Tóm tắt Luận văn Research on18f-Fdg pet / ct images in postsurgical differentiated thyroid cancer patients with high serum thyroglobulin and negative 131i whole body scan

ardiac and neuro diseases. One decade later, the researchers also noted that PET was a valuable diagnostic tool in oncology. Not likeother structure and anatomy based diagnostic methods such as computed tomography (CT) or magnetic resonance imaging (MRI), PET records qualitative and quantitative images of physiopathological and metabolic process of diseases via labelled pharmaceutical isotopes. The combination of PET and CT in one system PET/CT allowed optimal exploitationof the advantages of both PET (metabolic informations of tissues) and CT (structural changes and localization of les ions). Currently, the most common pharmaceutical isotope used in PET scan was 18F-FDG (18F-2-fluoro-2-deoxy-D-glucose), an analogue of glucose(replacement of the 2nd hydrogen atom in the glucose moleculewith fluor-18(18F). 18F-FDG is transfered into cells via glucose transpoters in membrane.18F-FDG is phosphorylated to become 18F-FDG-6-phosphate and is accumulated inside cells because it cannot be metabolised or deposited in the form of glycogen like glucose. 18F-FDG uptake in malignant cells is mainly due to the increase of glucose transporter (especially GluT-1) in cell membrane and hexokinase such as HK-II... Due to the decreasing of natri/iodine symmporter (NIS) and increase of glucose transpoter (GLUT) in cell membrane, 18F-FDG PET/CT plays an important role in diagnosis of recurrence, 4 metastasis and change of treatment strategy in postsurgica l DTC with high serum Tg and negative 131I WBS. 1.3. Studies about diagnostic value of 18F-FDG PET/CT in postsurgical DTC with high Tg negative131I WBS 1.3.1. Foreign studies The main application of 18F-FDG PET/CT in postsurgica l DTC is to localize recurrent and metastatic lesions in patients with high serum Tg (Tg > 10 ng/ml) and negative 131I WBS. Numerous foreign studies have shown that the average sensitivity and specificity of 18FDG PET/CT in diagnosis of recurrence and metastasis in postsurgical DTC with this condition were 83% (50 – 100%) and 84% (42 – 100%), respectively. Several foreign studies also demonstrated that 18F-FDG PET/CT had changed the treatment plan in 44 – 78.4% of DTC patients with high serum Tg and negative 131I WBS. 1.3.2. Studies in Vietnam There were very few researches about the diagnostic value of 18F-FDG PET/CT in DTC with high serum Tg and negative 131I WBSin Vietnam. A study from Le Ngoc Ha et al (2016) showned that the sensitivity, accuracy and negative predictive value of PET/CT were 88%; 87% and 76%, respectively.The best SUVmax threshold for diagnosis was 4,5 with sensitivity 92.3% and specificity 100%. PET/CT also changed treatment strategy in 47,8% of patients. However, most of those studies had limited number of patients and did not fully evaluate the imaging characteristics as well as values of 18F-FDG PET/CT in postsurrgical DTC with high serum Tg and negative 131I WBS. 5 Chapter 2 SUBJECTS AND METHODS 2.1. SUBJECTS 109 DTC patients whom were followed up and treated in Department of Nuclear Medicine, 108 Military Central Hospital from 5/2010 to 12/2018 2.1.1. Selection criteria - Postsurgical and post RAI DTC patients (papillary, follicular, follicular variant of papillaryand Hurthle cell thyroid carcinomas). - Serum Tg > 10 ng/ml after TSH stimulation(TSH ≥ 30 µUI/ml) and negative131I WBS. - A-Tg < 115 UI/ml. - Patients who agree to participate in the study. 2.1.2. Exclusion criteria - Patients with second primary tumor apart from thyroid cancer. - Patients cannot cooperate to undergo PET/CT scan. -18F-FDG PET/CT images cannot be analysed. 2.1.3. Research site: Department of Nuclear Medicine, 108 Military Central Hospital. 2.2. METHODS 2.2.1. Study design:a cross-sectional descriptive, prospective study. 