Incidental Diffuse Thyroid ¹⁸F-FDG Uptake Related to Autoimmune Thyroiditis May Be a Favorable Prognostic Factor in Advanced Breast Cancer

Patients

A total of 616 patients with both available PET/CT images and thyroid function test results were selected from patients who had undergone surgery for primary breast cancer at Pusan National University Hospital between January 2006 and December 2009. Of these 616 patients, 52 were excluded because of the following reasons: coexisting papillary thyroid carcinoma (n = 20), focal thyroid uptake by benign thyroid nodules on PET/CT (n = 17), other concurrent malignancies (n = 12: cervical cancer, n = 3; lung cancer, n = 2; stomach cancer, n = 2; sigmoid colon cancer, n = 2; malignant lymphoma, n = 1; acute myeloid leukemia, n = 1; and gastrointestinal stromal tumor, n = 1), and death from other combined medical disorders (n = 3: hepatic failure, n = 1; liver cirrhosis, n = 1; and cardiovascular disorder, n = 1). Finally, a total of 564 were enrolled in this study. Patients were divided into 2 groups according to the absence or presence of incidental diffuse uptake of ¹⁸F-FDG in the thyroid on PET/CT images.

Two surgeons performed all breast surgeries during the study period. Immunohistochemical analyses for the estrogen receptor (ER), progesterone receptor (PR), c-erb-B2 (protooncogene), and p53 were performed using specific monoclonal antibodies. Hormone therapy consisted of an ER antagonist or an aromatase inhibitor. Adjuvant radiotherapy, chemotherapy, and hormone therapy were used to treat patients according to the institution’s protocol. Patients were also subdivided into 2 groups: those with early cancer and those with locally advanced (defined by the TNM classification as stages IIB, IIIA, and IIIB) and secondary cancer (14).

Patients diagnosed with breast cancer routinely underwent thyroid function tests (free T4 and thyroid stimulating hormone [TSH]) and thyroid autoantibody tests (thyroperoxidase or thyroglobulin antibodies) during the follow-up period after surgery. Serum thyroid autoantibody analyses were performed by radioimmunoassay with a commercial kit (Brahms, for both antithyroperoxidase and antithyroglobulin). The analytic sensitivities of the assays for antithyroperoxidase and antithyroglobulin antibodies were 5.5 and 5.5 IU/mL, respectively, and the intraassay coefficients of variation ranged from 2.9% to 4.5% and from 2.0% to 7.5%, respectively. The reference ranges for thyroperoxidase and thyroglobulin antibodies were less than 60 IU/mL each. If patients with breast cancer had an abnormal result in their thyroid function tests (TSH, either <0.3 or >5.0 mIU/L; or free T4, either <0.8 or >2.1 ng/dL) or PET/CT, they were routinely referred to the thyroid clinic and underwent thyroid ultrasonography or cytologic investigation. Thyroid ultrasonography was performed with a scanner (HDI 5000 [Philips] or Vivid I [GE Healthcare]) equipped with a 10- to 13-MHz linear probe. The ultrasonography examination was performed by 3 endocrinologists according to their schedule during the study period. The ultrasonography features of chronic (autoimmune) thyroiditis include fibrous, enlarged, and lobulated glands with ill-defined hypoechoic heterogeneous areas or micronodulation (15). Hypothyroidism (overt or subclinical) was defined as previous prescription of thyroid hormone or a TSH level of more than 5.0 mIU/L. Positivities for the 2 thyroid autoantibodies were defined as a thyroperoxidase antibody of at least 60 U/mL and a thyroglobulin antibody of at least 60 U/mL. Thyroid dysfunctions related to chronic autoimmune thyroiditis were defined as a positivity for either thyroperoxidase antibody or thyroglobulin antibody, cytologic confirmation of Hashimoto thyroiditis, or ultrasonography findings of chronic thyroiditis.

Physical examination was regularly performed on all patients during the follow-up period. The imaging studies for the detection of recurrence or metastasis of breast cancer were routinely performed in all patients every 6–12 mo after treatment. Mammography, ultrasonography of the breasts and abdomen, bone scanning, chest radiography or CT, and PET/CT were performed at the time of each imaging study for recurrence or metastasis of breast cancer. Recurrence was defined as the reappearance of disease after treatment and was confirmed by cytologic or histopathologic examination or by a suggestive lesion in imaging studies. The endpoint of the analysis was disease-free survival (DFS). DFS was defined as the length of time from the first operation until the event of recurrence or metastasis, or if no event occurred, until the last follow-up visit to our hospital. This study was approved by the Institutional Review Board of Pusan National University Hospital, and each patient gave informed consent to participate in the study.

¹⁸F-FDG PET/CT Analysis

¹⁸F-FDG PET/CT images were obtained with a dedicated PET/CT scanner (Gemini; Philips) consisting of a dedicated germanium oxyorthosilicate full-ring PET scanner and a dual-slice helical CT scanner. Standard patient preparation included at least 8 h of fasting and a serum glucose level of less than 120 mg/dL before ¹⁸F-FDG administration. PET/CT was performed 60 min after injection of ¹⁸F-FDG (mean dose ± SD, 383.7 ± 47.4 MBq; range, 314.5–488.4 MBq). After this administration of ¹⁸F-FDG, low-dose CT (30 mAs, 120 kV) covering the area between the base of the skull and the proximal thighs was performed for the purpose of attenuation correction and precise anatomic localization. Thereafter, an emission scan was obtained in 3-dimensional mode. The emission scan time per bed position was 3 min, and 9 bed positions were acquired. PET data were obtained using a high-resolution whole-body scanner with an axial field of view of 18 cm. The average axial resolution varied between 4.2 mm in full width at half maximum in the center and 5.6 mm at 10 cm. The average total PET/CT examination time was 30 min. After scatter and decay correction, PET data were reconstructed iteratively with attenuation correction and reoriented in axial, sagittal, and coronal slices. The row-action maximum-likelihood algorithm was used for 3-dimensional reconstruction.

¹⁸F-FDG PET/CT images were reviewed by 2 experienced nuclear physicians on a workstation (Extended Brilliance Workstation; Philips) as maximum-intensity-projection coronal, sagittal, and axial images, both visually and quantitatively. Findings were recorded by consensus. A third reviewer was assigned to resolve differences in visual interpretation. The nuclear physicians were masked to all other clinical and imaging information. In ¹⁸F-FDG PET/CT images, thyroid uptake was considered present when there was increased uptake in the thyroid gland above the physiologic background level (below or above the level of liver uptake). Diffuse thyroid uptake was defined as uniform distribution of the tracer above the background level throughout both lobes. To calculate maximal standardized uptake values (SUV_max), manually defined regions of interest were drawn over both lobes, with the higher of the 2 values used in the analyses.

Statistical Analysis

All statistical analyses were performed using SPSS (version 15.0; SPSS, Inc.). Continuous data are expressed as mean ± SD for normally distributed values and median and interquartile range for nonparametric values. The independent 2-sample t test was used to compare 2 independent groups. Categoric variables were compared using the χ² test. DFS was evaluated with the Kaplan–Meier method after surgery. Comparison of the overall DFS between the 2 groups was examined using the log-rank test in univariate analysis. Variables with a P value of less than 0.2 in univariate analysis were included in multivariate analysis. A Cox proportional hazards model and the forward stepwise method were used to analyze various prognostic factors for DFS in multivariate analysis. The relative importance of prognostic factors was presented as hazard ratios (HRs) and 95% confidence intervals (95% CIs), which were calculated using binomial disturbance. A P value of less than 0.05 derived from the 2-tailed test was considered statistically significant.