Ann Nucl Med (2015) 29:170–176 DOI 10.1007/s12149-014-0925-7
ORIGINAL ARTICLE
Cardiac blood pool activity on postablation radioiodine imaging Ays¸ e Aktas¸ • Beyza Kocabas¸ • Seval Erhamamcı Arzu Genc¸og˘lu • Cevdet Liman
•
Received: 8 July 2014 / Accepted: 29 October 2014 / Published online: 9 November 2014 Ó The Japanese Society of Nuclear Medicine 2014
Abstract Objective There are reports on physiologic and pathologic mediastinal uptake on radioiodine imaging in patients with thyroid carcinoma. The most commonly reported physiologic causes of mediastinal uptake are esophageal retention of salivary secretion and uptake by hyperplastic or normal thymus gland. In this study, we evaluated physiologic cardiac blood pool (CBP) activity and its associated findings on radioiodine imaging. Methods Cardiac blood pool activity was evaluated in 186 postablation and 32 posttherapy scans. After oral radioiodine administration, imaging was initiated on day 7. Thyroglobulin, anti-thyroglobulin and TSH blood level determination was carried out in all patients. Whole-body scans were inspected with regard to residual thyroid uptake, esophageal uptake, CBP activity, hepatic activity and metastatic iodine uptake. Uptake in the residual thyroid tissue was graded visually as mild (m), moderate (M) and significant (S). Whenever CBP activity was detected on visual inspection, its intensity was graded as mild (1), moderate (2), and significant (3). Results Cardiac blood pool activity was detected in 61 postablation scans (33 %). Residual thyroid uptake was observed in all patients with CBP. A significant correlation existed between the intensity of uptake and the presence of CBP (p \ 0.05). The mean Tg in patients with CBP was significantly higher than those without CBP (p \ 0.05). Cardiac blood pool activity was not observed in any
A. Aktas¸ (&) B. Kocabas¸ S. Erhamamcı A. Genc¸og˘lu C. Liman Department of Nuclear Medicine, Faculty of Medicine, Bas¸ kent University, Fevzi C¸ak. Cad. 10. sk. No: 45, 06480 Bahc¸elievler, Ankara, Turkey e-mail: [email protected]
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posttherapy scans and in those scans with distant metastases in the postablation group. Linear or irregular activity pattern thought to be due to esophagus was detected in 4 % of postablation scans. Conclusions The results have revealed CBP to be common on postablation scans. Its presence correlated with the intensity of residual thyroid uptake and had a significant association with increased thyroglobulin levels. Its absence on posttherapy scans despite increased Tg levels suggested that this activity is due to labeled thyroid hormones released by the residual thyroid tissue. Its presence might imply a high level of blood radiation dose. Keywords Cardiac blood pool Thyroglobulin Postablation Radioiodine Remnant Metastases
Introduction Abnormal extrathyroidal focal uptake in a diagnostic or posttherapy whole-body radioiodine scan can be due to metastatic foci in a patient with thyroid carcinoma. When detected on a diagnostic scan, this finding might necessitate the administration of therapeutic radioiodine doses especially when it is together with abnormal thyroglobulin levels. Its presence on a diagnostic or posttherapy scan may lead to further evaluation with other imaging modalities and may also change patient follow-up protocols. There are reports on false-positive physiologic and pathologic radioiodine uptake. Therefore, it is essential to recognize conditions causing false-positive radioiodine scans. The most commonly reported physiologic causes of mediastinal uptake are esophageal retention of salivary secretion and uptake by an hyperplastic or normal thymus gland [1, 2].
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The Na(?)/I(-) symporter (NIS) is a cytoplasmic membrane protein mediating the active transport of iodide into the thyroid gland, the first step in thyroid hormone biosynthesis. The same symporter is also responsible for iodide transport into salivary glands, gastric mucosa and breast tissue. Depending on the time interval between radioiodine administration and scintigraphic imaging, physiologic radioiodine uptake on whole-body radioiodine scans can be observed in iodine concentrating, excreting or metabolizing organs. Within the thyroid gland, radioiodine becomes concentrated in the functioning thyroid cells. Under the influence of thyroidstimulating hormone (TSH), it is metabolized into thyroxine which is released into the circulation as required. Thyroxine is predominantly bound to thyroxine binding globulin in the circulation. This circulating protein-bound iodine is described as organic as opposed to the inorganic free iodine. Circulating radioiodine can either be due to protein-bound thyroid hormone, labeled thyroglobulin (Tg) or free radioiodine. Although blood pool activity, when significant, can be seen on large vessels as external iliac artery, its mild– moderate degrees can only be delineated on cardiac outline. Therefore, in this study, physiologic blood pool activity which is referred to as cardiac blood pool (CBP) activity and its presence on initial and subsequent postthyroidectomy high-dose scans were evaluated. Its effect on the interpretation of radioiodine scans and its association with residual thyroid tissue (RTT), thyroglobulin levels, and the presence of local or distant metastases were analyzed.
remnant ablation. The remaining 68 patients had one of the following: extracapsular invasion, lymph node (LN) metastases, distant metastases or significantly elevated Tg levels that were more than 50 ng/ml. The dose range in this group was 125–175 mCi. In patients receiving radioiodine postthyroidectomy, the time interval between operation and radioiodine administration ranged between 30 and 75 days. The study was a retrospective evaluation of postthyroidectomy radioiodine scans. Since majority of our patients were referred from other hospitals for getting radionuclide therapy only, followup data were not available for more than half of the patients.
Methods
Imaging
The experiments comply with the current laws of Turkey, inclusive of Ethics approval.