2.2.2. Radiopharmaceuticals, research tools and equipments  Radiopharmaceuticals -Liquid of131I (Egis Pharmaceutical – Hungary)or 131I capsule (Samyoung, South Korea and Pharmatopes, Australia). - 18F-FDG produced atNational Cyclotron Center, 108 Military Central Hospita l. 6  Research tools and equipments - Roche Diagnostics Elecsys 2010 (Switzerland). - GE gamma camera Milenium and Infinia (USA). - Philips EPIQ 5 ultrasound (Holland). - GE PET/CT Discovery LightSpeed (USA). 2.2.3. Research protocol - Patients were thoroughly examined: hisptory, physical check up, medical record review, purpose of the study and research protocol, 18F-FDG PET/CT scan protocol, treatment and follow up schedule. - Diagnosis of DTC was based on histopathology findings. - Postoperative and post - RAI therapy restaging, before18F-FDG PET/CT scan according to AJCC 7 (2010). - Patients were instructed to withdraw from thyroid hormon (4 weeks for T4 or 2 weeks for T3), undergo iodine restricted diet for 2 weeks before diagnostic WBS and RAI therapy. - Serum Tg, A-Tg, TSH test(TSH level must be greater than 30 µUI/ml). - Neck ultrasound was performed by several physicians following a standard protocol before PET/CT scan to evaluate neck lymphnode and thyroid bed lesions. - Patients underwent diagnostic WBSafter taking 5 mCi 131I orally 48 hours.Post-therapy WBS scan was performed 5 – 7 days after RAI therapy. - All patients underwent whole body 18F-FDG PET/CT scan. Head and neck dedicated PET/CT scan was performed in 84 patients during TSH stimulation (immediately when negative WBS was determined) or when TSH was not stimulated (2 – 3 months post negative WBS). - Number of cervical lesions (cervical lymphnodes, thyroid bed lesions) 7 detected by neck ultrasound, whole body PET/CT, and head and neck dedicated PET/CT were compared. - Diagnostic values of PET and PET/CT, whole body PET/CT and head and neck dedicated PET/CT were compared. - Most suitable SUV threshold for diagnosis of recurrent/metastatic thyroid cancer was determined. - Patient management protocol post PET/CT scan was as follows: + Patients were discussed at thyroid tumor board meeting to decide the suitable treatment after finding lesions in PET/CT: (1) surgery, radiation therapy for localized lesions;(2)chemotherapy and targeted therapy for progressive and multiple lesions, (3) empiric RAI therapy, TSH suppression and follow-up for small and slow-growing lesions. + If PET/CT results were negative, patients could be considered to undergo empiric RAI therapy or TSH suppression and follow-up. - Routine follow-up protocol after PET/CT scan was as follows: + Patients were scheduled for checkup 6 months post PET/CT scan: physical examination, serum Tg and A-Tg testing, neck ultrasound, FNA, CT scanas required. + If no recurrence/metastasis of thyroid cancer, patients were appointed for checkup every 6 months. + If recurrence/metastasis of thyroid cancer were detected, patients would undergo consultation at thyroid tumor board meeting to decide the suitable treatment. 2.2.4. Technical procedures: - Serum Tg was tested in Elecsys 2010 (Roche) at Department of Biochemistry, 108 Military Central Hospital. - Neck ultrasound was performed in Phillips EPIQ by several physicians following a standard protocol. 8 - 131I WBS was performed in GE Milenium and Infinia gamma camerafollowing the Society of Nuclear Medicine Guidelines (USA). - Whole body PET/CT scan was performed in GE PET/CT DiscoveryLightSpeed following the Society of Nuclear Medicine Guidelines (USA). - 84patients underwenthead and neck dedicated PET/CT scanfollowing the Duke University Hospital protocol after whole body PET/CT. 2.2.4.Criteria used for evaluation in the study - Patient clinical characteristics: + Age: 2 age groups< 45 and≥ 45. + Gender: male and female. + Histopathology: papillary, follipapillary and follicular carcinomas. - High serum Tg level: > 10 ng/ml with TSH stimulation. - Serum Tg level classification: mean, median, and quartile. - 131I WBS interpretation: + Negative: no abnormal focal 