- CLINICAL MEDICINE AND PHARMACY Vol 10 - A p r / 2 0 1 5
Value of FDG-PET/CT in detecting recurrent/metastatic lesions in post-surgical differentiated thyroid carcinoma patients with high serum thyroglobulin and negative '^*I whole body scan
Bui Quang Bieu, L e N g o c H a 108 Military Central Hospital
Summary
OtvectiVe:To evaluate value of FDG-PET/CT in detecting recurrent/metastatic lesions in post-surgical DTC patients w i t h high serum thyroglobulin and negative " ' I whole body scan. Subject and method: A cross sectional, descriptive was carried out 69 post-surgical DTC patients with high serum thyroglobulin and negative " ' i whole body scan w h o m already underwent " ' I therapy in Department of Nuclear Med- icine, 108 Central Military Hospital. FDG-PET/CT was performed when patients was on thyroxine therapy.
Result: 92 lesions detected in 43 patients (62.3%) with positive PET/CT scan compared to only 39 lesions in 26 patients (37.7%) detected on positive CT scan. The sensitivity, accuracy and NPV of FDG-PET/CT were 87%, 88% and 76% higher than those of CT (54.3%, 67.2% and 48.8%, respectively). Specificity and PPV of FDG-PET/CT (90.5% and 95.2%, respectively) were similar to those of CT (95.2% and 96.2%, re- spectively). SUVmax threshold with best diagnostic value were 4.5 (sensitivity 92.3%, specificity 100%).
FDG-PET/CT had altered treatment plan in 33/49 patients (47.8%). Conclusion: FDG-PET/CT was very use- ful in detecting recurrent/metastatic lesions in post-surgical differentiated thyroid carcinoma patients with high serum thyroglobulin and negative " ' I whole body scan.
Keywords: FDG PET/CT, thyroglobulin, differentiated thyroid carcinoma.
. J therapy. After undergoing total thyroidectomy and
* ^ ^ ^ remnant ablation w i t h radioactive iodine (RAI), DTC Thyroid carcinoma is u n c o m m o n , accounted for patients are followed-up t o detect recurrence and approximately 1 % o f all cancers. However, it is t h e metastasis by t w o main tests: serum thyroglobulin most c o m m o n endocrine cancer. Thyroid carcinoma (i-gj ^„^ diagnostic " ' I whole body scan (WBS).
occurs 2 t o 3 times more in w o m e n t h a n in men. Dif- Treatment decision making are also based on these ferentiated t h y r o i d carcinoma (DTC) accounted for , „ o parameters. In clinical practice, 15-20% DTC pa- 90% of all t h y r o i d cancers and often has a g o o d ^^^^^^ ]„^^ l,lg(, serum Tg but negative " ' I WBS.
prognosis d u e t o iodine-avid ability but also has xhese patients usually did not response t o RAI and considerably h i g h rate of recurrence and metastasis, j^j^j g poorer prognosis than those w i t h positive " ' I Up t o 3 0 % of patients w i t h DTC may have t u m o r re- y ^ g j Because " ' I WBS cannot detect recurrent or currences d u r i n g several decades and 66% of these metastatic lesions in these patients so other diag- recurrences occur w i t h i n t h e first decade after initial „ostic imaging tools are needed t o solve the prob- lem. So far several studies have proved the diagnos-
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We have treated and followed-up about four thousands of DTC patients at Department of Nuclear Medicine, 108 Central Military Hospital and f o u n d that It was challenging in management of DTC pa- tients w i t h high serum Tg and negative " ' I WBS in clinical practice. Hence w e carried o u t t h e study w i t h t h e purpose as follow: To evaluate value of FDG- PET/CT in detecting recurrent/metastatic lesions in post-surgical DTC patients with high serum thy- roglobulin and negative '^'1 whole body scan.
2. Subject and m e t h o d
Subject: 69 postoperative DTC patients treated and followed-up at Department of Nuclear Medi- cine, 108 Central Military Hospital.