Whole-body I-131 scans were performed routinely on day 7 after oral administration of radioiodine in all patients. Serial images were acquired on subsequent days as necessary. A two headed gamma camera (Siemens, e.cam) equipped with high-energy collimator was used for image acquisition. The energy peak was 364 keV with a 20 % window. In addition to whole-body images, static images of head/neck, thoracal/abdominal regions and pinhole thyroid images were acquired. Scans were inspected visually for CBP activity and the presence of uptake in RTT, mediastinum, esophagus, and liver. In scans with CBP, general whole-body background activity was compared to that of scans without CBP and posttherapy scans. The degree of uptake in RTT was graded visually as mild (m), moderate (M) and significant (S). Whenever CBP activity was detected on visual inspection, its intensity was graded as mild (1), moderate (2), and significant (3).
The study group For evaluating cardiac blood pool activity, whole-body radioiodine scans acquired at following clinical settings were used: Postablation scans (group 1) This group consisted of 186 patients with differentiated thyroid carcinoma who had their first postthyroidectomy high-dose scan after total thyroidectomy. These scans are referred to as postablation scans. None of the patients had renal or hepatic failure. Out of 186 patients, 118 had 100 mCi Iodine-131 (I-131) for residual thyroid
Posttherapy scans (group 2) This group consisted of 32 patients receiving their second or third high-dose radioiodine. The dose range in this group was 150–225 mCi. Among 32 scans, 15 were from patients with thyroglobulin elevation only (C10 ng/ml) and 17 from patients with known local or distant metastases. Among this 17 scans, 4 belonged to patients who had undergone second operation due to recurrent LN metastases that was confirmed with biopsy. Patient preparation All subjects had TSH, Tg and anti-thyroglobulin (AntiTg) blood level determination 1 day before radioiodine administration. Thyroid hormone withdrawal and iodinerestricted diet were continued for at least 2 weeks before hospitalization.
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Table 1 Clinical, laboratory and radioiodine imaging findings in patients with and without cardiac blood pool activity on postablation scans Tga
AntiTg (?)b
(-)
(?)
CBP (?) (n = 61)
1
57
3
CBP (-) (n = 113)
56
50
7
Mean Tgc
Residual thyroid tissue (-)
m
M-S
32.1 ± 20.2
0
13
48
8.1 ± 7.3
7
73
33
This table consists only of patients from group 1. Patients with distant metastases were not included in CBP (-) group CBP cardiac blood pool, m mild, M moderate, S significant a
Tg (-): \3 ng/ml; Tg (?) C3 ng/ml
b
AntiTg (?): C20 IU/ml
c
Tg values are in ng/ml as mean ± standard deviation
Table 2 Cardiac blood pool activity and Tg in patients with local and distant metastases on postablation scans Local metastases (n = 40) CBP (?) CBP (-)
Distant metastases (n = 12)
20 20 Tg (?)
Tg (-)
20
12
Tg (?)
Tg (-)
Tg (?)
Tg (-)
7
10
10
2
This table consists only of patients from group 1 CBP cardiac blood pool Tg (-): \3 ng/ml; Tg (?) C3 ng/ml
Statistical analysis The mean Tg values were expressed as mean ± SD. Differences in score values in postablation and posttherapy scans were analyzed by using Mann–Whitney U test for independent data and Student t test for paired data. p value less than 0.05 was considered significant. Thyroglobulin level in patients with increased AntiTg was not included in the final analysis of mean Tg determination.
Results All patients had TSH [30 lIU/ml at the time of radioiodine administration. Thyroglobulin was considered to be elevated when it was C3 ng/ml under stimulation. Postablation scans (group 1) Linear or irregular activity pattern thought to be due to esophagus was detected in 8 patients (4 %). Mild focal
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uptake thought to be due to thymus was observed in only one patient. The results in patients with and without CBP are summarized in Tables 1 and 2. Patients with CBP Among 186 patients, CBP activity was detected in 61 radioiodine scans (33 %). Out of 61 patients, 41 were given a radioiodine dose of 100 mCi and the remaining 20 patients were treated with higher doses. A moderate to significant degree of CBP activity was detected in a total of 22 patients (Fig. 1). Cardiac blood pool activity in the remaining 39 patients was of a mild degree. In 11 patients with grade 3 CBP activity and in 7 of 11 patients with grade 2 CBP activity, blood pool could also be detected on large vessels as external iliac artery. On posterior thoracic images, CBP appeared as diffuse uptake on lower left lung region (Fig. 2). Seven patients with grade 2–3 CBP activity had serial thoracic images taken on the consecutive days which revealed no significant difference in CBP activity on serial scans (Fig. 2). Three patients with grade 3 CBP activity had a second treatment dose within the following 2 years due to persistently elevated Tg levels. Residual thyroid uptake was detected in all patients with CBP. A moderate-significant RTT was present in 48 patients (79 %). All patients except one with grade 2–3 CBP activity exhibited a moderate-significant RTT. A significant correlation existed between the intensity of uptake and the presence of CBP (p \ 0.05). All patients with CBP activity except one had increased Tg levels. Three patients had increased AntiTg levels. In the remaining 57 patients, a significant correlation existed between the intensity of CBP activity and Tg level (p \ 0.05). The mean Tg in patients with CBP was 32.1 ± 20.2 ng/ml. Twenty patients had metastatic lymph nodes. All patients with LN metastases in this group had increased Tg levels. Patients without CBP Among the remaining 125 patients without CBP activity, 20 had LN metastases and 12 had distant metastases with or without LN metastases. None of the patients with distant metastases had CBP. Four patients with distant metastases had moderate-significant RTT. Out of 20 patients with LN metastases, Tg was normal in 10 patients and increased in 7 patients; three subjects had increased AntiTg levels. Among patients with a LN metastases having a normal Tg, 5 had multicenter disease. Among patients with distant metastases, 2 patients with diffuse lung uptake had Tg \ 3 ng/ml, one patient with bone metastases had a Tg level of 9.2 ng/ml, 8 patients with multifocal lung
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Fig. 1 The relation between RTT and CBP. a, c Whole-body image and spot views in a 38-year-old male patient with papillary thyroid carcinoma and LN metastases who had 150 mCi radioiodine postthyroidectomy. There is a significant RTT with grade 3 CBP activity. Thyroglobulin was 31 ng/ml. b, d Whole-body image and
spot views in a 42-year-old female patient with papillary thyroid carcinoma who had 100 mCi radioiodine postthyroidectomy. There is a moderate degree of RTT with a grade 2 CBP activity. Thyroglobulin was 16.9 ng/ml. In both patients, blood pool activity can also be observed on external iliac and femoral arteries
metastases and one patient with multifocal skeletal metastases had a Tg level [50 ng/ml. Excluding the patients with distant metastases, 56 patients (10 with LN metastases) had normal and 50 patients (7 with LN metastases) had increased Tg levels in CBP negative patient group (50 and 44 %, respectively). The mean Tg in these 50 patients was 8.1 ± 7.3 ng/ml. The mean Tg in patients without CBP was significantly lower than those with CBP (p \ 0.05). A total of 7 patients (3 with LN metastases) had increased AntiTg levels.
