC . Therefore, negative Tg with the presence of positive TgAb could lead to a clinical dilemma in terms of therapeutic decision and follow-up. Department of Nuclear Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China. Zhong-Ling Qiu and Wei-Jun Wei contributed equally to this work. Correspondence and requests for materials should be addressed to Z.-K.S. (email: email@example.com) or Q.-Y.L. (email: firstname.lastname@example.org) Scientific Repo R ts | 7: 2849 | DOI:10.1038/s41598-017-03001-7 1 www.nature.com/scientificreports/ N = 82 patients Sex Male 32 (39%) Female 50 (61%) Age (years) ≥45 35 (43%) <45 47 (57%) Mean age (range) 48 (17–76) Subtypes of PTC Classical 71 (86%) Follicular variant 4 (5%) Aggressive 7 (9%) Tumor size (mm) ≤20 21 (26%) 20–40 43 (52%) >40 18 (22%) Extrathyroid extension 19 (23%) Central lymph node dissection None 5 (6%) Central only 26 (32%) Central + ipsilateral only 35 (43%) Central + bilateral 16 (19%) Bilateral tumor 21 (26%) Multifocal tumor 25 (30%) N stage N0 9 (11%) N1a 39 (47%) N1b 27 (33%) Nx 7 (9%) Pathology with lymphocytic thyroiditis 13 (16%) Mean TgAb level prior to elevation, IU/mL (range) 102 (12–1902) Mean TgAb level at diagnosis, IU/mL (range) 479 (98–3726) Table 1. Patients’ characteristics. Whether or not elevated serum TgAb concentrations can be used as a surrogate marker of persistent or recur- 9, 10 rent disease remains controversial . Some argued that TgAb levels did not predict disease status in DTC because TgAb production primarily arises in coexisting lymphocytic thyroiditis or Graves’ disease in DTC patients . It has been reported that only the progressively increased TgAb level was useful for predicting clinical recurrence or 12, 13 persistence of Tg-negative patients with PTC . 18 18 F-fluorodeoxy-D-glucose positron emission tomography/computed tomography ( F-FDG PET/CT) is rou- tinely performed to search for the recurrent or persistent disease in patients with DTC . However, only a few studies including a small case series evaluated the value of F-FDG PET/CT in DTC patients who have negative 131 15, 16 I-WBS, negative Serum Tg, and increased TgAb titer . In the present study, we aimed to investigate the diagnostic accuracy of F-FDG PET/CT, performed over one year aer t ft heir first remnant ablation, in detecting recurrent disease of PTC in a relatively large clinical sam- ples of patients with negative Tg, negative I-WBS at first postablation and progressively increased TgAb level. Moreover, we also identified the correlation of clinical and pathological factors with positive F-FDG PET/CT findings in this specific cohort. Results Patient’s characteristics. According to the inclusion and exclusion criteria, eighty-two PTC patients 18 131 who underwent F-FDG PET/CT scans with negative Tg, negative I-WBS at first post-ablation and progres- sively increased TgAb level were confirmed and included. Of them, 58 (71%) PTC patients with serum Tg lev- els < 0.2 ng/mL (TSH suppression) and 24 (29%) PTC patients with serum Tg levels < 1 ng/mL (TSH stimulation >30 IU/mL) at 6 months aer fir ft st remnant ablation. Serum Tg levels were always < 0.2 ng/mL under TSH sup- pression for all these patients in the follow-up. The characteristics of the study cohort at diagnosis of recurrent PTC were shown in Table 1. 18 18 F-FDG PET/CT finding. Of 82 patients with F-FDG PET/CT findings, 59 (72%) patients had results interpreted as positive and 23 (28%) patients as negative. In 59 cases with positive F-FDG PET/CT findings, 54 (91.5%) patients were classified as true-positive confirmed pathologically by surgical specimens (Fig. 1). Neck Scientific Repo R ts | 7: 2849 | DOI:10.1038/s41598-017-03001-7 2 www.nature.com/scientificreports/ Figure 1. A true-positive lesion on the left neck region was detected by F-FDG PET/CT. A 35-year old woman underwent total thyroidectomy with central lymph node dissection on the right neck region and radioiodine ablation for remnant PTC and thyroid tissue. I-WBS obtained 5 days aer a ft n oral administration of 3.7 GBq of I showed negative finding. Six months aer a ft blation, the patient had negative Tg (<0.1 ng/mL) but abnormal TgAb of 108 IU/mL at TSH suppression status. Subsequently, during the follow-up 3.5 years later, 18 18 TgAb level progressively increased from 108 IU/mL to 623 IU/mL. F-FDG PET/CT revealed F-FDG-avid nodal lesion with SUV of 4.7 in the left neck (a,b and c, crossing line). Surgical pathology confirmed the max metastatic nodal lesion from PTC aer left n ft eck dissection. The patient had markedly decreased TgAb level aer ft wards. Sites of recurrent diseases No. of patients/foci Cervical lymph nodes 39/51 y Th roid bed 5/5 Left 16/22 Right 18/24 Parapharyngeal lymph nodes 2/2 Parotid lymph nodes 1/1 Mediastinal lymph nodes 6/7 Lungs 4 Table 2. Sites for recurrent diseases in 54 patients with true-positive F-FDG PET/CT findings. US was performed in all patients before F-FDG PET/CT scan. 39 patients with 51 lymph node metastases were found in the neck, among which 34 patients with 42 lesions were detected by neck US. Two cases with 2 lymph nodes metastases, one case with 1 lymph node metastasis and 6 cases with 7 lymph node metastases were found in pharyngeal space, parotid, and mediastinum, respectively, all of which were detected by contrast-enhanced 18 18 CT ae ft r F-FDG PET/CT scanning. 