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Implications of mediastinal uptake of 131I with regard to surgery in patients with differentiated thyroid carcinoma
Article first published online: 24 NOV 2004
Copyright © 2004 American Cancer Society
Volume 103, Issue 1, pages 59–67, 1 January 2005
How to Cite
Haveman, J. W., Phan, H. T. T., Links, T. P., Jager, P. L. and Plukker, J. T. M. (2005), Implications of mediastinal uptake of 131I with regard to surgery in patients with differentiated thyroid carcinoma. Cancer, 103: 59–67. doi: 10.1002/cncr.20725
- Issue published online: 17 DEC 2004
- Article first published online: 24 NOV 2004
- Manuscript Accepted: 9 SEP 2004
- Manuscript Revised: 26 AUG 2004
- Manuscript Received: 10 JUN 2004
- 131I uptake
Findings of mediastinal uptake of 131I after surgical treatment for differentiated thyroid carcinoma (DTC) are common, especially in young patients. Given the frequency of false-positive findings, a protocol for diagnostic and therapeutic strategies would be useful. With the goal of accurately selecting management strategies, the authors analyzed their data and data found elsewhere in the literature for correlations with the incidence of mediastinal 131I uptake and with treatment for patients exhibiting such 131I uptake.
All patients with DTC who were treated between 1978 and 2000 at Groningen University Hospital (Groningen, The Netherlands) and who received adjuvant 131I ablation therapy were included in the current analysis, which involved retrospective review of all relevant data.
Five hundred four patients with DTC initially underwent total thyroidectomy, with additional 131I ablation performed for 489 of these patients. In 48 of 489 patients (9.8%), 131I uptake was seen in the mediastinum on a posttreatment scan. Analysis of those 48 patients and of cases in the literature demonstrated that serum thyroglobulin levels, risk status, and the presence of thymus on radiologic images were important in the surgical decision-making process.
Mediastinal uptake of 131I on posttreatment scans was found in approximately 10% of patients after total thyroidectomy for DTC. Based on the current data and the data presented in the literature, the authors developed a flow chart for determining appropriate treatment strategies, which included mediastinal dissection for high-risk patients and for patients with serum thyroglobulin levels > 10 ng/mL. Cancer 2005. © 2004 American Cancer Society.
Total thyroidectomy followed by 131I ablation generally is recommended for the initial treatment of patients with differentiated thyroid carcinoma (DTC).1, 2 After the administration of an ablative dose of 131I, follow-up consists of regular serum thyroglobulin (Tg) measurements and 131I whole-body scans (WBS). In this manner, previously undetectable foci of 131I uptake outside the thyroid bed can be identified. On posttreatment radioiodine scans, mediastinal 131I uptake is reported in up to 26% of patients, and it is even more common among younger patients.3, 4 However, false-positive mediastinal uptake of 131I has been reported frequently.3–6 Physiologic mediastinal/thoracic uptake of 131I can be observed in the thymus, in the area of bronchiectasis, in tuberculosis, in breast tissue, in swallowed radioactive saliva, and in reflux of radioactive gastric fluid.7–13 Mediastinal uptake of 131I can lead to unnecessary doubt about tumor recurrence and additional 131I therapy, with a possible risk of secondary malignancies.14, 15 Furthermore, in several reported instances, posttreatment WBS has revealed mediastinal 131I activity that, on subsequent surgical exploration, was found to be attributable to physiologic enlargement of the thymus.5, 16–20 Without appropriate guidelines, it is difficult to obtain a consensus regarding diagnostic and therapeutic strategies for patients with mediastinal uptake of 131I. Therefore, we performed a retrospective analysis of patients with DTC and mediastinal uptake on posttreatment 131I scans and reviewed the literature to establish an appropriate treatment strategy.