131I uptake. + Positive:when abnormal focal uptakes at thyroid bed, cervical lymph node, lung were notified, apart from physical normal uptake. - TNM restagingaccording to AJCC 7 postsurgical and before PET/CT scan. - Neck untrasound interpretation: + Recurrence at thyroid bed: hypoechoic nodule,size > 6 mm with marginal spiculation, peripheral hypervascularity. + Suspected cervical lymphnodes with at least one feature: round shape, abscene of an echogenic hilum, microcalcifications, hyperchogenicity, cystic change, peripheral flow. - Follow up after 18F-FDG PET/CT scan:number of patients 9 identified with recurrence, metastasis. - Evaluation of lesions in low dose whole body CT and head and neck dedicated CT of 18F-FDG PET/CT: + Recurrence at thyroid bed: suspected when short axis ≥ 1 cm, marginal irregularity, calcification. + Suspected metastatic cervical and mediastinal lymphnodes with at least one feature:short axial diameter≥ 1 cm, round shape, irregular margin, extracapsular spread, central necrosis, three or more contiguous lymphnodes in drainage chain of the tumor. + Suspected metastatic lesions in other sites: soft tissue attenuation, well circumscribed, rounded les ions, often in the periphery of the lung;lytic, sclerotic or mixed bone lesions. - 18F-FDG PET and PET/CT results were interpreted by two nuclear medicine physicians according to Shammas S (2007): + Positive: when abnormal focal FDG uptakes are identified. + Abnormal FDG uptakes which correspondedto abnormal lesions in CT are considered as recurrence or metastasis. + FDG uptakes which not related with corresponding structures in CT of PET/CT are considered positive. + Lesions in CT which not related to abnormal FDG uptakes are considered positive if they have these characteristics: contrast enhancing, abscene of lymph node fatty hilum, lymph node with necrosis, lung nodule. - 18F-FDG PET/CT results were compared with recurrent, metastatic status identified during follow-up post PET/CT scan: postsurgical histopathology results, neck ultrasound, CT, serum Tg. They are gold standard to define the diagnostic values of PET/CT. - Quantity, location and SUVmax of les ions found in 18F-FDG 10 PET/CT were evaluated. - Numbers and rates of recurrence, metastasis in cervical lymph node, thyroid bed and distant metastasis found in 18F-FDG PET/CTwere also evaluated. - Calculate diagnostic values of PET, whole body PET/CT and head and neck đeicated PET/CT: sensitivity, specificity, accuracy, predictive positive value, predictive negative value, false positve and negative rates. Diagram 2.1. Study design 2.3. Data analysis 11 Data were collected and analysed by SPSS software version18.0 for Windows. Chapter 3 RESEARCH RESULTS 3.1. Patient and 18F-FDG PET/CTimaging characteristics 3.1.1.Patient characteristics - 109 patients recruited including 81 females and 28 males, femal/male ratio≈3/1, mean age 45.7 ± 14.9. - Histopathology type: mainly papillary thyroid carcinoma 93,6%,follicular variant of papillary- thyroid carcinoma 6.4%. - TNM stage: stage I 56,9%, stage II and III only 1.8% and 0.9%; stage IV 37.6%; not identified 2.8%. - Average number of RAI and 131I total cumulative dose before PET/CT scan were 3.13 treaments and 418.8 mCi, respectively. 3.1.2. Lab test characterisitcs Table 3.9. Serum Tg, A-Tg, TSH levels before PET/CT scan Level Minimum Maximum Median Mean ± SD Tg (ng/ml) 20.5 1000 217 297.9 ± 250.0 A-Tg (UI/ml) 10 61.5 23.6 25.7 ± 11.6 TSH (µUI/ml) 31.1 101 100 86 ± 20.1 Remarks: Serum Tg levelshad a wild range with the median of 217 ng/ml and meanvalueof 297,9 ng/ml. 12 Table 3.11. Neck ultrasound results before PET/CT scan Characteristics Number (n) Percentage (%) Results Positive 68 62.4 Negative 41 37.6 Lesions’ site Thyroid bed 4 3.3 Cervical LN level I 0 0 Cervical LN level II 30 25 Cervical LN level III 22 18.3 Cervical LN level IV 49 40.8 Cervical LN level V 2 1.7 Cervical LN level VI 13 10.8 Sum 120 100 Remarks: - Positive neck ultrasound was in 62.4% of patients. - 120 lesions were noted in nek ultrasound: mostly was lymphnodes in level IV (40.8%), then lymph nodes in levelII l (25%), level III (18.3%), level VI (10.9%) and the least was lesions in thyroid bed (3.3%) andlevel V lymphnodes (1.7%). 