Residual thyroid uptake could not be detected in 7 patients. A moderate-significant RTT was detected in 33 patients (29 %). Posttherapy scans (group 2) None of the patients in this group had cardiac blood pool activity. Among 32 scans, mild residual thyroid uptake was detected in 2 patients. On visual inspection, general wholebody background activity was lower than that of group 1
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Fig. 2 Serial CBP activity on thoracic images. Anterior and posterior thoracic spot views taken on days 7 (a) and 8 (b) after 100 mCi radioiodine administration in a 36-year-old female patient with papillary thyroid carcinoma. There is a grade 2 CBP activity together with a mild bilateral slightly asymmetric physiologic mammary uptake. On posterior thoracic images, CBP appears as mild diffuse left lower lung uptake. No significant change in CBP can be observed on the serial scan
patients with CBP activity (Fig. 3). All patients except 3 had increased Tg levels at the time when the therapy dose was administered. The mean Tg in the posttherapy patient group was significantly higher than that of group 1 patients with CBP activity (p \ 0.05). Patients with normal Tg were among those who had been reoperated due to recurrent local LN metastases. Metastatic foci on radioiodine imaging could be detected in 16 scans. In this group, one patient had a suspected esophageal retention of activity.
Discussion Radioiodine uptake on thoracic images in a patient with thyroid carcinoma can be due to pulmonary, skeletal or mediastinal metastases. Various conditions have been reported to cause false-positive radioiodine uptake in the chest area. The most commonly reported cause is physiologic retention of salivary secretions by a normal or abnormal esophagus. Retention in a normal esophagus can be focal, diffuse or linear in pattern and has a tendency to disappear or change location on delayed images. Salivary retention was also reported to occur in abnormal esophagus due to decreased esophageal motility, achalasia, esophageal stricture and Zenker’s diverticulum (1). Uptake in a normal or hyperplastic thymus was also reported (2). It was shown that with higher radioiodine doses, diffuse or dumbbell-shaped physiological thymic uptake was common in young patients. Thymic activity was more apparent on the 7-day scan compared to the scan obtained at 3–4 days. In our study, the incidence of both esophageal
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and thymic uptake was lower compared to CBP activity. Other frequently reported causes of physiologic mediastinal radioiodine uptake are accumulation by the lactating and nonlactating breast, foci of ectopic thyroid tissue, and displaced gastric mucosa. External contamination of skin and/or garment with body secretions is another well-known cause of false-positive findings. The most commonly reported causes for false-positive nonphysiological mediastinal radioiodine uptake are tumors of nonthyroidal origin, infection, and pericardial effusion. Mild to moderate diffuse liver uptake indicating functioning thyroid remnant can be detected on posttherapy I-131 whole-body scans. This activity was thought to be mainly due to the metabolism of labeled thyroid hormones and/or Tg in the liver. Diffuse liver uptake was shown to be more common in high-dose I-131 administrations and in patients with remnant thyroid tissue [3]. In patients without residual thyroid tissue, Tg was thought to be responsible for hepatic visualization. Liver uptake without uptake by the thyroid or metastases on whole-body scan was suggested to be due to hidden metastases [4]. The authors speculated that Iodine-131 was first taken into metastatic cells and subsequently washed out as forms of Iodinelabeled-Tg and organic components which eventually accumulated in the liver. They suggested earlier wholebody imaging to be potentially helpful in detecting metastatic lesions in these cases. It has been reported that radiation can cause inhibition of the organification pathway before the I-131 accumulating faculty is damaged [5]. A positive scan for RTT may indicate the presence of functioning thyroxine forming
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Fig. 3 Postablation and subsequent posttherapy images in the same patient. a Whole-body image and spot views in a 42 year female patient with papillary carcinoma and LN metastases who had 150 mCi radioiodine postthyroidectomy. There is a grade 1 CBP activity, a significant uptake in RTT, and accumulation in LN metastases. Thyroglobulin was 12.6 ng/ml. b Whole-body image of
the same patient taken after 200 mCi radioiodine administration 1 year after the first study owing to a further increase in Tg level. There is significant uptake in left middle cervical and mild uptake in right lower cervical LN. In spite of an increased dose and higher Tg levels compared to the first study, there is no CBP activity
tissue or if further iodine synthesis is blocked it can only be due to the accumulation of iodide. Hammersley et al. evaluated the value of serial protein-bound iodine (PBI) measurements in patients with thyroid carcinoma treated with radioiodine [6]. PBI was measured between days 1 and 6 post-radioiodine administration and evaluated together with the results of the whole-body scan performed on day 3. It was shown that 92 % of patients with a falling PBI had negative scans and 78 % with a rising PBI showed positive scans for the presence of RTT. A falling PBI indicated a small volume of functioning thyroid tissue. Thus, they suggested PBI assay as a useful method of quantifying the absorbed dose from I-131 therapy. A small number of patients in this study also had a falling PBI in spite of a positive scan. In the current study, CBP was most commonly observed in patients with moderate-significant RTT and consequently whole-body background activity appeared to be higher in these patients. Since we did not get earlier scans and serial daily scans in all patients, we do