MATERIALS AND METHODS
Between 1978 and 2000, 504 patients with DTC were referred to the Department of Endocrinology at the Groningen University Hospital (Groningen, The Netherlands) for adjuvant radioiodine treatment. All patients received 131I ablation of residual thyroid tissue after surgical treatment. After obtaining approval from the ethics board at our institution, we collected data from clinical and pathologic reports. All available 131I scans were reevaluated by a panel of experienced nuclear medicine specialists.
Surgery typically consisted of total thyroidectomy with or without additional lymph node dissection. Clinically suspicious cervical lymph nodes were confirmed by preoperative cytologic or intraoperative frozen section examination. Patients with proven metastases underwent selective neck dissection of region II–V (according to Robbins et al.21), including the lymph nodes along the jugular chain, the tracheoesophageal grooves, and the posterior triangle of the neck.
Between 1978 and 1991, an ablation dose of 50 millicuries (mCi) 131I was used. After 1991, low-risk patients were treated with a fixed dose of 50 mCi 131I, and all high-risk patients received a fixed dose of 150 mCi 131I (Fig. 1). Low-risk patients included individuals age < 40 years with T0–T3 papillary thyroid carcinoma and without distant metastases as well as individuals with intrathyroid follicular carcinoma or Hürthle cell carcinoma without lymph node or distant metastases. High-risk patients included individuals age ≥ 40 years who had extrathyroid carcinoma (T4), follicular or Hürthle cell carcinoma accompanied by lymph node metastases (N1), or distant metastases (M1). Ten days after administration of the ablation dose of 150 mCi 131I, a posttreatment WBS was obtained to assess the completeness of ablation treatment. Completeness was assessed once more 3 months after ablation, during hypothyroidism, with a routine diagnostic dose of 2 mCi 131I and a WBS obtained 48 hours later. In high-risk patients with negative diagnostic WBS findings, a diagnostic dose of 10 mCi 131I was administered on the same day, and a second diagnostic WBS was performed 72 hours later. In patients with positive findings on either of these 2 diagnostic WBS, a fixed dose of 150 mCi 131I was administered the next day, and a posttreatment scan was obtained 10 days later. Ablation was considered successful if no uptake was present on the 2 mCi diagnostic WBS and/or the 10 mCi diagnostic WBS and if serum Tg levels were < 1.5 ng/mL. In patients who had negative 2 mCi or 10 mCi WBS findings and detectable Tg levels, a fixed dose of 150 mCi was administered, and WBS was performed 10 days later. When posttreatment scans showed uptake of 131I, further images were obtained to determine whether additional therapy was necessary. In patients with Tg antibodies, additional magnetic resonance images (MRIs) of the neck and mediastinum were obtained to exclude the possibility of local recurrence.
Diagnostic validation of 131I uptake in the upper mediastinum consisted of computed tomography (CT) or MRI scans. In low-risk patients with thymus enlargement on concomitant imaging, no therapeutic intervention was initiated, whereas patients in the high-risk group received an additional dose of 150 mCi 131I. Mediastinal dissection was carried out if radiographic findings were consistent with the presence of mediastinal lymph node metastases. Patients with aggressive or dedifferentiated disease underwent palliative treatment, which typically consisted of external radiation therapy.
Patients were considered free of disease if there were no clinical or biochemical signs of recurrence (i.e., Tg < 1.5 ng/mL accompanied by negative diagnostic and [if available] posttreatment scans) 2 weeks after the discontinuation of thyroid hormone suppression. If posttreatment or diagnostic 131I scans were unavailable, then freedom from disease was defined as the absence of clinical or biochemical signs (Tg < 1.5 ng/mL) of recurrent disease for at least 6 months during thyroid hormone suppression therapy (Tg-on). During follow-up, a suppression dose of levothyroxine was administered, and Tg-on measurements and physical examinations of the neck were performed yearly. In patients with detectable Tg levels, a diagnostic 131I WBS was obtained using a two-headed gamma camera (Multispect 2; Siemens, Hoffman Estates, IL) equipped with a high-energy collimator.
