The Utility of ¹⁸F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Differentiated Thyroid Cancer Patients with Biochemical Recurrence and Negative Whole-Body Radioiodine Scintigraphy and Evaluation of the Possible Role of a Limited Regional Scan

Introduction

Differentiated thyroid cancer (DTC) is the most common malignant endocrine tumor.[1] It has a favorable prognosis, with reported 5-year survival rates of 95% for women and 87% for men.[2] The incidence of DTC has increased over the past two decades, with an increase in small, low-risk tumors.[3] The standard treatment depends on the tumor stage and risk category. It includes total thyroidectomy, followed by radioiodine remnant ablation (radioactive iodine [RAI]) and further thyroid hormone replacement therapy.[4] A whole-body scan (WBS) with radioiodine (¹³¹I) is the most effective method for tumor detection and staging posttotal thyroidectomy.[5] It determines the differentiation of the tumor based on its avidity to iodine, identifies remnant thyroid tissue, and evaluates distant metastases.[6]

Because of the risk of recurrence, these patients are kept on long-term follow-up with the periodic measurement of serum thyroglobulin (Tg) and anti-Tg antibody level (ATg) with or without WBS.[7] In a few patients, cancer cells undergo dedifferentiation, but continue to secret Tg or Atg. These cells lose the ability to concentrate iodine. Thus, a negative WBS is noted.[8] 18F-fluorodeoxyglucose (¹⁸F-FDG) is being taken up by malignant cells, and positron emission tomography/computed tomography (PET/CT) using ¹⁸F-FDG is an established modality in oncology. Feine et al. demonstrated that PET/CT scan might detect tumor lesions that are missed by I-131-scintigraphy known as “flip-flop phenomenon.”[9] DTC cells show iodine uptake due to the expression of sodium-iodide symporter (NIS) and low glucose uptake, representing the low metabolic activity. Less differentiated cells that cease to express NIS exhibit upregulated glucose transporter and FDG uptake.[1011]

Initial evaluation with neck ultrasonography or CT could be done in these patients. Several meta-analyses have shown that ¹⁸F-FDG PET is a useful method for detecting recurrent DTC.[1213] PET scanning has also shown a promising role in patients presenting with raised Atg.[1415] Surveillance, Epidemiology, and End Results-Medicare databases have shown a significant increase in the utilization of the PET scans in the postoperative surveillance of DTC patients.[16] The authors have demonstrated that FDG uptake has prognostic significance for survival, and avid cancers are considered more aggressive.[171819] Few studies have demonstrated that PET/CT may change therapy management in a substantial number of patients.[2021] DTC usually spreads to cervical and thoracic regions and distant bones with relative sparing of other visceral organs. The prevalence of metastasis to the other sites is low.[22]

We retrospectively evaluated the performance of ¹⁸F-FDG PET in DTC patients presented with raised serum Tg or Atg levels and negative WBS. This study also evaluated the predictors of the positive FDG PET/CT scan. At last, this study explores the possibility of a regional “limited PET/CT” protocol in these patients rather than whole-body PET/CT protocol.

Materials and Methods

Results

Discussion

Patients with DTC, who present with high serum Tg or Atg levels and a negative WBS, present an essential and challenging clinical scenario.[23] This Tg elevation and a negative iodine scintigraphy entity have described by the acronym TENIS (Tg elevation/negative iodine scintigraphy syndrome). Due to a no uptake on the WBS, RAI is less likely to show significant clinical benefit. Empirical RAI is this setting is reserved for few specific clinical settings.[24] Several imaging modalities are used to evaluate this entity with variable results. A sensitive and accurate imaging modality is required to disclose the locoregional disease status but also explore systemic metastases. Imaging should be able to guide surgical resection of the disease, thus avoiding unnecessary local radical treatments in the presence of systemic metastases.

¹⁸F-FDG PET/CT has proved its efficacy and clinical utility in DTC patients. Dong et al. carried out a meta-analysis of DTC patients with a negative WBS scan and included 25 studies (789 patients). They found a sensitivity and specificity of 94% and 84%, respectively.[25] A similar performance of PET/CT has noted in a recent meta-analyses that included 34 (2639 patients) and 20 studies (958 patients).[1213] In our single-center study, which includes a large number of patients, similar results are observed. We found FDG positive lesions in ~ 64% (88/137) of patients. In addition, one-fourth (38/137) of the patients had metabolically inactive lung lesions on the CT. Histopathological analysis of all lesions could not be done as many of them were noted in the mediastinum and lung. The biopsy was difficult, and many patients did not give consent for the invasive procedure.