4 patients with F-FDG PET lung metastases were diagnosed, all of which were detected and conr fi med by chest CT (Table 2). 7 false-positive lesions were found on F-FDG PET/CT scan in 5 patients in the neck, 5 FDG-avid lesions in 4 patients and 2 FDG-avid lesions in 1 patient were diagnosed as reactive infection of lymph node and hyperplasia of lymph nodes (Fig. 2). All these patients had suspicious lymph nodes for recurrence on the neck US. In 23 cases with negative F-FDG PET/CT findings, 10 patients were interpreted as false-negative, among which 13 lymph node metastases from 8 patients were detected in the neck and 2 lymph node metastases from the remaining 2 patients were found in the mediastinum. All the 10 patients with false-negative results received I treatment once again. 2 cases with 2 neck lymph node metastases and one case with 1 mediastinal lymph 131 131 131 node metastasis were diagnosed by I-WBS combined with I-SPECT/CT aer ft I treatment. The remaining 7 patients with 10 lesions who had negative I-WBS results were confirmed by surgical pathology. All these patients had suspicious lymph node recurrence on the neck US or contrast-enhanced CT of chest (Table 3). Of 13 true-negative patients, neck US finding was suspicious for recurrence in 7 patients with 12 lesions, but disease recurrence was not detected by surgical excision. The remaining 6 patients underwent I treatment once again and negative findings were shown on the I-WBS, and recurrent diseases were not be detected by US neck and chest contrast-enhanced CT in these 6 patients. In addition, bone metastases from PTC weren’t detected on 99m the Tc-bone scan, but TgAb levels were gradually rising in the follow-up. es Th e 6 patients were also classified as true-negative. Factors influencing positive F-FDG PET/CT results. Patient age, sex, subtypes of PTC, tumor size, extrathyroid extension, bilateral tumor, multifocal tumor, whether patient with neck lateral dissection at initial surgery, N stage, whether pathology with lymphocytic thyroiditis not significantly associated with positive F-FDG PET/CT results (P > 0.05). TgAb level at diagnosis and span for progressively increased TgAb level were statistically significant in predicting positive F-FDG PET/CT findings (P < 0.05). Compared with TgAb level <150 IU/mL at diagnosis and span for progressively increased TgAb level less than 3 years, univariate Scientific Repo R ts | 7: 2849 | DOI:10.1038/s41598-017-03001-7 3 www.nature.com/scientificreports/ Figure 2. A false-positive lesion on the left neck region was revealed by F-FDG PET/CT. A 62-year-old woman underwent total thyroidectomy with radical left neck dissection for PTC followed by radioiodine 131 131 therapy with 3.7 GBq of I. Three days later, post-therapy I WBS was performed and showed negative results. Six months aer a ft blation. The serum Tg level was 0.18 ng/mL and TgAb level was 46 IU/mL at TSH suppression status. TgAb level was stable for 4.2 yr aer ft I therapy. But subsequently, TgAb gradually increased at TSH suppression status. TgAb level elevated from 51 IU/mL to 137 IU/mL in the next follow-up of 2.2 years. F-FDG PET/CT demonstrated increased foci radiotracer uptake in the left submandibular region (a,b, crossing line), which was localized by CT image to the left submandibular lymph nodes with SUV of 2.6 max (c, crossing line). However, infectious lymph node was diagnosed on histopathology aer s ft urgery. regression analysis showed that OR value of TgAb level ≥ 150 IU/mL at diagnosis and span for progressively increased TgAb level longer than 3 years were as much as 4.18 [CI:1.52–11.54] and 3.60 [CI:1.24–10.41] times for progressively increased TgAb level (Table 4). Diagnostic accuracy of F-FDG PET/CT scans. In all these patients, the true-positive, false-positive and false-negative, true-negative cases of F-FDG PET/CT findings were 54, 5, 10, and 13, respectively. e s Th en- sitivity, specificity, positive predictive value, negative predictive value, and accuracy of F-FDG PET/CT in this patient group were determined as 84%, 72%, 92%, 57% and 82%, respectively (Table 5). When comparing different TgAb levels at diagnosis, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of F-FDG PET/CT for patients whose TgAb levels ≥ 150 IU/mL at diagnosis is higher than for those whose TgAb levels < 150 IU/mL at diagnosis. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy increased from 62% to 95%, from 67% to 78%, from 81% to 95%, from 43% to 78% and from 63% to 94% respectively (Table 5). When comparing dif- ferent span for progressively increased TgAb level, the sensitivity, specificity, positive predictive value, and accuracy of F-FDG PET/CT for span for progressively increased TgAb level longer than 3 years at diagnosis were superior to that less than 3 years at diagnosis, the sensitivity, specificity, positive predictive value, and accuracy of F-FDG PET/CT scan increased from 76% to 91%, from 71% to 75%, from 85% to 97%, from 74% to 90%. However, the negative predictive value of F-FDG PET/CT for patients whose span for progressively increased TgAb level ≥ 3 years at diagnosis was inferior to that <3 years at diagnosis. The negative predictive value decreases from 59% to 50% (Table 5). Discussion Our study demonstrated that F-FDG PET/CT was a useful method for detecting recurrent disease in PTC patients with negative Tg, negative I-WBS at first post ablation and progressively increased TgAb level. In the current study, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of F-FDG PET/CT for this patient group were confirmed as 84%, 72%, 92%, 57% and 82%, respectively. The diagnostic performance of F-FDG PET/CT scanning for detecting the recurrent thyroid cancer with negative 131 16–21 Tg, negative I-WBS and increased TgAb has been reported several retrospective studies (Table 6). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of F-FDG PET/CT examination for these patients ranged from 75% to 100%, from 50% to 100%, from 50% to 100%, from 50% to 100%, from 25% to 100% and from 72.7% to 88.4%. The difference within these several studied may reflect the heterogeneity of the number and patients included, definition of Tg negativity, selection criteria for TgAb level, follow-up time, specific F-FDG PET/CT technique used, or the reference standard against which the accuracy of F-FDG PET/CT scan were analyzed. Among them, five articles have a small number of cases (16, 18–21), so the results were very easy to produce deviation. The largest F-FDG PET/CT series to date was the retrospective study by Asa et al. and included 40 DTC patients, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy in this large study were 78.5%, 50%, 91.6%, 25% and 75% , all of which lower than those reported by ours. This die ff rence may reflect possibly definition of Tg negativity, selection criteria bias of TgAb and follow-up time. In our study, Negative serum Tg was defined as Tg < 0.2 ng/mL (TSH suppression) or Tg < 1 ng/mL (aer s ft timulation) at 6 months aer t ft he first I remnant ablation, while Asa et al. considered that the PTC patients had negative serum Tg level as Tg ≤ 1 ng/mL (TSH suppression) or Tg ≤ 2 ng/mL (after 131 21 stimulation) in the follow-up period aer t ft otal-near total thyroidectomy and I ablation . If DTC patients with coexistent clinical Hashimoto thyroiditis Graves’ disease, or focal autoimmune thyroiditis, all TgAb disappeared Scientific Repo R ts | 7: 2849 | DOI:10.1038/s41598-017-03001-7 4 www.nature.com/scientificreports/ Sites of Contrast- Progressive Serum TgAb level prior Serum TgAb level at recurrent enhanced increase in TgAb Patient No. Age/Sex Histology to elevation (IU/mL) diagnosis (IU/mL) diseasSe (No.) Neck US CT of Chest level (years) Confirmation methods 1 27/Male Classical 76 148 Left neck (1) Suspicious — 2.2 Histopathology 2 47/Female Classical 29 134 Left neck (1) Suspicious — 3.6 Histopathology 3 51/Female Classical 73 126 right neck (1) Suspicious — 3.0 I-WBS + SPECT/CT 4 57/Female Aggressive 98 142 right neck (2) Suspicious — 5.5 Histopathology 5 32/Male Classical 12 98 Meditational (1) — Suspicious 4.2 Histopathology 6 21/Female Classical 45 122 right neck (1) Suspicious — 4.4 I-WBS + SPECT/CT 7 36/Female Classical 89 132 right neck (2) Suspicious — 2.8 Histopathology 8 42/Female Classical 58 179 right neck (1) Suspicious — 3.3 Histopathology 9 69/Male Classical 324 419 Left neck (4) Suspicious — 4.6 Histopathology 10 41/Female Classical 171 635 Meditational (1) Suspicious Suspicious 5.6 I-WBS + SPECT/CT Table 3. Clinical and pathological characteristics for 10 patients with false-negative F-FDG PET/CT findings. Positive FDG PET/ Univariate analysis Factors CT (Yes/Total) OR (CI 95%) χ p Sex 0 1 Male 23/32 (72%) 1 Female 36/50 (72%) 1.00[0.37–2.67] Age(years) 0.17 0.69 ≥45 26/35 (74%) 1 <45 33/47 (70%) 1.22[0.46–3.27] Subtypes of PTC 0.09 0.77 Classical 52/71 (64%) 1 Others 7/11 (73%) 1.56[0.41–5.95] Tumor size(mm) 3.36 0.19 ≤20 12/21 (57%) 1 20–40 34/43 (79%) 0.83[0.91–8.81] >40 13/18 (72%) 1.95[0.51–7.49] Extrathyroid extension 0.15 0.70 Yes 13/19 (68%) 1 No 46//63 (73%) 1.25[0.41–3.81] Bilateral tumor 0.004 0.951 Yes 15/21 (71%) 1 No 44/61 (72%) 1.04[0.36–3.11] Multifocal tumor 1.13 0.29 Yes 16/25 (64%) 1 No 43/57 (75%) 1.73[0.63–4.77] Neck lateral dissection 0.74 0.39 Yes 35/51 (69%) 1 No 24/31 (77%) 1.57[0.56–4.39] N stage 2.43 0.12 N0-Nx 9/16 (56%) 1 N1 50/66 (76%) 2.43[0.78–7.58] Pathology with lymphocytic 0.83 0.36 thyroiditis No 51/69 (74%) 1 Yes 8/13 (62%) 0.57[0.16–1.95] TgAb level at diagnosis (IU/mL) 8.13 <0.001 <150 16/30 (53%) 1 ≥150 43/52 (83%) 4.18[1.52–11.54] Progressive increase in TgAb 5.9 0.02 level (years) <3 26/43 (61%) 1 ≥3 33/39 (85%) 3.60[1.24–10.41] Table 4. Risk factors for positive F-FDG PET/CT results in this specific cohort. Scientific Repo R ts | 7: 2849 | DOI:10.1038/s41598-017-03001-7 5 www.nature.com/scientificreports/ F-FDG PET-CT All patients TgAb level at diagnosis (IU/mL) Progressive increase in TgAb level (years) 82 <150 ≥150 <3 ≥3 True-positive 54 13 41 22 32 