S t u d y t / m e : f r o m April/2010 t o August/2013 Patient selection:
- Postoperative DTC patients already underwent radioiodine therapy.
- Off-T4 serum Tg > 2 ng/ml and anti-Tg < 115 U/l.
- Negative'^^1 WBS.
- Non pregnant w o m e n . - Without co-morbidity.
- Agreed t o attend the study.
Study des/gn: Cross-sectional descriptive study.
Study implementation:
- DTC was diagnosed by histopathology, staging based on AJCC 7 (2010).
- Patients were thoroughly examined, medical records were stored.
- Explained study protocol t o patients.
- Serum Tg was determined by Elecsys system (Roche Diagnostics) at Department of Biochemistry, 108 Military Central Hospital.
^^^1 WBS was carried out on Millenium MG gamma camera (GE Healthcare) 2 days after oral administration of 5 mCi '^'1 and during T4 w i t h - drawal w i t h serum TSH > 30 pUl/ml.
- FDG PET/CT was carried out on Discovery Light Speed PET/CT scanner (GE Healthcare) when " ' I WBS was negative and patient was off-T4. FDG dose was 0.14
0.2 mCi/kg with intravenous Injection. FDG PET/CT images were showed in dedicated software and
analysed by t w o nuclear medicine physicians and di- agnostic doctors to reach a final conclusion. The maxi- m u m standard uptake values (SUVmax) of the sus- pected lesions on FDG PET/CT were also recorded.
Treatment strategies for DTC patients with positive serum Tg and negative '^'1 WBS based on FDG PET/CT were as follow: (1) Large, localized op- erable lesions: patients were indicated to surgery and lesions were confirmed by histopathology; (2) Large, multiple lesions w h i c h cannot be totally dis- sected by surgery: surgery and/or external beam radiation therapy; (3) Small lesions (<10 mm) which is not suitable for surgery or no lesions are found:
considering adjuvant RAI or watchful waiting.
- if patient has negative FDG PET/CT result, he/she will be routinely followed-up every six months w i t h clinical examination, serum Tg and neck ultrasound.
Criteria for evaluation
- Positive FDG PET: Focal abnormal FDG uptake determined by visual analysis.
- Lymph nodes measuring more than 1 cm in the short axis diameter in CX scan are considered abnormal.
- Positive FDG PET/CT: Positive FDG PET and/or abnormal lymph node in CT scan.
- FDG PET/CT results were collated w i t h the in- formation collected during patient follow-up: Post- operative histopathological results {gold standard for diagnosis of recurrence/metastasis), Tg trend, neck ultrasound, CT scan.
- Patient follow-up t i m e must be at least 12 months, if serum Tg increasing during follow-up pe- riod, t h e patient was considered t o have recurrence and/or metastasis. If serum Tg decreased gradually w i t h o u t any additional treatment, t h e increasing Tg before were considered false positive.
- Recurrence/metastasis was determined if pa- tient had one or t w o criteria:(1) Postoperative histo- pathology confirmed t h y r o i d carcinoma; (2) Increas- ing serum Tg during follow-up t i m e and/or positive neck ultrasound, CT.
Data analysis
We used SPSS software version 18.0 t o analyze collected data. FDG PET/CT and CT diagnostic values were calculated based on 2x2 contingency table.
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Diagnostic . . i f cT and PET/CT were compared was determined by ROC curve analysis, p value less using area u n a , e curve (AUC) of receiver operat- than 0.05 was considered statistically significance, ing characteristic (ROC) curve. IVlost suitable SU-
Vmax threshold for recurrent/metastatic diagnosis 3. Result
Patient characteristics are shown in Table 1.