3.1.3. 18F-FDG PET/CT imaging characteristics Table 3.12. Number of lesions found in PET và PET/CT Modality Number of les ions PET PET/CT p Total 272 294 0.007 Mean (Range) 3.36 ± 2.39 (1 – 13) 3.46 ± 2.41 (1 – 13) 13 Remarks: Mean number of lesions found in PET/CT was 3.46 lesions significantly higher than that found in PET (3.36 lesions). Table 3.13. Compare the number of lesions found in PET and PET/CT according to lesion site Number of les ions Lesion site PET PET/CT PET/CT finfing more than PET n % Cervical lymph node 159 173 14 8.8 Mediastinal lymph node 45 46 1 2.2 Thyroid bed 35 35 0 0 Lung 20 27 7 35 Bone 5 5 0 0 Other sites 8 8 0 0 Total of lesions 272 294 22 8.1 Remarks: - Cervical lymph node was most the lesion found in PET và PET/CT, then lesions in mediastinal lymph node, thyroid bed, and lung. - PET/CT found more than PET 22 lesions (8.1%) including: 14 cervical node (8.8%), 1 mediastinal lymph node (2.2%), and 7 lung lesions (25%). Chart 3.7. Rates of recurrence, metastasis found in PET/CT 0 20 40 60 80 Distant metastasis Cervical node metastasis Thyroid bed 34 31.2% 71 65.1% 29 26.6% 14 Remarks:Cervical node metastasis was most found in PET/CT in 71 patients (65.1%), then distant metastasisin 34 patients (31.2%) and the lowest rate was lesion in thyroid bedin 29 patients (26.6%). Table 3.19. Compare the number of lesions found in neck ultrasound and whole body PET and withhead and neck dedicated PET/CT Number of les ions Lesion site Neck ultraso -und Whole body PET Head and neck dedicated PET/CT Head and neck dedicated PET/CT finding more than whole body PET n % Cervical lymph node 91 126 137 11 8.7 Thyroid bed 3 31 31 0 0 Total number 94 157 168 11 7.0 Remarks: - Head and neck dedicated PET/CT found 74 lesions more than neck ultrasound including 46 cervical nodes and 28 les ions in thyroid bed. - Head and neck dedicatedPET/CT found 11 les ions (8,7%) more than whole body PET. Table 3.20. Lesion characteristics in PET/CT Characteristics Value n % Mean lesion size (mm) (Range) 14,0 ± 8,4 (3 – 58) Classification of les ion size < 5 mm 3 1.0 5 - 9 mm 48 16.4 10 - 19 mm 212 72.1 ≥ 20 mm 31 10.5 Total 294 100 Remarks: - Mean lesion size in PET/CT was 14 mm. 15 - Lesion size 10 – 19 mm had the highest rate of 55.9%, then lesion size 5 – 9 mm (16.4%), lesion size≥ 20 mm (10.5%) and the lowest rate was lesion size < 5 mm (1%). Table 3.21.Characteristics of lesion’s SUVmax in PET/CT Characteristics Value n % SUVmax (g/ml) (Range) 9.3 ± 7.3 (2.5 – 64) SUVmax subgroup < 5 g/ml 80 2722 5 – 9.9 g/ml 120 40.8 10 – 19.9 g/ml 73 24.8 ≥ 20 g/ml 21 7.2 Total 294 100 Remarks: - Mean SUVmax of lesions in PET/CT was 9.3 g/ml. - Lesions with SUVmax 5 – 9,9 g/ml had the highest rate 40.8%, and the lowest rate was ones with SUVmax > 20 g/ml (7.2%). 3.2. Diagnostic values of 18F-FDG PET/CT in differentiated thyroid cancer with high Tg and negative 131I whole body scan 0% 20% 40% 60% 80% 100% PET PET/CT 28 25.7% 24 22% 81 74.3% 85 78% Positvie Negative 16 Chart 3.11.Results of 18F-FDGPET and PET/CT Remarks:PET/CT results were positive in85 patients (78%) higher than that of PET (positive in 81 BN; 74.3%). Table 3.29. Follow-up time and results post PET/CT scan (n = 109) Follow-up time and results n % Follow-up time (months) Mean± SD 35.9 ± 20.6 Range 12 - 89 Follow-up results Recurrence, metastatis Yes Postsurgical histopathology 57 52.3 Clinical, lab and test follow-up 28 25.7 No 24 22.0 Remarks: - Patients’s mean follow-up time post PET/CT scan was 35.9 months. - Recurrence/metastasis was identified in 85 patients (78%), 24 patients (22%) had no recurrence, metastasis during follow-up time. Table 3.30. ComparePET and PET/CT results with follow-up results post PET/CT scan(n = 109) Recurrence/ metastasis Modality Yes No p n % n % PET Positive 75 92.6 6 7.4 <0,001 Negative 10 35.7 18 64.3 PET/CT Positive 79 92.9 6 7.1 <0,001 Negative 6 25 18 75 Remarks: - PET results showed that 6/81patients (7.4%) were false positive and 10/28 patients (35.7%) were false negative. 