False-positive 5 3 2 4 1 False- negative 10 8 2 7 3 True-negative 13 6 7 10 3 Sensitivity 84% 62% 95% 76% 91% Specificity 72% 67% 78% 71% 75% Positive predictive 92% 81% 95% 85% 97% value Negative predictive 57% 43% 78% 59% 50% value Accuracy 82% 63% 92% 74% 90% Table 5. F-FDG PET-CT findings of the included patients. Author Publication year No. of patients Sensitivity Specificity Positive predictive value Negative predictive value Accuracy Chung et al. 2002 26 84.6% 92.3% — — 88.4% Viedma et al. 2011 22 100% 62.5% 50% 100% 72.7% Bogsrud et al. 2011 15 83.3% 100% 100% 71.4% 70.6% Ozkan et al. 2012 31 75% 76% 75% 86% 80% Ozkan et al. 2013 10 100% 50% 75% 100% 80% Asa et al. 2014 40 78.5% 50% 91.6% 25% 75% Table 6. Diagnostic efficacies of F-FDG PET/CT in patients with DTC and elevated serum TgAb in other studies. more slowly and the median disappearance time was 3 years for TgAb aer t ft otal thyroidectomy and radioiodine ablation . Therefore, increased TgAb level without upward trend in a short follow-up time might not be viewed as persistent or recurrent diseases of DTC. In our cases, increased TgAb level without upward trend has been excluded. Although Asa et al. selected the TgAb standard for persistently/progressive increased TgAb, whether the content of the article including increased TgAb level without upward trend was unclear . Otherwise, it was reported that the TgAb levels measured 6–12 months aer a ft blation therapy were significantly rising in the DTC patients with residual disease compared to those with no residual disease . Whether this situation for DTC patients ruled out was indeterminate for the study by Asa et al. because DTC patients in their groups have rela- tively short follow-up times (9–36 months). In our study, of 59 cases with positive F-FDG PET/CT finding, 54 (91.5%) patients were classified as true-positive confirmed pathologically by surgical resection and 5 patients were diagnosed for false-positive on 18 18 F-FDG PET/CT scans. False-positive F-FDG uptake in the neck was oen c ft aused by several sources including muscle, brown fat, salivary glands, vocal cords, tonsils, and other lymphoid tissues. Moreover, reactive hyper- plasia lesions, inflammatory lesions and benign tumors can also lead to FDG uptake . All false-positive uptakes were located in the neck, which was similar to what Ozkan et al. reported . Ozkan et al. considered that it was dif- ficult to distinguish recurrent lesions from false-positive lesions using SUV ≥ 2.5 t in the neck region because max 16 18 of overlapping SUVs between them . Therefore, the criterion for positive lesion was accepted as F-FDG uptake greater than that of the normal surrounding tissue or when the SUV was ≥ 2.5 in our study. max With respect to distant metastases from included PTC patients, only 4 cases with lung metastases were 18 131 detected by F-FDG PET/CT scan, all of which showed that PTC patients with negative Tg, negative I-WBS and progressively increased TgAb level weren’t prone to distant metastases. It was very possible because distant metastases of DTC produced more serum Tg which couldn’t be completely interfere by TgAb . All of them 131 131 received additional I therapy and showed negative post therapy I-WBS scan results. Of 23 cases with negative F-FDG PET/CT finding, 10 patients were interpreted as false-negative. Suspicious recurrent lymph node metastases were detected on the neck, which may suggest that negative F-FDG PET/ CT finding may represent a small or well-differentiated metastatic lesions . Subsequently, these patients under- went empirical I therapy using 150 mCi. Aer 3–5 d ft ays, 3 patients with metastatic lesions were detected and 131 131 131 confirmed by I-WBS combined with I-SPECT/CT. The remaining 7 patients showed negative I-WBS and recurrent lesions were confirmed pathologically by surgical resection. In the current study, there are also 13 true-negative patients with progressively increased TgAb level, while 7 out of these patients were surgically con- firmed as disease free, and the remaining 6 cases were confirmed by follow-up. With regard to true-negative and false-positive finding in these patients, it was not uncertain whether a few other reasons made serum TgAb rise continuously except for the recurrent diseases of PTC, for that a few other diseases could lead to the increased TgAb, such as type 1 diabetes, rheumatoid arthritis, pernicious anemia, Scientific Repo R ts | 7: 2849 | DOI:10.1038/s41598-017-03001-7 6 www.nature.com/scientificreports/ collagen vascular diseases, scleroderma, chronic urticarial, autoimmune hyperthyroidism and increasing age in 22, 27–30 healthy women has been reported . In our series, univariate analysis revealed that different TgAb level at diagnosis and span for progressively increased TgAb level was related to the positive F-FDG PET/CT finding. The results showed that the sensi- tivity, specificity of F-FDG PET/CT when TgAb level ≥ 150 IU/mL at diagnosis and span for progressively increased TgAb level ≥ 3 years were clearly higher than that when TgAb level < 150 IU/mL at diagnosis and span for progressively increased TgAb level 3 