Table 1 . Patient characteristics (n = 69) Characteristic
Gender
Age
Histologic subtypes
TNM staging
Numbers of'^^1 therapy
Total " ' 1 dose (mCi)
Off-T4Tg (ng/ml)
A-Tg (lU/ml)
Reference standard
Follow-up time (month) Male Female Mean ± SD Range (year)
Papillary thyroid carcinoma Folicullar thyroid carcinoma Stage 1
Stage II Stage III Stage IV Unidentified Range M e a n ± S D Range Mean ± SD Range M e a n ± S D Range Mean ± SD
Postoperative positive histopathology (n) Follow-up positive images and/or Tg trend (n) Range
Mean±SD
Value 13(18.8%) 56(81.2%) 45.6 ±13.2 2 0 - 8 0 66 (95.6%) 3 (4.4%) 26 (37.7) 10(14.51 3 (4.3) 17(24.6%) 13(18.8%) / - l O 3.5 ± 1 7 150-1400 468.6 ±271.3 11.4-1000 218.3 ±262.1 10-66.5 204 ±10.7 32 13 12-43 24 1 ± 9.0
Lesion characteristics in CT and FDG PET/CT are described in Table 2. There were 92 lesions in 43 pa- tients detected by FDG PET/CT compared t o 39 le- sions in 26 patients shown by CT Lesion's SUVmax ranged wildly from 3 t o 28 (mean 7.8 ± 5.3). FDG
PET/CT discovered more lesions in thyroid bed, cer- vical and mediastinal node than CT did alone. How- ever, CT and FDG PET/CT had same ability in finding lung metastasis {5 lesions).
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Table 2. Lesion characteristics in CT a n d FDG PET/CT CT Number of patients with positive findings
Number of lesions Lesion size (mm)
SUVmax (g/ml)
Minimum Maximum Mean ± SD Minimum Maximum Mean ± SD Thyroid bed Cervical lymph node (LN) Mediastinal LN Lung
26 (37.7%) 39 5 27 12.8 + 4.3
10 20 4 5
43 (62.3%) 92 4 27 9.6 ±4.6 3.0 28 7.8 ±5.3 20 55 12 5
Figure 1.65-year-old male with papillary thyroid cancer undenwent total thyroid thyroidectomy and then received ^'1 therapy with total dose of550mCi.'^'l WBS after the 3rd treatment showed no abnormal
uptake and his stimulated Tg was > 1000 ng/ml. (B) Axial PET and (C) Axial PET/CT images show focal FDG uptake in thyroid bed and pretrachea lymph node, which is not clearly seen in low dose CT (A). Surgical
resection ofthese lesions confirmed recurrence/metastasis of papillary thyroid carcinoma.
Sensitivity, accuracy and negative predictive value of FDG PET/CT (87%; 88% and 76% respec- tively) were higher than those of CT alone (54.3%;
67.2% and 48.8% respectively). Specificity and posi- tive predictive value of b o t h CT and FDG PET/CT were similar: 95.2% and 96.2% for CT and 90.5% and 95.2% for FDG PET/CT (Figure 2). Area under t h e curve (AUC) of FDG PET/CT (0.887) was significantly
larger than that of CT (0.748) (Figure 3). It means that FDG PET/CT are superior t h a n CT in diagnosis of re- current/metastatic thyroid cancer. By analyzing the ROC curve of lesion's SUVmax, w e f o u n d that SU- Vmax threshold of 4.5 was most accurate for diag- nosis of recurrent/metastatic thyroid cancer with sensitivity 92.3% and specificity 100% (Figure 4).
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PPV: Positive predictive value; NPV: Negative predictive value
Figure 2. CT and FDG PET/CT diagnostic values for recurrence/metastasis of thyroid cancer.
AUC PET/CT 0,887 AUC a SCAN 0,748 p = 0,00!
Figure 3. ROC curve comparison between CT and FDG PET/CT in diagnosis of recurrent/metastatic thyroid
cancer.
Figure 4. ROC curve analysis of lesion's SUV in diagno- sis of recurrent/metastatic thyroid cancer.
FDG PET/CT changed treatment strategy 'n 33/69 (47.8%) DTC patients w i t h high serum Tg and negative ^^'1 WBS including 31 patients underwent surgery and 2 patients underwent external beam radiation therapy (Table 3).