Serum Tg levels and thyroid-stimulating hormone (TSH) levels were measured at ablation during hypothyroidism, just before administration of the therapeutic 131I dose. Between 1978 and 1984, serum Tg levels were measured using a localized radioimmunoassay. Between 1984 and 1989, a commercially available radioimmunoassay (Cis Bio International, Gif-sur-Yvette, France) with a detection limit of 3.0 ng/mL was used. In 1989, the detection limit of this radioimmunoassay was decreased further, to 1.5 ng/mL. Tg levels measured before 1989 were converted to allow comparison with serum Tg concentrations measured using the post-1989 radioimmunoassay (new (ng/ml) = ; this conversion algorithm was validated in our laboratory. If serum Tg levels were undetectable, then the presence of Tg antibodies was evaluated by recovery of added standard Tg to the patient's serum sample. Serum TSH levels were measured using a chemiluminescence-based immunoassay (Amersham, Little Chalfont, United Kingdom) with reference values ranging from 0.3 to 5.0 milliunits per liter.
Data are presented either as median values with interquartile ranges (IQRs) or as patient counts. To identify individual patients in the current study, we assigned each patient a unique number, which is used throughout the text, tables, and figures.
The characteristics of the 504 patients with DTC are summarized in Table 1. The mean duration of follow-up was 9 years. Nearly 40% of patients were followed for > 10 years, with a 10-year overall survival rate of 83% and a disease-free survival rate of 72%. Four to 6 weeks after surgery, 489 patients (97%) received ablative treatment with 131I, which had a success rate of 85%.
|Characteristic||Total group (n = 504)||131I uptake in the mediastinum (n = 48)|
|Median age in yrs (IQR)||46 (33–61)||41 (26–57)|
|Female||375 (74)||25 (52)|
|Male||129 (26)||23 (48)|
|Lymph node dissection (%)||108 (21)||21 (44)|
|Papillary carcinoma||306 (61)||34 (71)|
|Follicular carcinoma||170 (34)||11 (23%)|
|Hürthle cell carcinoma||28 (6)||3 (6)|
Forty-eight of 489 patients (9.8%) had 131I uptake in the upper mediastinum on a posttreatment WBS. The group included 25 female patients and 23 male patients with a median age of 41 years (IQR, 26–57 years) (Table 1). Tg antibodies were not found in any of those patients. Sixteen patients (33%) had only mediastinal uptake of 131I, and 32 patients also had 131I uptake outside the mediastinum (Tables 2, 3).
|Tg status||No. of patients (%)|
|131I uptake only in the mediastinum||131I uptake outside the mediastinum|
|Tg-off < 1.5 ng/mL||4 (25.0)||4 (12.5)|
|Tg-off, 1.5–10 ng/mL||10 (62.5)||7 (21.9)|
|Tg-off > 10 ng/mL||2 (12.5)||21 (65.6)|
|Patient no.||Age (yrs)||Gender||Tumor type||Persistent 131I uptake outside the mediastinum||S or M uptakea||Tg dose before therapy (ng/mL)||Total 131I treatment (mCi)b||Disease status||Follow-up (yrs)c|
|21||70||Female||Papillary||Neck, lung, bone||S||1.7||600||MD, LRd||1.3|
|37||50||Male||Papillary||Neck, lung, bone||M||68||RTx, 150||MD, LRd||0.7|
|43||60||Female||Follicular||Neck, lung, bone||M||416||RTx, 1200||MDd||0.2|
|48||57||Female||Follicular||Neck, lung, bone||S||3120||600||MDd||1.1|
Mediastinal Uptake Only
In 4 of the 16 patients (Patients 1–4) with mediastinal uptake only, Tg was not detectable at the time of the diagnostic 131I scan (Fig. 2). In all of those patients, the 131I uptake pattern seen on a diagnostic WBS was consistent with physiologic enlargement of the thymus, which was confirmed by MRI or CT studies. Treatment of those patients consisted of inhibition of TSH secretion by thyroid hormone suppression (target TSH level, 0.03–0.3 milliequivalents per liter) without performing additional surgery or radioiodine treatment during follow-up. The median duration of follow-up in those patients was 8.6 years (range, 8.3–8.9 years), and all were free of disease at last follow-up.