years, respectively. In previous studies, a varying prevalence of TgAb value for predicting persistent or recurrent of DTC after total thyroidectomy has been reported. Chung et al. considered a serum TgAb level below 100 U/mL as negative, and found elevated TgAb levels in 22.6% of 131 17 DTC patients after I ablation . Seo et al. reported that recurrence for DTC was more frequent in patients who showed a persistently elevated TgAb level over 140 U/mL . While other studied have defined TgAb level 32, 33 of 6–100 U/mL as positive . In our study, different TgAb levels were used as cutoff values to evaluate the 18 18 diagnostic performances of F-FDG PET/CT scan in the detection of recurrent PTC. F-FDG PET/CT results could be ae ff cted by lesion size, false-positive finding and degree of differentiation of PTC and so on, therefore, above research results for TgAb level may be not related to the positive F-FDG PET/CT finding. Our study also showed that longer span for progressively increased TgAb level (≥3 years) rather than shorter pan for progressively increased TgAb level (<3 years) indicated a higher sensitivity, specificity of F-FDG PET/CT scanning in detecting recurrent PTC, suggesting the recurrent diseases of these PTC patients developed more slowly and have a relatively good prognosis. However, several limitations of this study should be discussed. First, of 13 true negative patients, 6 patients weren’t confirmed having metastases by pathology. These cases were classified as true negative through follow-up. In the course of follow-up, these 6 patients showed negative findings on the post-therapy I-WBS, neck US and 99m contrast-enhanced chest CT, Tc-MDP bone scan, but some occult lesions may still not be found. Second, Of 131 131 10 false-negative patients, 3 patients were confirmed by I-WBS combined with I-SPCET/CT rather than the results of pathology, because I-SPECT/CT effectively excluded residual noncancerous thyroid tissue located outside the thyroid bed (substernal goiter or ectopic foci along the thyroglossal duct), physiologic uptake in 34, 35 non-thyroidal tissues, and contamination . The retrospective nature of the data in the present study may be another limitation. Conclusions Our study demonstrated that the F-FDG PET/CT scanning had a good diagnostic performance in the selected PTC patients with negative Tg, negative I-WBS at first postablation and progressively increased TgAb level. Span for progressively increasing TgAb level and TgAb level at diagnosis were closely associated with positive 18 18 F-FDG PET/CT findings. Therefore, F-FDG PET/CT scanning could be performed routinely for PTC patients with negative Tg, negative I-WBS at first postablation ablation and progressively increased TgAb level, espe- cially for those whose span for progressively increased TgAb level ≥3 years and/or progressively increased TgAb value up to 150 IU/mL. Patients and Methods Patients. This retrospective study was approved by our institutional review board. Informed consents have been waived for most patients except for two patients, whose SPECT/CT images were used in the current study. All methods were performed in accordance with the relevant guidelines and regulations. Files of consecutive 7843 patients treated with I between January 2005 and January 2014 were reviewed. Clinical follow-up data of 1257 patients with DTC who underwent F-FDG PET/CT scanning were evaluated retrospectively. The inclu - sion criteria were as follows: (1) patients with histologically proven PTC. (2) patients with PTC treated with total 131 131 or near-total thyroidectomy and postoperative I ablation. (3) postablation negative I-WBS defined by the 131 131 absence of non-physiological I uptake outside the thyroid bed or abnormal I uptake confirmed for phys- iological uptake or contamination by I single photon emission computed tomography/computed tomogra- phy ( I-SPECT/CT) outside the thyroid bed. (4) negative Tg defined as Tg < 0.2 ng/mL (TSH suppression) or Tg < 1 ng/mL (aer s ft timulation) 6 months aer t ft he first remnant ablation. (5) progressively increased TgAb level including TgAb which persistently rose or TgAb which kept stable/decreased for some time but subsequently rose aer r ft emnant ablation. (6) F-FDG PET/CT was performed more than 1 year aer t ft he first remnant ablation. The exclusion criteria were as follows: (1) Tg ≥ 0.2 ng/mL (TSH suppression) or ≥1 ng/mL (aer s ft timulation) in the follow-up. (2) persistently high TgAb but had no rising trend (3) a temporarily increased TgAb at 6–12 months aer a ft blation therapy. I empiric treatment. After surgery, each patient received an ablative dose of I and was put on a low iodine diet for 3–4 weeks before I therapy (TSH reached 30 mIU/L). Subsequently, the patients were subjected to oral administration of I aer t ft he following conventional measurements, including FT3, FT4, TSH, Tg, TgAb, neck ultrasonography (US), and CT scans. The dose of oral standard administration of 3.7GBq (100 mCi) of I 131 131 was used to ablate the thyroid remnants. I-WBS and/or I-SPECT/CT fusion imaging was performed 3–5 131 131 days after I oral