1

Introduction

Treatment for patients with differentiated thyroid cancer frequently involves total thyroidectomy followed by ¹³¹ I ablation . After initial treatment, thyroglobulin (Tg) levels are followed to evaluate for recurrent disease . In patients with elevated Tg levels, ¹³¹ I scintigraphy can be utilized to localize recurrences. However, ¹³¹ I scans are negative in 10% to 30% of patients with recurrent thyroid cancer and elevated Tg .

Several studies have reported the usefulness of positron emission tomography with ¹⁸ F-fluorodeoxyglucose- (FDG-PET) to identify ¹³¹ I-negative recurrent disease. The sensitivity of FDG-PET for detection of ¹³¹ I-negative recurrent disease ranges from 63% to 98% . However, there is a paucity of data regarding the outcome of patients who underwent PET to assess for Tg-positive, ¹³¹ I-negative thyroid cancer recurrence. The purpose of this study was to report the clinical outcomes of thyroid cancer patients with elevated Tg and negative ¹³¹ I scintigraphy in relationship to the findings of FDG-PET and additional therapy. We hypothesized that presence and location of FDG uptake would predict for disease outcome.

2

Materials and methods

This retrospective study was approved by the Human Research Protection Office at Washington University School of Medicine. All patients with thyroid cancer who were referred to the Department of Radiation Oncology at Washington University were entered into a prospective tumor registry beginning in 1974. Through 2009, a total of 1712 patients were included in the registry. The original data set was interrogated for patients with thyroid carcinoma of follicular cell origin who were treated with total thyroidectomy and ¹³¹ I ablation, were subsequently found to have elevated serum Tg (> 1 ng/mL) and negative ¹³¹ I scintigraphy, and underwent FDG-PET (first used to evaluate our patients beginning in 1999). Patients with anaplastic thyroid carcinoma and medullary thyroid cancer were excluded. The histology of the patient’s tumors was papillary in 52, follicular variant in 9, insular in 8, tall cell in 4, pure follicular in 2, and poorly differentiated in 1. All patients with positive Tg antibody were excluded. Seventy-six patients meeting these inclusion criteria were identified. The following data were reviewed for these subjects: demographic information, serum Tg levels, FDG-PET findings, history of further surgical treatment or external beam radiation therapy (XRT).

All patients underwent total thyroidectomy followed by ¹³¹ I therapy and post-treatment scintigraphy according to institutional standard practices. Patients were treated with repeated ¹³¹ I administration if the Tg level was elevated and current diagnostic ¹³¹ I scintigraphy was positive. Thyroid hormone replacement was prescribed for all patients, with a goal of achieving a serum thyroid stimulating hormone (TSH) level of < 0.1 μIU/mL. Follow-up consisted of regularly scheduled physical examinations, serum Tg levels, and diagnostic ¹³¹ I scintigraphy (performed with a 185 mBq [5 mCi] adult dosage of ¹³¹ I). If a patient was found to have an unsuppressed Tg level > 1 ng/mL in the setting of negative post-therapy ¹³¹ I scintigraphy, the patient underwent FDG-PET. Conventional FDG-PET was performed in 15 patients; the remaining 61 patients had FDG-PET/CT. In the early years of the study, thyroid hormone was not withdrawn as preparation for FDG-PET. In the later part of the study, FDG-PET was obtained after withdrawal of thyroid hormone or after the patient had been treated with recombinant TSH, in order to achieve a TSH level > 25 μIU/mL (16 patients had TSH < 25 μIU/mL at time of PET). Further surgery or irradiation was performed as clinically indicated. Neck ultrasonography was not routinely performed after negative FDG-PET. Staging was in accordance with AJCC 7th ed.

For PET, patients fasted, except for liberal water intake, for at least 4 h before injection of FDG. The blood glucose level was measured before FDG injection, and was less than 200 mg/dL in all patients. Each patient received 400–610 MBq (11–16.5 mCi) of FDG intravenously, and then rested quietly during the FDG uptake period. PET or PET/CT was initiated approximately 60 min after injection of the FDG. For conventional PET, attenuation correction was performed with segmented transmission data obtained at each bed position with rotating ⁶⁸ Ge/ ⁶⁸ Ga rod sources. For PET/CT, typical parameters for whole-body craniocaudal CT scanning were 120–130 kVp, 80–120 effective mA, and 5-mm collimation. During the CT scan, patients were asked to maintain shallow respiration. Rescaled CT images were used to produce attenuation correction values for the PET emission reconstruction. The PET data acquisition included 4–6 bed positions (2–4 min per bed position depending on body weight) over the same axial extent. PET images were reconstructed using ordered-subset expectation maximization.

Interpretation of all FDG-PET and PET/CT studies was performed in routine clinical fashion by board-certified nuclear medicine physicians. Subjective visual assessment was used in interpretation of FDG-PET images. Any increased FDG uptake was compared with the anatomic findings on CT images. All FDG-PET imaging results (based on the reports of these studies in the medical record) were correlated with the subsequent final histologic diagnosis, findings at surgery, or clinical observation from the time of FDG-PET.