Table 3. Therapeutic change after implematation of FDG PET/CT
Surgery External beam radiation therapy (EBRTl Empirical ^^^1 therapy Watchful waiting
n 31 2 27
9
%
44.9 2.9 39.1 13.1
4. Discussion
Some studies have proved the role of FDG-PET and PET/CT in localizing sites of recur- rence/metastasis and changing treatment decision in DTC patients w i t h high serum Tg and negative ^^'l WBS. Schlutter B at al. (2001) performed FDG PET scan in 64 DTC patients w i t h positive Tg, negative
^^^l WBS and found that FDG PET was positive in 44 and negative in 20 patients, in those patients there were 34 true positive and resulted in 19/34 patients underwent surgery and/or EBRT. PPV and NPV of
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FDG PET/CT for recurrence/metastasis were 83% and 25%, respectively [2]. Study o f Chung JK et al on 54 DTC patients w i t h negative '^'1 WBS w h o m under- w e n t off-T4 FDG PET scan showed that sensitivity and specificity of FDG PET for recurrence/metastasis were 93.9% and 95.2%, respectively. The author also f o u n d that FDG PET detected more metastatic cervi- cal LN (87.9%) and less lesions in lung, mediastinum and bone (27.3%; 33.3% and 9 . 1 % respectively) [3].
Recently, several studies have verified t h e role o f FDG PET/CT in improving diagnostic accuracy for recurrent/metastatic thyroid cancer when compared w i t h FDG PET alone. Palmedo H et al performed FDG PET/CT scan in 40 DTC patients w i t h positve Tg, negative '''^l WBS and found that diagnostic accu- racy of FDG PET/CT 93.9% was significantly higher than that of FDG PET 78% (p < 0.05). This study also revealed that PET/CT showed more detail about le- sions location than PET or CT did alone and FDG PET/CT changed treatment decision in 48% o f DTC patients [4]. Another study of Sammas S et al on 61 DTC patients w i t h high Tg, negative '^'1 WBS and f o u n d that sensitivity, specificity and accuracy of FDG PET/CT in diagnosis of recurrence/metastasis were 68.4%; 82.4% and 73.8%, respectively. Thera- peutic change including surgery, EBRT and chemo- therapy due t o FDG PET/CT result was 44% [5].
In our study, 43/69 patients {62.3%} had positive FDG PET/CT result while only 26/69 patients (37.7%) had positive CT result. 92 lesions were detected by FDG PET/CT which is more than twice that detected by CT (39 lesions). From this result, we deduce that FDG PET/CT are superior than CT in detecting recur- rence/metastasis of DTC patients w i t h high Tg, neg- ative '^'1 WBS. It is because FDG PET/CT have advan- tage of combining b o t h abilities of metabolic diag- nosis of PET and anatomic diagnosis of CT. Gener- ally, criteria for suspected malignant cervical LNs in CT was LNs w i t h short axis diameter > 1 cm. How- ever, we f o u n d that 16/43 patients w i t h positive FDG PET/CT had lesion diameter less than 10 m m and recurrence/metastasis was confirmed by postopera- tive histopathology in 10 patients. Hence, there will be chances of omitting recurrent/metastatic lesions
if w e use this criteria w h e n interpreting CT images.
Diagnostic accuracy of FDG PET/CT for recur- rent/metastatic t h y r o i d carcinoma depends on se- rum Tg levels. Na SJ et al analyzed FDG PET/CT im- ages of 60 DTC patients w i t h elevated Tg (^2.0 n g / m l after TSH stimulation) or elevated anti-Tg (£70.0 lU/ml) and negative diagnostic radioiodine scan. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of PET/CT were 69.4, 66.7, 69.1, 95.6, and 17.4%, re- spectively. The sensitivity o f FDG PET/CT according t o Tg levels was 28.6% w h e n Tg was between 2 and 5, 5 7 . 1 % between 5 and 10, 60.0% between 10 and 20, and 85.7% w h e n Tg was equal t o or greater than 20 ng/ml sub-groups, respectively. The author con- cluded that diagnostic accuracy of FDG PET/CT in radioiodine negative thyroid cancer may vary de- pending on serum Tg levels at imaging. FDG PET/CT is useful in detection and localization of recurrent thyroid cancer in patients w i t h negative diagnostic radioiodine scan despite elevated Tg greater than 20 n g / m l or high anti-Tg. In contrast, PET/CT provides little additional information when t h e Tg is less than 5 n g / m l [6].