administration. I-WBS was performed in both anterior and posterior projections using a dual-head SPECT with High-energy collimators and a 364-keV photo peak. I-SPECT/CT images were acquired immediately aer p ft lanar imaging for PTC patients who presented suspicious finding on I-WBS. F-FDG PET/CT Scan. Patients were instructed to fast for at least 6 hours before the injection of F-FDG. Blood glucose level was measured before injection and F-FDG was administered at glucose levels < 150 mg/dL. 18 18 F-FDG PET/CT scanning was performed aer a ft n i.v. injection of 3–4MBq/Kg F-FDG, followed by a one hour uptake phase. No intravenous contrast agent was administered. F-FDG PET/CT images were performed using Scientific Repo R ts | 7: 2849 | DOI:10.1038/s41598-017-03001-7 7 www.nature.com/scientificreports/ a dedicated GE Discovery PET/CT scanner including 64 slice CT scanners with a dedicated PET (BGO plus crystal). F-FDG images were acquired for 4 minutes at each bed position from the skull base to the superior mediastinum with patients’ arms along the chest and from the neck to the mid-thigh with patients’ arms above the head. No specific breathing instructions were given. The CT scan was obtained from the orbitomeatal line and progressed to the mid-thigh with the use of a standardized protocol involving 140 kV, 110 mA, 0.8 seconds/ rotation, pitch of 1.75:1, length of scan: 1.0 to 1.6 m, 0.625 spatial resolution, and slice thickness of 3.75 mm. Attenuation correction of PET images was performed using attenuation data from CT and images reconstruction was done using a standard reconstruction algorithm with ordered subset expectation maximization (OSEM). Image fusion was performed using coordinate based fusion software and subsequently reviewed at a workstation (Xeleris) that provided multi-planar reformatted images and displayed PET, CT, and PET/CT fusion images. 131 131 Neck US. US were performed on the day of I administration and every 3–6 months after I ablation on a high-resolution ultrasound system equipped with a high-energy 14 MHz linear probe, allowing to work in fundamental B-mode and in power Doppler mode. The thyroid bed, central and lateral neck compartments were included for neck US examination. Suspicion of lymph node metastases of PTC was based on the following crite- ria: hyperechoic punctuations, cystic appearance, hypervascularization, round shape node without hyperechoic hilum and a short axis greater than 7 mm . Tg and TgAb measurement. Serum Tg and TgAb levels were measured by electrochemiluminescence immunoassay (ECLIA) methods on the Cobas analyzer (Roche Diagnostics GmbH). The analytical sensitivity was <0.1 μg/L with reference range 1.4–78 μg/L. The analytical sensitivity of TgAb is < 10 IU/mL with a reference range of 10–4000 IU/mL. Follow-up. Serum Tg was performed at TSH suppression or at after TSH suppression 6 months after first remnant ablation. Subsequently, FT3, FT4, TSH, Tg, TgAb at TSH suppression and neck US were measured and performed every 3–6 months in the follow-up of the period, respectively. Progressively increased TgAb lev- els were measured no less than three times. All F-FDG PET/CT scan were performed at TSH suppression. Contrast-enhanced CT was performed for a few patients aer ft F-FDG PET/CT scan. e Th last neck US at diag- nosis, contrast-enhanced CT and F-FDG PET/CT scan were performed at a maximum interval of less than 30 days. The follow-up period was 2–9 yr with a median follow-up of 5.1 yr. Image analysis. F-FDG PET/CT images were reviewed and interpreted by 2 experienced nuclear medicine physicians (Z-L Qiu and W-J Wei). All F-FDG PET/CT were considered as negative or positive. The criterion for positive lesion was accepted as F-FDG uptake greater than that of the normal surrounding tissue or when the SUV was ≥ 2.5. The anatomical confirmation with a lesion was detected with matched CT scan. The criterion max for negative lesion was that there was no F-FDG uptake and no corresponding identifiable lesion on matched CT scans. 18 18 Evaluation of F-FDG PET/CT findings. F-FDG PET/CT results were correlated with surgical and his- 131 131 131 topathological findings, I-WBS combined with I-SPECT/CT aer ft I treatment once again, other imaging 99m modalities including neck US, chest CT, Tc-MDP bone scan and follow-up. A true-positive finding was con- firmed when a lesion was detected as positive by F-FDG PET/CT and the patient was found to have recurrent disease by surgical pathology. A false-positive finding was confirmed when a lesion was excluded by surgical pathology in the patients with positive lesions on F-FDG PET/CT. A false-negative finding was confirmed when a lesion couldn’t be detected on F-FDG PET/CT, but it could be found to be recurrent disease by surgical pathol- 131 131 131 ogy or by I-WBS combined with I-SPECT/CT aer ft I treatment once again. A true-negative finding were confirmed when a lesion was detected as negative by F-FDG PET/CT and the patient was found to have benign disease by surgical pathology or it could be wasn’t found to have recurrent disease on other imaging modalities 131 99m including neck US, chest