not know whether CBP increases or decreases with time. However, in a small number of patients, CBP did not change significantly beyond 7th day scan. The absence of CBP on posttherapy scans raises the possibility of a lower total radiation dose despite higher administered doses owing to the absence of a residual thyroid tissue. The radiation absorbed dose to the blood was considered to be a significant indicator of ablation success in several studies. In one study, the data from quantification of blood samples, whole-body probe measurements and whole-body scans were used to deduce retention curves for blood and whole body [7]. A correlation was found between residence time of radioiodine in blood and fractional uptake into thyroid remnant. In one study, absorbed dose to the blood was found to be a better predictor of ablation success than the administered radioiodine activity [8]. In that study, 14 % of the whole-body residence time was attributed to the blood. These authors assumed that the residence time of I-131 in the blood is a likely measure of the amount of
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I-131 that is available for uptake by thyroid remnant tissue and thus the radiation absorbed dose to the target tissue. However, the results of our study suggest that blood residence of radioiodine is a measure of the amount of RTT and is not an indication of free radioiodine available for uptake by the thyroid. This may also indicate that percentage of blood pool activity differs from patient to patient depending on the amount of RTT. Thyroglobulin is a thyroid-specific protein that is produced by normal thyroid cells, by benign thyroid conditions, and by functioning thyroid cancer metastases. Serum Tg levels should fall to near zero after total thyroidectomy if there is no significant normal thyroid tissue or residual malignant thyroid tissue. The measurement of serum Tg is now the standard procedure in the follow-up of differentiated thyroid carcinoma and is being utilized as a prognostic tool. Rising Tg levels after thyroidectomy and radioiodine ablation indicates disease recurrence. The first Tg measurement after total thyroidectomy is usually not considered to be of value as an indicator of metastatic disease since it may be influenced by TSH stimulation and the amount of residual normal thyroid tissue. However, several studies emphasized its prognostic importance. A first Tg value of more than 69.7 ng/ml was shown to be predictive of metastases in 90 % of cases and administering a higher ablation dose was suggested in order to have a therapeutic effect [9]. In our study, patients with CBP activity had significantly higher Tg level compared to those without CBP. However, this does not necessarily imply that it is due to labeled Tg in the blood. Since Tg is closely associated with residual thyroid mass, the association between Tg and early postthyroidectomy CBP activity is most probably due to labeled thyroid hormones that are secreted from RTT. The absence of blood pool activity despite elevated Tg levels and higher radioiodine dose in posttherapy scans supports this hypothesis. If blood pool activity would be due to free radioiodine, then it would be expected to be higher in patients with less RTT and in posttherapy scans. Since follow-up data were not available in our study, no information can be provided regarding the prognostic implication of CBP on a postablation scan. In a recent review of false-positive uptake on radioiodine whole-body scan, previous reports due to localized blood pool activity in individual cases of thoracic aortic aneurysm, pectus excavatum, and dilated venous activity were cited [10]. The results of the current study have shown that CBP activity can be observed on postablation scans obtained after total thyroidectomy. This type of uptake appeared to be the most common physiologic mediastinal uptake. In its mild–moderate degrees, it does not possess diagnostic consideration. When significant CBP exists, this activity appears as diffuse radioiodine
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uptake on lower left lung region on posterior thoracic images. Since pulmonary metastases are mostly diffuse in nature, the presence of a significant CBP should be ruled out when interpreting thoracic images. This exclusion may be more important when CBP activity is accompanied with bilateral mammary uptake in female patients. The presence of CBP correlated with the intensity of residual thyroid uptake and had a significant association with increased postoperative Tg levels. It was thought to be due to labeled thyroid hormones. The presence of CBP on a postablation scan might imply a high level of blood radiation dose. The absence of CBP activity in posttherapy scans despite elevated Tg levels can be an evidence that metastatic thyroid tissue is capable of producing Tg, but not thyroid hormones. The prognostic significance of grade 3 CBP and the absence of CBP in the presence of a significant RTT need to be determined.