The 10 patients who had only mediastinal uptake had Tg levels ranging from 1.5 to 10 ng/mL. In three low-risk patients (Patients 5–7), CT or MRI revealed an enlarged thymus, a finding that was compatible with the 131I uptake pattern observed on WBS. Those 3 patients did not require additional treatment, and they remained free of disease for 2 years, 4 years, and 8 years, respectively. Four other patients (Patients 8–11) received radioiodine treatment at a median dose of 150 mCi (range, 150–300 mCi). The retrospectively reviewed WBS was inconclusive in one low-risk patient (Patient 8) and revealed thymus enlargement in the other three patients (one low-risk patient [Patient 9] and two high-risk patients [Patients 10 and 11]). The MRI obtained after 131I therapy was normal in all four patients. Those 4 patients were free of disease after 2 years, 4 years, 6 years, and 24 years, respectively. Three other patients (Patients 12–14) had MRIs that showed possible recurrent disease near the thymus, and those patients underwent subsequent mediastinal dissection. Histologic examination revealed normal hyperplasia of the thymus in two of those three patients (Patients 12 and 14) and thyroid follicle–like structures in cystic Hassall bodies (Patient 13) in the other patient. All of those patients were free of disease after a median follow-up of 4.2 years (range, 1.6–12.8 years). Retrospective analyses of their WBS studies revealed findings that were consistent with thymus enlargement in 2 patients (Patient 13 [age, 12 years] and Patient 14 [age, 55 years]). For the other patient (Patient 12 [age, 39 years]), an 131I scan was not retrievable for analysis.
Two high-risk patients (Patients 15 and 16) had only uptake of 131I in the mediastinum and had Tg levels > 10 ng/mL. In 1 patient (Patient 15), the results of WBS and MRI were inconclusive, and after treatment with 300 mCi 131I, mediastinal uptake disappeared. However, 10 years later, the Tg-on level remained elevated (20 ng/mL), and the patient was without clinical evidence of recurrent disease. In the other patient (Patient 16), who had a Tg level of 615 ng/mL, WBS and MRI results confirmed the possible presence of mediastinal lymph node disease, and the patient subsequently underwent mediastinal dissection followed by 131I treatment (150 mCi). Histologic examination revealed recurrent papillary thyroid carcinoma, and the patient has remained free of disease for > 4 years.
Mediastinal and Extramediastinal Uptake
Thirty-two patients (64%) also had uptake of 131I outside the mediastinum (Tables 2, 3). Four of those patients (Patients 17–20) had Tg levels < 1.5 ng/mL with persistent uptake of 131I after total thyroidectomy in the neck and thymus that disappeared after radioactive treatment (at 131I doses of 150 mCi, 300 mCi, 300 mCi, and 450 mCi, respectively). At last follow-up, all 4 patients were free of disease (after 2 years, 4 years, 4 years, and 7 years, respectively).
The characteristics of the 28 patients who had mediastinal uptake of 131I and uptake outside the mediastinum with Tg > 1.5 ng/mL also are presented in Table 3 (Patients 21–48). Treatment of these patients was based on the existence of extramediastinal uptake of 131I. The median survival for these patients after the acquisition of positive WBS findings was 2.8 years (range, 1.0–11.6 years). Patients who had 131I uptake in the mediastinum and neck often had a relatively favorable prognosis, whereas the survival of patients who had bone metastases was poor. Nine patients underwent mediastinal dissection (Patients 12–14, 16, 30, 36, 38, 44, and 47).