CT and I-WBS and Tc-MDP bone scan in the follow-up period. Statistical analysis. Statistical analyses were performed with the SPSS v.17.0 statistical package (SPSS, Inc., Chicago, IL, USA). Descriptive statistics were represented as frequency and percentage. Categorical variables were compared by Pearson Chi-square. The categorical variables for positive F-FDG PET/CT were analyzed by univariate logistic regression. The sensitivity, specificity, positive and negative predictive values, and accuracy of F-FDG PET/CT for the detection of recurrent thyroid cancer were calculated. Together with their 95% confi- dence intervals (CIs), the odds ratios (OR) for F-FDG PET/CT findings were calculated by univariate logistic regression. A P value of <0.05 was considered to be statistically significant and all reported P values are two-side. References 1. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2015. CA Cancer J Clin 65, 5–29, doi:10.3322/caac.21254 (2015). 2. Brierley, J., Tsang, R., Panzarella, T. & Bana, N. Prognostic factors and the effect of treatment with radioactive iodine and external beam radiation on patients with differentiated thyroid cancer seen at a single institution over 40 years. Clin Endocrinol (Oxf ) 63, 418–427, doi:10.1111/cen.2005.63.issue-4 (2005). 3. Lin, J. D., Chao, T. C., Hsueh, C. & Kuo, S. F. High recurrent rate of multicentric papillary thyroid carcinoma. Ann Surg Oncol 16, 2609–2616, doi:10.1245/s10434-009-0565-7 (2009). 4. Filesi, M., Signore, A., Ventroni, G., Melacrinis, F. F. & Ronga, G. Role of initial iodine-131 whole-body scan and serum thyroglobulin in differentiated thyroid carcinoma metastases. J Nucl Med 39, 1542–1546 (1998). 5. Francis, Z. & Schlumberger, M. Serum thyroglobulin determination in thyroid cancer patients. Best Pract Res Clin Endocrinol Metab 22, 1039–1046, doi:10.1016/j.beem.2008.09.015 (2008). 6. Haugen, B. R. et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Die ff rentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Die ff rentiated y Th roid Cancer. Thyroid 26, 1–133, doi:10.1089/thy.2015.0020 (2016). Scientific Repo R ts | 7: 2849 | DOI:10.1038/s41598-017-03001-7 8 www.nature.com/scientificreports/ 7. Rosario, P. W., Mineiro Filho, A. F., Prates, B. S., Silva, L. C. & Calsolari, M. R. Postoperative stimulated thyroglobulin of less than 1 ng/mL as a criterion to spare low-risk patients with papillary thyroid cancer from radioactive iodine ablation. Thyroid 22, 1140–1143, doi:10.1089/thy.2012.0190 (2012). 8. Pacini, F. et al. Thyroid autoantibodies in thyroid cancer: incidence and relationship with tumour outcome. Acta Endocrinol (Copenh) 119, 373–380, doi:10.1530/acta.0.1190373 (1988). 9. Spencer, C. A. Clinical review: Clinical utility of thyroglobulin antibody (TgAb) measurements for patients with differentiated thyroid cancers (DTC). J Clin Endocrinol Metab 96, 3615–3627, doi:10.1210/jc.2011-1740 (2011). 10. Souza, S. L., Montalli Da Assumpcao, L. V. & Ward, L. S. Impact of previous thyroid autoimmune diseases on prognosis of patients with well-differentiated thyroid cancer. Thyroid 13, 491–495, doi:10.1089/105072503322021160 (2003). 11. Smooke-Praw, S. et al. Thyroglobulin antibody levels do not predict disease status in papillary thyroid cancer. Clin Endocrinol (Oxf ) 81, 271–275, doi:10.1111/cen.2014.81.issue-2 (2014). 12. Hsieh, C. J. & Wang, P. W. Sequential changes of serum antithyroglobulin antibody levels are a good predictor of disease activity in thyroglobulin-negative patients with papillary thyroid carcinoma. Thyroid 24, 488–493, doi:10.1089/thy.2012.0611 (2014). 13. Kim, W. G. et al. Change of serum antithyroglobulin antibody levels is useful for prediction of clinical recurrence in thyroglobulin- negative patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 93, 4683–4689, doi:10.1210/jc.2008-0962 (2008). 14. Palmedo, H. et al. Integrated PET/CT in differentiated thyroid cancer: diagnostic accuracy and impact on patient management. J Nucl Med 47, 616–624 (2006). 15. Liu, Y. The role of F-FDG PET/CT in the follow-up of well-differentiated thyroid cancer with negative thyroglobulin but positive and/or elevated antithyroglobulin antibody. Nucl Med Commun 37, 577–582, doi:10.1097/MNM.0000000000000480 (2016). 16. Ozkan, E., Aras, G. & Kucuk, N. O. Correlation of F-FDG PET/CT findings with histopathological results in differentiated thyroid cancer patients who have increased thyroglobulin or antithyroglobulin antibody levels and negative I whole-body scan results. Clin Nucl Med 38, 326–331, doi:10.1097/RLU.0b013e318286827b (2013). 17. Chung, J. K. et al. Clinical significance of elevated level of serum antithyroglobulin antibody in patients with differentiated thyroid cancer aer t ft hyroid ablation. Clin Endocrinol (Oxf ) 57, 215–221, doi:10.1046/j.1365-2265.2002.01592.x (2002). 18. Sanz Viedma, S. et al. Use of F FDG-PET in patients with suspicion of recurrent differentiated thyroid cancer by elevated antithyroglobulin antibodies levels and negative I scan. Rev Esp Med Nucl 30, 77–82, doi:10.1016/j.remn.2010.10.012 (2011). 