References 1. Bakheet SM, Powe J, Hammami MM. Radioiodine uptake in the chest. J Nucl Med. 1997;38:984–6. 2. Wilson LM, Barrington SF, Morrison ID, Kettle AG, O’Doherty MJ, Coakley AJ. Therapeutic implications of thymic uptake of radioiodine in thyroid carcinoma. Eur J Nucl Med. 1998;25:622–8. 3. Ziessman HA, Bahar H, Fahey FH, Dubiansky V. Hepatic visualization of Iodine-131 whole-body thyroid cancer scans. J Nucl Med. 1987;28:1408–11. 4. Chung JK, Lee YJ, Jeong JM, Lee DS, Lee MC, Cho BY, et al. Clinical significance of hepatic visualization on Iodine-131 whole-body scan in patients with thyroid carcinoma. J Nucl Med. 1997;38:1191–5. 5. Myant NB. Early effects of radioiodine on human thyroid function. Clin Sci. 1953;12:235–45. 6. Hammersley PAG, Al-saadi A, Chittenden S, Flux GD, McCready VR, Harmer CL. Value of protein-bound radioactive iodine measurements in the management of differentiated thyroid cancer treated with I-131. Br J Radiol. 2001;74:429–33. 7. Hanscheid H, Lassmann M, Luster M, Thomas SR, Pacini F, Ceccarelli C, et al. Iodine biokinetics and dosimetry in radioiodine therapy of thyroid cancer: procedures and results of a prospective international controlled study of ablation after rTSH and hormone withdrawal. J Nucl Med. 2006;47:648–54. 8. Verburg FA, Lassmannn M, Mader U, Luster M, Reiners C, Hanscheid H. The absorbed dose to the blood is a better predictor of ablation success than the administered I-131 activity in thyroid cancer patients. Eur J Nucl Med. 2011;38:673–80. 9. Ronga G, Filesi M, Ventroni G, Vestri AR, Signore A. Value of first serum thyroglobulin level after total thyroidectomy for the diagnosis of metastases from differentiated thyroid carcinoma. Eur J Nucl Med. 1999;26:1448–52. 10. Jong-Ryool Oh, Ahn Byeong-Cheol. False-positive uptake on radioiodine whole-body scintigraphy: physiologic and pathologic variants unrelated to thyroid cancer. Am J Nucl Med Mol Imaging. 2012;2:362–85.
ORIGINAL ARTICLE
Cardiac blood pool activity on postablation radioiodine imaging Ays¸ e Aktas¸ • Beyza Kocabas¸ • Seval Erhamamcı Arzu Genc¸og˘lu • Cevdet Liman
•
Received: 8 July 2014 / Accepted: 29 October 2014 / Published online: 9 November 2014 Ó The Japanese Society of Nuclear Medicine 2014
Abstract Objective There are reports on physiologic and pathologic mediastinal uptake on radioiodine imaging in patients with thyroid carcinoma. The most commonly reported physiologic causes of mediastinal uptake are esophageal retention of salivary secretion and uptake by hyperplastic or normal thymus gland. In this study, we evaluated physiologic cardiac blood pool (CBP) activity and its associated findings on radioiodine imaging. Methods Cardiac blood pool activity was evaluated in 186 postablation and 32 posttherapy scans. After oral radioiodine administration, imaging was initiated on day 7. Thyroglobulin, anti-thyroglobulin and TSH blood level determination was carried out in all patients. Whole-body scans were inspected with regard to residual thyroid uptake, esophageal uptake, CBP activity, hepatic activity and metastatic iodine uptake. Uptake in the residual thyroid tissue was graded visually as mild (m), moderate (M) and significant (S). Whenever CBP activity was detected on visual inspection, its intensity was graded as mild (1), moderate (2), and significant (3). Results Cardiac blood pool activity was detected in 61 postablation scans (33 %). Residual thyroid uptake was observed in all patients with CBP. A significant correlation existed between the intensity of uptake and the presence of CBP (p \ 0.05). The mean Tg in patients with CBP was significantly higher than those without CBP (p \ 0.05). Cardiac blood pool activity was not observed in any
A. Aktas¸ (&) B. Kocabas¸ S. Erhamamcı A. Genc¸og˘lu C. Liman Department of Nuclear Medicine, Faculty of Medicine, Bas¸ kent University, Fevzi C¸ak. Cad. 10. sk. No: 45, 06480 Bahc¸elievler, Ankara, Turkey e-mail: [email protected]
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posttherapy scans and in those scans with distant metastases in the postablation group. Linear or irregular activity pattern thought to be due to esophagus was detected in 4 % of postablation scans. Conclusions The results have revealed CBP to be common on postablation scans. Its presence correlated with the intensity of residual thyroid uptake and had a significant association with increased thyroglobulin levels. Its absence on posttherapy scans despite increased Tg levels suggested that this activity is due to labeled thyroid hormones released by the residual thyroid tissue. Its presence might imply a high level of blood radiation dose. Keywords Cardiac blood pool Thyroglobulin Postablation Radioiodine Remnant Metastases
Introduction Abnormal extrathyroidal focal uptake in a diagnostic or posttherapy whole-body radioiodine scan can be due to metastatic foci in a patient with thyroid carcinoma. When detected on a diagnostic scan, this finding might necessitate the administration of therapeutic radioiodine doses especially when it is together with abnormal thyroglobulin levels. Its presence on a diagnostic or posttherapy scan may lead to further evaluation with other imaging modalities and may also change patient follow-up protocols. There are reports on false-positive physiologic and pathologic radioiodine uptake. Therefore, it is essential to recognize conditions causing false-positive radioiodine scans. The most commonly reported physiologic causes of mediastinal uptake are esophageal retention of salivary secretion and uptake by an hyperplastic or normal thymus gland [1, 2].
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The Na(?)/I(-) symporter (NIS) is a cytoplasmic membrane protein mediating the active transport of iodide into the thyroid gland, the first step in thyroid hormone biosynthesis. The same symporter is also responsible for iodide transport into salivary glands, gastric mucosa and breast tissue. Depending on the time interval between radioiodine administration and scintigraphic imaging, physiologic radioiodine uptake on whole-body radioiodine scans can be observed in iodine concentrating, excreting or metabolizing organs. Within the thyroid gland, radioiodine becomes concentrated in the functioning thyroid cells. Under the influence of thyroidstimulating hormone (TSH), it is metabolized into thyroxine which is released into the circulation as required. Thyroxine is predominantly bound to thyroxine binding globulin in the circulation. This circulating protein-bound iodine is described as organic as opposed to the inorganic free iodine. Circulating radioiodine can either be due to protein-bound thyroid hormone, labeled thyroglobulin (Tg) or free radioiodine. Although blood pool activity, when significant, can be seen on large vessels as external iliac artery, its mild– moderate degrees can only be delineated on cardiac outline. Therefore, in this study, physiologic blood pool activity which is referred to as cardiac blood pool (CBP) activity and its presence on initial and subsequent postthyroidectomy high-dose scans were evaluated. Its effect on the interpretation of radioiodine scans and its association with residual thyroid tissue (RTT), thyroglobulin levels, and the presence of local or distant metastases were analyzed.