17 - PET/CT results showed that 6/85 patients (7.1%) were false positive and 6/24 patients (25%) were false negative. Table 3.31.Diagnostic values of PET and PET/CT in detection of recurrent/metastatic thyroid cancer (n = 109) Modality Value PET PET/CT Sensitivity (%) 88.2 92.9 Specificity (%) 75 75 Positive predictive value (%) 92.6 92.9 Negative predictivevalue (%) 64.3 75 False positive rate (%) 25 25 Falsenegative rate (%) 11.2 7.1 Accuracy (%) 85.3 89 Remarks: - PET/CT had 92.9% sensitivity, 75% negative predictivevalue and 89% accuracy, higher than that of PET (88.2%; 64.1% and 85.3%, respectively). - False positve rate of both PET/CT and PET were 25%. False negative rate of PET was 11.2% higher than that of PET/CT (7.1%). Table 3.33. Compare the diagnostic values of head and neck dedicated PET/CT and whole body PET/CT (n = 84) Protocols Diagnostic values Head and neck dedicated PET/CT Whole body PET/CT Sensitivity (%) 93.7 90.9 Specificity (%) 76.2 66.7 Positive predictive value (%) 92.2 95.2 Negative predictive value (%) 80 50 False positive rate (%) 23.8 33.3 Falsenegative rate (%) 6.3 9.1 Accuracy (%) 89.3 88 18 Remarks: - Head and neck dedicated PET/CT had 93.7% sensitivity, 76.2% specificity, 80% negative predictive value and 89.3% accuracywhich were higher than that of whole body PET/CT (90.9%; 66.7%; 50% and 88%, respectively). - Whole body PET/CT had 95.2% positive predictive value, 33.3% false positive rate and 9.1% false negative rate, which wre higher than that head and neck dedicated PET/CT. Chart 3.13. Analysis of ROC of SUVmax in diagnosis of recurrent/metastatic thyroid cancer Remarks:Via analysis of ROC, SUV threshold of 5.6 g/ml was determined as the optimal value for diagnosis of recurrent/metastatic thyroid carcinoma with 84% sensitivity and 83.3% specificity. 19 Chapter 4 DISCUSSION 4.1. Patient and 18F-FDG PET/CTimaging characteristics 4.2.1. Patient characteristics In this study, patient’s mean age was 45.7 years. Our result was similar to results of Na SJ (2012) and Bannas P (2012)but lower than results of other authors.The female/male ratio in our study was 3/1 higher than the ratios in other studies.The reason for this may be the equivalence or difference of study sample, geographic and socioeconomic conditions. In our study, patient’s median and mean off-T4 serum Tg levels and pre-PET/CT scan were 217 ng/ml and 297.9 ng/ml, respectively. Mean Tg level of patients in our study was higher than most of other studies, may be because of difference in patient’s characteristics between studies. The higher the Tg level, the more possibility of recurrent, metastatic thyroid cancer. 4.2.2. 18F-FDG PET/Ct imaging characteristics  Number and site of lesions 294 lesions were found in PET/CT, more than that found in PET (272 lesions)(Table 3.12). When comparing the number and percentage of lesions, PET/CT detected more than PET 22 lesions (8.1%) (Table 3.13). This result showed the advantage of PET/CT to PET alone due to the combination of metabolic and functional information in PET and the anatomical information in CT. About les ion site, cervical lymph node was the most lesion 20 detected in both PET/CT andPET. PET/CT discovered more lesions cervical lymph node and thyroid bed than PET did (Table 3.13). May be patients with thyroid cancer had already undergone surgery in neck region that caused the anatomical change so it is difficult for PET only to identify small les ions. Besides that, some suspected lesions in CT did not uptake FDG in PET, so that low dose whole body CT and head and neck dedicated CT would supplement anatomical information for PET and help to evaluate lesions more accurately.  