The American Thyroid Association guidelines suggest obtaining PET/CT in high-risk DTC patients with elevated Tg levels (more than 10 ng/dl) and a negative WBS.[24] However, some studies have demonstrated the utility of PET/CT scans in patients with lower Tg levels, which may reflect the production of mutant Tg not detectable by conventional assays or loss of Tg synthesis.[26] In our study, we found that a rising serum Tg level predicts the positive PET/CT. However, other multiple factors, such as metastases to central or lateral compartment lymph node and distant metastases, could not predict it. Serum Atg levels were not a predictor of a positive PET/CT scan. Female sex was significantly associated with a more positive scan (71.6%) in comparison to male patients (51.3%). This finding needs further evaluation in future studies. This result also indicates that male sex is associated with a larger number of PET/CT-negative biochemical recurrence. Few studies have demonstrated a change in therapy management using PET/CT.[2021] Although we did not intend to document it, we observed that many patients with thyroid bed or cervical lymph node recurrence had coexisting mediastinal lymphadenopathy or lung metastases that excluded radical local treatments.

Most of the patients in our study had a very high serum Tg or Atg level. Even at this high level of tumor markers, most of the patients had lesions limited to the neck and thoracic region. We did not note any evidence of the metachronous cancers in any of the 137 patients. Few previous studies have also shown that most of the recurrences are noted in the area of the neck and thorax, although most of them have not detailed the sites of distant metastases [Table 4].[1827282930313233] In our study, only four patients showed distant metastases to the brain, skull, acetabulum, and sacrum outside the proposed limited PET CT field of view. However, all these lesions were known by previous WBS or clinical history.

In our study group, more than half of the patients (79 out of 137) were of <40 years of age. Out of these, fifty were female. It would be an ideal strategy to decrease the overall radiation exposure and minimizing pelvic radiation in patients of the reproductive age. Radiation exposure remains a significant concern for PET/CT imaging. We use CARE Dose4D (Siemens Healthineers) to keep the radiation exposure to the optimized level. A limited PET/CT will decrease the scan length to half, thus effectively reducing radiation exposure by CT component of PET/CT study to the half. It has recommended that all efforts should take to eliminate unnecessary imaging examinations and to lower the amount of radiation used in necessary imaging examinations to only that needed to acquire appropriate medical images.[34] Limited PET/CT will also lead to reducing scan time by 8–10 min. This decrease in acquisition time would be welcome by the patient and may reduce movement-related artifacts. By reducing the acquisition time, overall patient throughput may be increased. A similar observation is noted in head and neck cancer patients undergoing limited PET/CT.[35] However, in patients presenting symptoms outside the planned limited PET/CT or known distant skeletal metastases, the field may be extended.

Our study has a few significant limitations. It was a single-center retrospective study. As patients have very high Tg or Atg levels, a large proportion of the patients have metastatic disease. We did not compare the findings of PET/CT with other imaging modalities. Histopathological confirmation could not be done in half of the patients. A cost-effective analysis or radiation burden measurement was not done.

Clinicians should consider the availability, cost of PET/CT, and risk of radiation exposure. A neck USG followed by a chest CT may be done if PET-CT is not available. It offers advantages of wide availability, lesser radiation, and possibly lower cost. A regional limited PET/CT suffices the need of most of the patients with a minimal possibility of missing distant metastases below the diaphragm. In a resource-limited developing country, regional “limited PET/CT” may result in shorter imaging timing, better patient throughput, thus increasing performance in busy nuclear medicine facility.

Conclusions

¹⁸F-FDG PET/CT is an excellent investigational modality in DTC patients presenting with biochemical recurrence either in the form of raised serum Tg or Atg level. It finds the disease spread and guides in restaging and management decision-making of more than 80% of the patients. Hence, we propose that regional “limited PET/CT” from the base of the skull to the adrenal region is sufficient for most of the patients. It may lead to shorter procedure time, more comfortable with possible lesser radiation exposure. Further prospective and cost-effectiveness studies are needed before this approach is incorporated into clinical practice.