remnant ablation. The remaining 68 patients had one of the following: extracapsular invasion, lymph node (LN) metastases, distant metastases or significantly elevated Tg levels that were more than 50 ng/ml. The dose range in this group was 125–175 mCi. In patients receiving radioiodine postthyroidectomy, the time interval between operation and radioiodine administration ranged between 30 and 75 days. The study was a retrospective evaluation of postthyroidectomy radioiodine scans. Since majority of our patients were referred from other hospitals for getting radionuclide therapy only, followup data were not available for more than half of the patients.
Methods
Imaging
The experiments comply with the current laws of Turkey, inclusive of Ethics approval.
Whole-body I-131 scans were performed routinely on day 7 after oral administration of radioiodine in all patients. Serial images were acquired on subsequent days as necessary. A two headed gamma camera (Siemens, e.cam) equipped with high-energy collimator was used for image acquisition. The energy peak was 364 keV with a 20 % window. In addition to whole-body images, static images of head/neck, thoracal/abdominal regions and pinhole thyroid images were acquired. Scans were inspected visually for CBP activity and the presence of uptake in RTT, mediastinum, esophagus, and liver. In scans with CBP, general whole-body background activity was compared to that of scans without CBP and posttherapy scans. The degree of uptake in RTT was graded visually as mild (m), moderate (M) and significant (S). Whenever CBP activity was detected on visual inspection, its intensity was graded as mild (1), moderate (2), and significant (3).
The study group For evaluating cardiac blood pool activity, whole-body radioiodine scans acquired at following clinical settings were used: Postablation scans (group 1) This group consisted of 186 patients with differentiated thyroid carcinoma who had their first postthyroidectomy high-dose scan after total thyroidectomy. These scans are referred to as postablation scans. None of the patients had renal or hepatic failure. Out of 186 patients, 118 had 100 mCi Iodine-131 (I-131) for residual thyroid
Posttherapy scans (group 2) This group consisted of 32 patients receiving their second or third high-dose radioiodine. The dose range in this group was 150–225 mCi. Among 32 scans, 15 were from patients with thyroglobulin elevation only (C10 ng/ml) and 17 from patients with known local or distant metastases. Among this 17 scans, 4 belonged to patients who had undergone second operation due to recurrent LN metastases that was confirmed with biopsy. Patient preparation All subjects had TSH, Tg and anti-thyroglobulin (AntiTg) blood level determination 1 day before radioiodine administration. Thyroid hormone withdrawal and iodinerestricted diet were continued for at least 2 weeks before hospitalization.
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Table 1 Clinical, laboratory and radioiodine imaging findings in patients with and without cardiac blood pool activity on postablation scans Tga
AntiTg (?)b
(-)
(?)
CBP (?) (n = 61)
1
57
3
CBP (-) (n = 113)
56
50
7
Mean Tgc
Residual thyroid tissue (-)
m
M-S
32.1 ± 20.2
0
13
48
8.1 ± 7.3
7
73
33
This table consists only of patients from group 1. Patients with distant metastases were not included in CBP (-) group CBP cardiac blood pool, m mild, M moderate, S significant a
Tg (-): \3 ng/ml; Tg (?) C3 ng/ml
b
AntiTg (?): C20 IU/ml
c
Tg values are in ng/ml as mean ± standard deviation
Table 2 Cardiac blood pool activity and Tg in patients with local and distant metastases on postablation scans Local metastases (n = 40) CBP (?) CBP (-)
Distant metastases (n = 12)
20 20 Tg (?)
Tg (-)
20
12
Tg (?)
Tg (-)
Tg (?)
Tg (-)
7
10
10
2
This table consists only of patients from group 1 CBP cardiac blood pool Tg (-): \3 ng/ml; Tg (?) C3 ng/ml
Statistical analysis The mean Tg values were expressed as mean ± SD. Differences in score values in postablation and posttherapy scans were analyzed by using Mann–Whitney U test for independent data and Student t test for paired data. p value less than 0.05 was considered significant. Thyroglobulin level in patients with increased AntiTg was not included in the final analysis of mean Tg determination.