Recurrence, metastasis detected in PET/CT About the rate of recurrence, metastasis detected in PET/CT, node metastasis accouted for the highest rate 65.1%, then distant metastasis 31.2% and recurrence in thyroid bed 26.6% (Chart 3.7). Our result was similar to Chung JK’s results (1999) in South Korea with lesions most found in PET were cervical nodes (87.9%), then mediastinal lymph nodes (33.3%), lung (27.3%) andbone (9.1%).The ability to discover distant metastasis is an advantage of PET/CT to conventional diagnostic imaging modalities such as ultrasound, CT and MRI.  Lesion’s size and SUVmax Mean lesion’s size in PET/CT was 14.0 mm, there were 3 lesions< 5 mm (1%) and 48 lesions with size from 5 – 9mm (16.4%) (Table 3.20). This results showed the advantage of PET/CT in detecting small recurrent/metastatic lesions in patients with thyroid cancers. It is because PET/CT combined both the abilities of metabolic diagnosis in PET and anatomic diagnosis in CT. The mean lesion’s SUVmax was 9.3 g/ml. (Table 3.21). Our result was higher than that of Iagaru A (2007), Na SJ (2012) và Ha 21 LN (2016). The difference may be due to the mean serum Tg level in our study was higher than the ones in the studies above and the difference of PET/CT units and scan protocols between centers . 4.2. Diagnostic values of18F-FDG PET/CT in differentiated thyroid cancer patients with high serum Tg and negative whole body131I scan 4.2.1. 18F-FDG PET/CT results Studies around the world showed that the rates of positive PET ranged from 43.5 - 76% and the rates of positive PET/CT ranged from 49.1 - 80%. The rates of positive PET and PET/CT in our study were higher than that of other authors may be due to the higher mean serum Tg levelof patients in this study (Chart 3.11). Stangiersky A (2013) noted that the rate of positive PET/CTwas 20.3% higher than that of PET beacause low dose whole body CT detected more lesions that did not uptake FDG in PET. 4.2.2. Diagnostic values of 18F-FDG PET/CT  Diagnostic values of PET/CT for recurrent, metastatic thyroid cancer In this study, the diagnostic values of PET/CT were as follow: sensitivity 92.9%, specificity 75%, positive predictive value 92.9%, negative predictive value 75%, fale positive rate 25%, false negative rate 7.1% and accuracy 89% (Table 3.31). Our results were similar to that of Vural GU but lower than that of Palmedo H, Giovanelly L, Ha LN and higher than that of Shammas S, Na SJ. It may be due to the differences in patients’ characteristics and criteria for evaluation between studies. When compared the diagnostic values of PET/CT and PET in detection of recurrent/metastatic thyroid cancers, we noted that 22 PET/CT had higher sensitivity, negative predictive value and accuracy than PET. However, false negative rate of PET/CT was lower that of PET (Table 3.31). This results demonstrated the supplementary role of low dose whole body CT in providing anatomical information to PET. Our results were partly similar and partly different to that of Palmedo H (2006) and Freudenberg LS (2007).  Compared the diagnostic values of head and neck dedicatedPET/CT and whole body PET/CT Combined head and neck dedicated PET/CT with whole body PET/CT had not only increased sensitivity, specificity, negative predictive value, and accuracy but also decreased false positive rate,false negative rate in diagnosis of recurrent, metastatic thyroid cancers in this study (Table 3.33). Theresults reaffirm the important complementery role of head and neck dedicated PET/CT protocol to whole body PET/CT to help increase the diagnostic quality in differentiated thyroid cancer patients with high serum Tg and negative I 131Iwhole body scan.  Determined the optimal SUVmax threshold in PET/CT result analysis Via ROC analysis, we found that optimal SUVmax threshold for diagnosis of recurrent/metastatic thyroid cancers in PET/CT was 5.6 with corresponding sensitivity and specificity of 84% and 83.3%, respectively. (Chart 3.13). Some other aut