Based on these data, we developed a flow chart outlining a protocol for treating patients with mediastinal 131I uptake (Fig. 3). In retrospect, eight patients were not treated according to this protocol. Two low-risk patients (Patients 8 and 9) with uptake in the mediastinum only who had Tg levels of 7.1 ng/mL and 9.9 ng/mL, respectively, were treated with 150 131I. WBS images revealed thymus enlargement or possible recurrence, and MRI revealed thymus enlargement in both of these patients. Four patients (2 high-risk patients [Patients 18 and 20] and 2 low-risk patients [Patients 17 and 19]) who had uptake of 131I in the thymus and neck and Tg < 1.5 ng/mL received 131I treatment at doses of 150 mCi, 300 mCi, 300 mCi, and 450 mCi, respectively. Thymus enlargement was observed on MRI in those patients. At the time of the study, we considered it acceptable not to treat these patients and either to repeat the WBS, as suggested by Baudin et al.,22 or to perform ultrasonography of the neck.23 Two patients (Patients 12 and 13) underwent mediastinal dissection, and their pathology reports revealed the presence of thymus tissue only. In retrospect, mediastinal dissection was not necessary for either patient. In the first low-risk patient (Patient 13 [age, 12 years; Tg level, 10.0 ng/mL]), MRI and positron emission tomographic scans revealed a structure above the enlarged thymus that was suspicious for recurrent disease, and this finding was compatible with the hotspot identified on the WBS. Histologic examination showed a thyroid follicle–like structure in cystic Hassall bodies and no evidence of recurrent disease. In the other low-risk patient (Patient 12 [age, 39 years; Tg level, 9.0 ng/mL]), MRI revealed an enlarged mass in the mediastinum that was compatible with the spot found on the WBS. Histologic examination showed hyperplasia of the thymus without evidence of recurrent disease. Although there was doubt regarding etiology, we elected to perform surgery in both patients because of elevated serum Tg levels. Thymus enlargement was considered unlikely in the 39-year-old patient, and MRI findings were highly suggestive of recurrent disease in the 12-year-old patient. It is noteworthy that in both patients, 131I uptake in the mediastinum and the presence of Tg were undetectable after surgery.
In the current study, mediastinal 131I uptake was found in 48 of 489 patients (9.8%) after total thyroidectomy for DTC. Our survey illustrated that serum Tg levels, patient risk status, and the presence of thymus on radiologic images were important (clinical) parameters in the surgical decision-making process. In the absence of practical guidelines for patients with postoperative mediastinal 131I activity, we developed a flow chart based on our experience and on data in the literature to assist clinicians in dealing with this problem (Fig. 3).
The current literature concerning mediastinal 131I uptake after surgical treatment for DTC includes only small series and case studies (Table 4). Data from those series, although limited, suggest that our protocol may be useful. According to those data, pathologic examination of the resected specimen revealed the presence of thymus in only one patient with elevated Tg levels. This patient, who was reported on by Alibazoglu et al.,20 was a woman age 54 years with a Hürthle cell carcinoma (high-risk) who also had histologically proven retrolaryngeal metastases, which probably increased her serum Tg level significantly. In a patient described by Michigishi et al.,19 a 19-year-old female with Tg antibodies, the thymus was removed but did not contain metastatic thyroid tissue; this patient also underwent therapeutic neck dissection for metastatic papillary thyroid carcinoma. Reports from the literature3–6, 16–20, 24–26 illustrate that our protocol can be useful in the treatment of patients with DTC and 131I uptake in the mediastinum after initial adequate surgical treatment. Furthermore, retrospective analysis of these patients and our own series suggests that for most patients, thymectomy is avoidable. However, for patients who have antibodies against serum Tg, the decision is more complicated and depends primarily on radiologic imaging studies and individual risk stratification.