Results All patients had TSH [30 lIU/ml at the time of radioiodine administration. Thyroglobulin was considered to be elevated when it was C3 ng/ml under stimulation. Postablation scans (group 1) Linear or irregular activity pattern thought to be due to esophagus was detected in 8 patients (4 %). Mild focal
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uptake thought to be due to thymus was observed in only one patient. The results in patients with and without CBP are summarized in Tables 1 and 2. Patients with CBP Among 186 patients, CBP activity was detected in 61 radioiodine scans (33 %). Out of 61 patients, 41 were given a radioiodine dose of 100 mCi and the remaining 20 patients were treated with higher doses. A moderate to significant degree of CBP activity was detected in a total of 22 patients (Fig. 1). Cardiac blood pool activity in the remaining 39 patients was of a mild degree. In 11 patients with grade 3 CBP activity and in 7 of 11 patients with grade 2 CBP activity, blood pool could also be detected on large vessels as external iliac artery. On posterior thoracic images, CBP appeared as diffuse uptake on lower left lung region (Fig. 2). Seven patients with grade 2–3 CBP activity had serial thoracic images taken on the consecutive days which revealed no significant difference in CBP activity on serial scans (Fig. 2). Three patients with grade 3 CBP activity had a second treatment dose within the following 2 years due to persistently elevated Tg levels. Residual thyroid uptake was detected in all patients with CBP. A moderate-significant RTT was present in 48 patients (79 %). All patients except one with grade 2–3 CBP activity exhibited a moderate-significant RTT. A significant correlation existed between the intensity of uptake and the presence of CBP (p \ 0.05). All patients with CBP activity except one had increased Tg levels. Three patients had increased AntiTg levels. In the remaining 57 patients, a significant correlation existed between the intensity of CBP activity and Tg level (p \ 0.05). The mean Tg in patients with CBP was 32.1 ± 20.2 ng/ml. Twenty patients had metastatic lymph nodes. All patients with LN metastases in this group had increased Tg levels. Patients without CBP Among the remaining 125 patients without CBP activity, 20 had LN metastases and 12 had distant metastases with or without LN metastases. None of the patients with distant metastases had CBP. Four patients with distant metastases had moderate-significant RTT. Out of 20 patients with LN metastases, Tg was normal in 10 patients and increased in 7 patients; three subjects had increased AntiTg levels. Among patients with a LN metastases having a normal Tg, 5 had multicenter disease. Among patients with distant metastases, 2 patients with diffuse lung uptake had Tg \ 3 ng/ml, one patient with bone metastases had a Tg level of 9.2 ng/ml, 8 patients with multifocal lung
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Fig. 1 The relation between RTT and CBP. a, c Whole-body image and spot views in a 38-year-old male patient with papillary thyroid carcinoma and LN metastases who had 150 mCi radioiodine postthyroidectomy. There is a significant RTT with grade 3 CBP activity. Thyroglobulin was 31 ng/ml. b, d Whole-body image and
spot views in a 42-year-old female patient with papillary thyroid carcinoma who had 100 mCi radioiodine postthyroidectomy. There is a moderate degree of RTT with a grade 2 CBP activity. Thyroglobulin was 16.9 ng/ml. In both patients, blood pool activity can also be observed on external iliac and femoral arteries
metastases and one patient with multifocal skeletal metastases had a Tg level [50 ng/ml. Excluding the patients with distant metastases, 56 patients (10 with LN metastases) had normal and 50 patients (7 with LN metastases) had increased Tg levels in CBP negative patient group (50 and 44 %, respectively). The mean Tg in these 50 patients was 8.1 ± 7.3 ng/ml. The mean Tg in patients without CBP was significantly lower than those with CBP (p \ 0.05). A total of 7 patients (3 with LN metastases) had increased AntiTg levels.
Residual thyroid uptake could not be detected in 7 patients. A moderate-significant RTT was detected in 33 patients (29 %). Posttherapy scans (group 2) None of the patients in this group had cardiac blood pool activity. Among 32 scans, mild residual thyroid uptake was detected in 2 patients. On visual inspection, general wholebody background activity was lower than that of group 1
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Fig. 2 Serial CBP activity on thoracic images. Anterior and posterior thoracic spot views taken on days 7 (a) and 8 (b) after 100 mCi radioiodine administration in a 36-year-old female patient with papillary thyroid carcinoma. There is a grade 2 CBP activity together with a mild bilateral slightly asymmetric physiologic mammary uptake. On posterior thoracic images, CBP appears as mild diffuse left lower lung uptake. No significant change in CBP can be observed on the serial scan
patients with CBP activity (Fig. 3). All patients except 3 had increased Tg levels at the time when the therapy dose was administered. The mean Tg in the posttherapy patient group was significantly higher than that of group 1 patients with CBP activity (p \ 0.05). Patients with normal Tg were among those who had been reoperated due to recurrent local LN metastases. Metastatic foci on radioiodine imaging could be detected in 16 scans. In this group, one patient had a suspected esophageal retention of activity.
Discussion Radioiodine uptake on thoracic images in a patient with thyroid carcinoma can be due to pulmonary, skeletal or mediastinal metastases. Various conditions have been reported to cause false-positive radioiodine uptake in the chest area. The most commonly reported cause is physiologic retention of salivary secretions by a normal or abnormal esophagus. Retention in a normal esophagus can be focal, diffuse or linear in pattern and has a tendency to disappear or change location on delayed images. Salivary retention was also reported to occur in abnormal esophagus due to decreased esophageal motility, achalasia, esophageal stricture and Zenker’s diverticulum (1). Uptake in a normal or hyperplastic thymus was also reported (2). It was shown that with higher radioiodine doses, diffuse or dumbbell-shaped physiological thymic uptake was common in young patients. Thymic activity was more apparent on the 7-day scan compared to the scan obtained at 3–4 days. In our study, the incidence of both esophageal
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and thymic uptake was lower compared to CBP activity. Other frequently reported causes of physiologic mediastinal radioiodine uptake are accumulation by the lactating and nonlactating breast, foci of ectopic thyroid tissue, and displaced gastric mucosa. External contamination of skin and/or garment with body secretions is another well-known cause of false-positive findings. The most commonly reported causes for false-positive nonphysiological mediastinal radioiodine uptake are tumors of nonthyroidal origin, infection, and pericardial effusion. Mild to moderate diffuse liver uptake indicating functioning thyroid remnant can be detected on posttherapy I-131 whole-body scans. This activity was thought to be mainly due to the metabolism of labeled thyroid hormones and/or Tg in the liver. Diffuse liver uptake was shown to be more common in high-dose I-131 administrations and in patients with remnant thyroid tissue [3]. In patients without residual thyroid tissue, Tg was thought to be responsible for hepatic visualization. Liver uptake without uptake by the thyroid or metastases on whole-body scan was suggested to be due to hidden metastases [4]. The authors speculated that Iodine-131 was first taken into metastatic cells and subsequently washed out as forms of Iodinelabeled-Tg and organic components which eventually accumulated in the liver. They suggested earlier wholebody imaging to be potentially helpful in detecting metastatic lesions in these cases. It has been reported that radiation can cause inhibition of the organification pathway before the I-131 accumulating faculty is damaged [5]. A positive scan for RTT may indicate the presence of functioning thyroxine forming