In 31 patients w i t h positive FDG PET/CT under- w e n t surgery, recurrence/metastasis was histopa- thologically confirmed in 30 patients, and only one patient had negative postoperative histopathology.
However, there were 3 patients w i t h negative FDG PET/CT had metastatic cervical LNs during follow-up time of 6-12 months after PET/CT scan. Therefore, w e should always keep in mind that FDG PET/CT re- sults may be false positive due t o FDG-uptake In inflammatory lesions or may be false negative in case of microscopic diseases that are beyond PET resolution. It Is important t o correlate FDG PET/CT results w i t h patient's clinical characteristics and oth- er diagnostic tools as well as routine follow-up with serum Tg, neck ultrasound for patients with nega- tive FDG P E T / a .
Undoubtedly, FDG PET/CT is more useful than CT alone in detecting recurrent/metastatic lesions in DTC patients w i t h high Tg, negative '^'1 WBS. How- ever, FDG PET/CT is expensive and not available in
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many nuclear medicine departments in Vietnam.
Therefore, c o m b i n a t i o n of conventional diagnostic tools such as neck ultrasound, CT scan and 5PECT with sestamibi is a reasonable approach for DTC pa- tients w i t h h i g h Tg, negative " ' I WBS in hospitals w i t h o u t PET/CT. When analyzing ROC curve of SU- Vmax of lesions detected in FDG PET/CT, w e f o u n d that SUVmax was more reliable criteria than lesion size. SUV represents metabolism of cancer cell and therefore reflect nature o f lesion while it is difficult to measure lesion size precisely in PET/CT image. We also determined t h e most suitable SUVmax thresh- old for diagnosis of recurrence/metastasis was 4.5 with sensitivity 92.3% and specificity 100%.
After performing FDG PET/CT scan, there were 31 patients undenvent surgery and 2 patients received EBRT. Therefore, in our study 33/69 patients (47.8%) had treatment strategy change due to FDG PET/CT.
(^her studies also showed that FDG PET/CT changed the treatment strategy in 44 - 48% of patients [4], [5].
Shammas A et al (2007) "FDG PET/CT in patients wrf/r suspected recurrent or metastatic v^ell- differentiated thyroid cancer, J NucI Med 48: 221- 226.
Na SJ et al (2012) Diagnostic accuracy of "'f- fluorodeoxyglucose positron emislon tomogra- phy/computed tomography in differentiated thyroid cancer patients iv/f/i elevated thyroglobulin and negative '^'1 whole body scan: evaluation by thy- roglobulin level. Ann NucI Med 26; 26-34.
5. Conclusion
FDG PET/CT was very useful in detection and lo- calization of recurrent/metastatic lesions in post- surgical DTC patients w i t h high serum Tg and nega- tive " ' I WBS. Treatment decision malcing for these patients could be made based on FDG PET/CT results.
References
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Thyroid 19(11): 1167-1214.
2. Schluter B et ai (2001) Impact of FDG PET on pa- tients with differentiated thyroid cancer who present with elevated thyroglobulin and negative "'I scan. J NucI Med 42: 71-76.
3. Chung JK et al (1999) Value of FDG PET in papillary thyroid carcinoma with negative "'I Whole-Bogy Scan. J NucI Med 40: 986-992.
, . Palmedo H et al (2006) Integrated PET/a in differenti- ated thyroid cancer: Diagnostic accuracy and impact on patient management. 1 NucI Med 47:616-624