|Study||No. of patients with uptake of 131I in the thymus/total no. of patients||Age (yrs)||Male gender (%)||Tg before treatment (no. of patients)||Treatment|
|Jackson et al., 19795||2/44||24, 43||1 (50)||NA||Thymus removed, no evidence of thyroid carcinoma|
|Ramanna et al., 19856||10/85||NA||NA||< 1.5 ng/mL (7), 28 ng/mL (1), 30 ng/mL (1), > 100 ng/mL (1)||Unknown, ectopic thyroid tissue suggested in the 7 patients with Tg < 1.5 ng/mL|
|Greenler et al., 198924||1/NA||20||0 (0)||Antibodies present||Follow-up|
|Michigishi et al., 199319||2/NA||19, 25||1 (50)||Antibodies present and 270 ng/mL in patients with metastases||Thymus removed, no evidence of thyroid carcinoma; LND|
|Bestagno et al., 199317||2/NA||15, 29||1 (50)||NA and ‘very low’||Thymus removed, no evidence of thyroid carcinoma|
|Muratet et al., 199625||1/NA||22||0 (0)||‘Low’||Follow-up, CT scan confirmed presence of thymus|
|Veronikis et al., 199618||2/NA||20, 21||2 (100)||0.8 ng/mL and antibodies present||Thymus removed, no evidence of thyroid carcinoma|
|Vermiglio et al., 199616||1/NA||14||1 (100)||NA||Thymus removed, no evidence of thyroid carcinoma|
|Salvatori et al., 199726||1/NA||28||0 (0)||2 ng/mL||Follow-up|
|Wilson et al., 19983||10/38||20–85||3 (30)||< 1 ng/mL (7; 1 dose ‘raised’ with metastases)||Nine patients received 131I therapy, including two with pulmonary metastases|
|Alibazoglu et al., 199920||1/NA||54||0 (0)||‘Elevated’||Thymus removed, no evidence of thyroid carcinoma after positive PET scan and MRI|
|Davidson and McDougall, 20004||6/175||22–51||0 (0)||NA||Follow-up|
|Current report||48/489||8–83||23 (48)||See Table 2||See Table 3 and Figure 2|
Recurrent disease occurs in 5–20% of patients with DTC and usually presents in the form of thyroid remnants or lymph node metastases, or, in the more aggressive subtypes, as disease in surrounding soft tissue.1, 2, 27–32 Mediastinal uptake of 131I after therapeutic doses of 131I may represent metastatic thyroid carcinoma, which typically necessitates mediastinal dissection. In the current series, nine patients underwent mediastinal dissection to remove recurrent thyroid carcinoma (Fig. 2; Table 3). Three patients (Patients 12–14) underwent surgery for mediastinal uptake of 131I, but no thyroid tissue could be identified. Histologic examination revealed hyperplasia of the thymus or Hassall bodies, as described above. However, 131I uptake and the slight elevation in Tg levels disappeared after surgery in all three patients. It is noteworthy that these findings have also been described by other authors,5, 16–20 suggesting the occurrence of 131I accumulation and Tg production in patients with thymic hyperplasia. Because the thyroid and the thymus are embryologically related organs, these observations may be attributable to ectopic thyroid tissue. Furthermore, ectopic thyroid tissue has been described as an incidental finding in patients without DTC.33, 34 However, ectopic thyroid tissue was not found on thorough histologic examination in the current series or in the other referenced studies.
It is generally believed that mediastinal uptake of 131I is seen only in patients age < 45 years. However, Alibazoglu et al. observed uptake of 131I in the thymus in a woman age 54 years, and there was a 56-year-old patient in the current series. Thus, even in patients age > 50 years, the thymus can lead to 131I uptake and, as a result, unnecessary fear of disease recurrence. Furthermore, despite the involution of the thymus after age 20 years, it still can be seen on CT in 17% of patients age > 49 years.35
Bias may have been a relevant issue in all of the referenced retrospective studies describing patients with mediastinal uptake of 131I after near-total or total thyroidectomy. Because there are no prospective studies dealing with the treatment of patients with DTC, such retrospective studies are useful in terms of gaining a better understanding of clinical problems such as mediastinal uptake of 131I; however, our flow chart requires prospective validation in a multicenter study.
In conclusion, mediastinal 131I uptake after surgical treatment for DTC was observed in 48 of 489 patients (9.8%) on posttreatment WBS. Based on the existing literature and on our experience, the need for surgical intervention depends on several parameters, including serum Tg levels, patient risk status, and radiologic findings from WBS or CT/MRI studies.