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Fig. 3 Postablation and subsequent posttherapy images in the same patient. a Whole-body image and spot views in a 42 year female patient with papillary carcinoma and LN metastases who had 150 mCi radioiodine postthyroidectomy. There is a grade 1 CBP activity, a significant uptake in RTT, and accumulation in LN metastases. Thyroglobulin was 12.6 ng/ml. b Whole-body image of
the same patient taken after 200 mCi radioiodine administration 1 year after the first study owing to a further increase in Tg level. There is significant uptake in left middle cervical and mild uptake in right lower cervical LN. In spite of an increased dose and higher Tg levels compared to the first study, there is no CBP activity
tissue or if further iodine synthesis is blocked it can only be due to the accumulation of iodide. Hammersley et al. evaluated the value of serial protein-bound iodine (PBI) measurements in patients with thyroid carcinoma treated with radioiodine [6]. PBI was measured between days 1 and 6 post-radioiodine administration and evaluated together with the results of the whole-body scan performed on day 3. It was shown that 92 % of patients with a falling PBI had negative scans and 78 % with a rising PBI showed positive scans for the presence of RTT. A falling PBI indicated a small volume of functioning thyroid tissue. Thus, they suggested PBI assay as a useful method of quantifying the absorbed dose from I-131 therapy. A small number of patients in this study also had a falling PBI in spite of a positive scan. In the current study, CBP was most commonly observed in patients with moderate-significant RTT and consequently whole-body background activity appeared to be higher in these patients. Since we did not get earlier scans and serial daily scans in all patients, we do
not know whether CBP increases or decreases with time. However, in a small number of patients, CBP did not change significantly beyond 7th day scan. The absence of CBP on posttherapy scans raises the possibility of a lower total radiation dose despite higher administered doses owing to the absence of a residual thyroid tissue. The radiation absorbed dose to the blood was considered to be a significant indicator of ablation success in several studies. In one study, the data from quantification of blood samples, whole-body probe measurements and whole-body scans were used to deduce retention curves for blood and whole body [7]. A correlation was found between residence time of radioiodine in blood and fractional uptake into thyroid remnant. In one study, absorbed dose to the blood was found to be a better predictor of ablation success than the administered radioiodine activity [8]. In that study, 14 % of the whole-body residence time was attributed to the blood. These authors assumed that the residence time of I-131 in the blood is a likely measure of the amount of
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I-131 that is available for uptake by thyroid remnant tissue and thus the radiation absorbed dose to the target tissue. However, the results of our study suggest that blood residence of radioiodine is a measure of the amount of RTT and is not an indication of free radioiodine available for uptake by the thyroid. This may also indicate that percentage of blood pool activity differs from patient to patient depending on the amount of RTT. Thyroglobulin is a thyroid-specific protein that is produced by normal thyroid cells, by benign thyroid conditions, and by functioning thyroid cancer metastases. Serum Tg levels should fall to near zero after total thyroidectomy if there is no significant normal thyroid tissue or residual malignant thyroid tissue. The measurement of serum Tg is now the standard procedure in the follow-up of differentiated thyroid carcinoma and is being utilized as a prognostic tool. Rising Tg levels after thyroidectomy and radioiodine ablation indicates disease recurrence. The first Tg measurement after total thyroidectomy is usually not considered to be of value as an indicator of metastatic disease since it may be influenced by TSH stimulation and the amount of residual normal thyroid tissue. However, several studies emphasized its prognostic importance. A first Tg value of more than 69.7 ng/ml was shown to be predictive of metastases in 90 % of cases and administering a higher ablation dose was suggested in order to have a therapeutic effect [9]. In our study, patients with CBP activity had significantly higher Tg level compared to those without CBP. However, this does not necessarily imply that it is due to labeled Tg in the blood. Since Tg is closely associated with residual thyroid mass, the association between Tg and early postthyroidectomy CBP activity is most probably due to labeled thyroid hormones that are secreted from RTT. The absence of blood pool activity despite elevated Tg levels and higher radioiodine dose in posttherapy scans supports this hypothesis. If blood pool activity would be due to free radioiodine, then it would be expected to be higher in patients with less RTT and in posttherapy scans. Since follow-up data were not available in our study, no information can be provided regarding the prognostic implication of CBP on a postablation scan. In a recent review of false-positive uptake on radioiodine whole-body scan, previous reports due to localized blood pool activity in individual cases of thoracic aortic aneurysm, pectus excavatum, and dilated venous activity were cited [10]. The results of the current study have shown that CBP activity can be observed on postablation scans obtained after total thyroidectomy. This type of uptake appeared to be the most common physiologic mediastinal uptake. In its mild–moderate degrees, it does not possess diagnostic consideration. When significant CBP exists, this activity appears as diffuse radioiodine
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uptake on lower left lung region on posterior thoracic images. Since pulmonary metastases are mostly diffuse in nature, the presence of a significant CBP should be ruled out when interpreting thoracic images. This exclusion may be more important when CBP activity is accompanied with bilateral mammary uptake in female patients. The presence of CBP correlated with the intensity of residual thyroid uptake and had a significant association with increased postoperative Tg levels. It was thought to be due to labeled thyroid hormones. The presence of CBP on a postablation scan might imply a high level of blood radiation dose. The absence of CBP activity in posttherapy scans despite elevated Tg levels can be an evidence that metastatic thyroid tissue is capable of producing Tg, but not thyroid hormones. The prognostic significance of grade 3 CBP and the absence of CBP in the presence of a significant RTT need to be determined.
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