19. Bogsrud, T. V. et al. Prognostic value of F-fluorodeoxyglucose-positron emission tomography in patients with differentiated thyroid carcinoma and circulating antithyroglobulin autoantibodies. Nucl Med Commun 32, 245–251, doi:10.1097/ MNM.0b013e328343a742 (2011). 20. Ozkan, E., Soydal, C., Araz, M., Aras, G. & Ibis, E. The additive clinical value of F-FDG PET/CT in defining the recurrence of disease in patients with differentiated thyroid cancer who have isolated increased antithyroglobulin antibody levels. Clin Nucl Med 37, 755–758, doi:10.1097/RLU.0b013e31825ae77b (2012). 21. Asa, S. et al. The role of FDG PET/CT in differentiated thyroid cancer patients with negative iodine-131 whole-body scan and elevated anti-Tg level. Ann Nucl Med 28, 970–979, doi:10.1007/s12149-014-0897-7 (2014). 22. Chiovato, L. et al. Disappearance of humoral thyroid autoimmunity aer co ft mplete removal of thyroid antigens. Ann Intern Med 139, 346–351 (2003). 23. Nam, H. Y. et al. Monitoring differentiated thyroid cancer patients with negative serum thyroglobulin. Diagnostic implication of TSH-stimulated antithyroglobulin antibody. Nuklearmedizin 53, 32–38, doi:10.3413/Nukmed-0604-13-06 (2014). 24. Nakamoto, Y. et al. Normal FDG distribution patterns in the head and neck: PET/CT evaluation. Radiology 234, 879–885, doi:10.1148/radiol.2343030301 (2005). 25. Qiu, Z. L., Song, H. J., Xu, Y. H. & Luo, Q. Y. Efficacy and survival analysis of I therapy for bone metastases from differentiated thyroid cancer. J Clin Endocrinol Metab 96, 3078–3086, doi:10.1210/jc.2011-0093 (2011). 26. Na, S. J. et al. Diagnostic accuracy of F-fluorodeoxyglucose positron emission tomography/computed tomography in differentiated thyroid cancer patients with elevated thyroglobulin and negative I whole body scan: evaluation by thyroglobulin level. Ann Nucl Med 26, 26–34, doi:10.1007/s12149-011-0536-5 (2012). 27. Oh, K. Y., Kim, Y. H., Yang, E. M. & Kim, C. J. Frequency of Diabetes and y Th roid Autoantibodies in Patients with Type 1 Diabetes and Their Siblings. Chonnam Med J 52, 136–140, doi:10.4068/cmj.2016.52.2.136 (2016). 28. Brcic, L. et al. Association of established thyroid peroxidase autoantibody (TPOAb) genetic variants with Hashimoto’s thyroiditis. Autoimmunity 1–6 (2016). 29. Gangemi, S., Saitta, S., Lombardo, G., Pata, M. & B fi envenga, S. Serum thyroid autoantibodies in patients with idiopathic either acute or chronic urticaria. J Endocrinol Invest 32, 107–110, doi:10.1007/BF03345696 (2009). 30. Ottesen, M., Feldt-Rasmussen, U., Andersen, J., Hippe, E. & Schouboe, A. Thyroid function and autoimmunity in pernicious anemia before and during cyanocobalamin treatment. J Endocrinol Invest 18, 91–97, doi:10.1007/BF03349707 (1995). 31. Seo, J. H., Lee, S. W., Ahn, B. C. & Lee, J. Recurrence detection in differentiated thyroid cancer patients with elevated serum level of antithyroglobulin antibody: special emphasis on using F-FDG PET/CT. Clin Endocrinol (Oxf ) 72, 558–563, doi:10.1111/j.1365-2265.2009.03693.x (2010). 32. Gorges, R. et al. Development and clinical impact of thyroglobulin antibodies in patients with differentiated thyroid carcinoma during the first 3 years aer t ft hyroidectomy. Eur J Endocrinol 153, 49–55, doi:10.1530/eje.1.01940 (2005). 33. Aras, G., Gultekin, S. S. & Kucuk, N. O. The additive clinical value of combined thyroglobulin and antithyroglobulin antibody measurements to define persistent and recurrent disease in patients with differentiated thyroid cancer. Nucl Med Commun 29, 880–884, doi:10.1097/MNM.0b013e328308e079 (2008). 34. Schmidt, D., Szikszai, A., Linke, R., Bautz, W. & Kuwert, T. Impact of I SPECT/spiral CT on nodal staging of differentiated thyroid carcinoma at the first radioablation. J Nucl Med 50, 18–23, doi:10.2967/jnumed.108.052746 (2009). 35. Blum, M., Tiu, S., Chu, M., Goel, S. & Friedman, K. I-131 SPECT/CT elucidates cryptic findings on planar whole-body scans and can reduce needless therapy with I-131 in post-thyroidectomy thyroid cancer patients. Thyroid 21, 1235–1247, doi:10.1089/ thy.2011.0010 (2011). 36. Nascimento, C. et al. Persistent disease and recurrence in differentiated thyroid cancer patients with undetectable postoperative stimulated thyroglobulin level. Endocr Relat Cancer 18, R29–40, doi:10.1677/ERC-10-0292 (2011). Author Contributions Z.-L. Qiu designed the study. Z.-L. Qiu and W.-J. Wei analyzed and interpreted the data, wrote the majority of the manuscript. C.-T. Shen, H.-J. Song, X.-Y. Zhang prepared the figures and tables. Z.-K. Sun indexed all the relevant references while Q.-Y. Luo supervised and edited the paper. All authors read and approved the final manuscript. Additional Information Competing Interests: The authors declare that they have no competing interests. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Scientific Repo R ts | 7: 2849 | DOI:10.1038/s41598-017-03001-7 9 www.nature.com/scientificreports/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Cre- ative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not per- mitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2017 Scientific Repo R ts | 7: 2849 | DOI:10.1038/s41598-017-03001-7 10
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