Clinically evident recurrent disease was defined as positive pathology or, if pathology was not available, positive subsequent FDG-PET. Patients were considered disease free despite an elevated Tg in the absence of positive pathology or imaging . Cause-specific survival (CSS) was based on death resulting from thyroid cancer and was calculated from the time of first FDG-PET. Recurrence-free survival (RFS) was calculated from the time of salvage neck surgery and was based on clinically evident recurrent disease. The Kaplan–Meier method was used to calculate survival rates. Log-rank was used to determine differences in survival rates using Statview.

2

Materials and methods

This retrospective study was approved by the Human Research Protection Office at Washington University School of Medicine. All patients with thyroid cancer who were referred to the Department of Radiation Oncology at Washington University were entered into a prospective tumor registry beginning in 1974. Through 2009, a total of 1712 patients were included in the registry. The original data set was interrogated for patients with thyroid carcinoma of follicular cell origin who were treated with total thyroidectomy and ¹³¹ I ablation, were subsequently found to have elevated serum Tg (> 1 ng/mL) and negative ¹³¹ I scintigraphy, and underwent FDG-PET (first used to evaluate our patients beginning in 1999). Patients with anaplastic thyroid carcinoma and medullary thyroid cancer were excluded. The histology of the patient’s tumors was papillary in 52, follicular variant in 9, insular in 8, tall cell in 4, pure follicular in 2, and poorly differentiated in 1. All patients with positive Tg antibody were excluded. Seventy-six patients meeting these inclusion criteria were identified. The following data were reviewed for these subjects: demographic information, serum Tg levels, FDG-PET findings, history of further surgical treatment or external beam radiation therapy (XRT).

All patients underwent total thyroidectomy followed by ¹³¹ I therapy and post-treatment scintigraphy according to institutional standard practices. Patients were treated with repeated ¹³¹ I administration if the Tg level was elevated and current diagnostic ¹³¹ I scintigraphy was positive. Thyroid hormone replacement was prescribed for all patients, with a goal of achieving a serum thyroid stimulating hormone (TSH) level of < 0.1 μIU/mL. Follow-up consisted of regularly scheduled physical examinations, serum Tg levels, and diagnostic ¹³¹ I scintigraphy (performed with a 185 mBq [5 mCi] adult dosage of ¹³¹ I). If a patient was found to have an unsuppressed Tg level > 1 ng/mL in the setting of negative post-therapy ¹³¹ I scintigraphy, the patient underwent FDG-PET. Conventional FDG-PET was performed in 15 patients; the remaining 61 patients had FDG-PET/CT. In the early years of the study, thyroid hormone was not withdrawn as preparation for FDG-PET. In the later part of the study, FDG-PET was obtained after withdrawal of thyroid hormone or after the patient had been treated with recombinant TSH, in order to achieve a TSH level > 25 μIU/mL (16 patients had TSH < 25 μIU/mL at time of PET). Further surgery or irradiation was performed as clinically indicated. Neck ultrasonography was not routinely performed after negative FDG-PET. Staging was in accordance with AJCC 7th ed.

For PET, patients fasted, except for liberal water intake, for at least 4 h before injection of FDG. The blood glucose level was measured before FDG injection, and was less than 200 mg/dL in all patients. Each patient received 400–610 MBq (11–16.5 mCi) of FDG intravenously, and then rested quietly during the FDG uptake period. PET or PET/CT was initiated approximately 60 min after injection of the FDG. For conventional PET, attenuation correction was performed with segmented transmission data obtained at each bed position with rotating ⁶⁸ Ge/ ⁶⁸ Ga rod sources. For PET/CT, typical parameters for whole-body craniocaudal CT scanning were 120–130 kVp, 80–120 effective mA, and 5-mm collimation. During the CT scan, patients were asked to maintain shallow respiration. Rescaled CT images were used to produce attenuation correction values for the PET emission reconstruction. The PET data acquisition included 4–6 bed positions (2–4 min per bed position depending on body weight) over the same axial extent. PET images were reconstructed using ordered-subset expectation maximization.

Interpretation of all FDG-PET and PET/CT studies was performed in routine clinical fashion by board-certified nuclear medicine physicians. Subjective visual assessment was used in interpretation of FDG-PET images. Any increased FDG uptake was compared with the anatomic findings on CT images. All FDG-PET imaging results (based on the reports of these studies in the medical record) were correlated with the subsequent final histologic diagnosis, findings at surgery, or clinical observation from the time of FDG-PET.

Clinically evident recurrent disease was defined as positive pathology or, if pathology was not available, positive subsequent FDG-PET. Patients were considered disease free despite an elevated Tg in the absence of positive pathology or imaging . Cause-specific survival (CSS) was based on death resulting from thyroid cancer and was calculated from the time of first FDG-PET. Recurrence-free survival (RFS) was calculated from the time of salvage neck surgery and was based on clinically evident recurrent disease. The Kaplan–Meier method was used to calculate survival rates. Log-rank was used to determine differences in survival rates using Statview.