Introduction

Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of the thyroid gland, originating from parafollicular C-cells with a frequency of 5% among all thyroid cancers. Sporadic (75%) and familial (25%) forms have been defined (1). The only curative therapy for medullary thyroid cancer is total resection of the primary tumor and metastatic lesions, and the prognosis is strongly related to the performance of surgery (2). However, despite all aggressive and effective surgeries performed, persistent or recurrent disease is commonly seen during medullary thyroid cancer. Serum calcitonin and carcinoembryonic antigen (CEA) are the tumor markers that are used in the follow-up. CEA has also been reported to be as a marker of dedifferentiation (1,3).

Biochemical recurrence necessitates accurate detection of the recurrent or the metastatic focus. In patients with increased serum calcitonin and/or CEA levels in the follow-up, a thorough examination and imaging of the whole body is crucial because early detection of recurrent disease enables clinicians and surgeons to perform effective surgeries, local or systemic therapies of the limited disease. With ultrasonography of the neck, computed tomography (CT) of the thorax, abdomen, and pelvis are usually performed for the detection of recurrence. When the levels of serum calcitonin exceeded 150 pg/mL, radionuclide whole-body imaging methods are also indicated because distant metastasis is likely (1,3,4).

Positron emission tomography (PET)/CT with ¹⁸F-fluorodeoxyglucose (FDG) is the most common radionuclide imaging tool in oncology. However, it has been reported that the performance of ¹⁸F-FDG PET/CT is highly related to serum calcitonin levels and is recommended for cases with serum calcitonin >500-1000 (5). Alternative tracers using different uptake pathways have been tested. Somatostatin receptor imaging with (Gallium-68) ⁶⁸Ga labeled somatostatin analogs (DOTATATE, DOTATOC or DOTANOC) and ¹⁸F-dihydroxyphenylalanine (FDOPA) have been proposed for restaging in case of biochemical recurrence. Being a cyclotrone-produced radiopharmaceutical, which can be highly expensive, ¹⁸F-FDOPA is not easily maintained throughout the world and the literature is still a lack of data about the role of ¹⁸F-FDOPA PET/CT in medullary thyroid cancer, a relatively rare tumor type of thyroid.

In this study, we evaluated the role of ¹⁸F-FDOPA PET/CT in the detection of recurrence in medullary thyroid cancer patients with elevated serum calcitonin levels.

Materials and Methods

Patients

This retrospective study was approved by the Ankara University Review Board (approval no: İ7-522-21, date: 06.09.2021). Medullary thyroid cancer patients who were referred to the nuclear medicine department for ¹⁸F-FDOPA PET/CT between January 2018 and January 2021 were included in the study. Inclusion criteria were i) >18 years old male or females with histopathologically confirmed medullary thyroid cancer diagnosis after thyroidectomy, ii) elevated levels of serum calcitonin in the follow-up after surgery for primary tumor, iii) clinical follow-up results of at least 2 years for confirmation of recurrence. Exclusion criteria were, i) age <18 years, ii) history of secondary malignancy, iii) lack of clinical follow-up.

¹⁸F-FDOPA PET/CT Protocol and Image Interpretation

Premedication with carbidopa was not performed. Following a minimum of 4 h fasting, 2 to 4 MBq/kg of ¹⁸F-FDOPA was intravenously administered by slow injection. Whole-body PET/CT images from the vertex to the upper thigh were obtained 60 min after radiopharmaceutical injection by using a hybrid PET/CT scanner (GE Discovery 710, General Electric Company, USA). PET images were acquired for 2 min per bed position. PET images were reconstructed with non-contrast low-dose CT images. CT images were obtained with a standardized protocol of 140 kV, 70 mA, tube rotation time of 0.5 s per rotation, a pitch of 6 and a slice thickness of 5 mm. Patients were allowed to breathe normally during the procedure. Attenuation-corrected PET/CT fusion images were reviewed in three planes (transaxial, coronal and sagittal) on Advanced Workstation Volumeshare 5 (GE Medical Systems).

All PET/CT images were reevaluated by two nuclear medicine specialists with consensus. Any area of focal uptake higher than the adjacent background activity outside the areas of physiological distribution of the radiotracer with a corresponding nodular lesion on CT were considered as pathological. Maximum standardized uptake value (SUV_max) was measured for all lesions for semiquantitative analysis.

Statistical Analysis

In this retrospective analysis, with demographics, serum calcitonin levels, results of any radiological or functional imaging studies, including neck US, CT of the thorax, abdomen or pelvis, Tc-99m methylenediphosphanate whole body bone scan, ¹⁸F-FDG PET/CT, or ⁶⁸Ga- DOTATATE PET/CT were recorded. Clinical follow-up or histopathological examination results in patients who underwent surgeries after ¹⁸F-FDOPA PET/CT were used for confirmation of results. Patient-based sensitivity, specificity, and accuracy were calculated for ¹⁸F-FDOPA PET/CT in the detection of disease recurrence.

Results

A total of 14 patients (9 F and 5 M; median age: 45) were included in the analysis. Three patients had MEN IIA syndrome and 1 patient MEN IIB syndrome, 10 patients had a diagnosis of sporadic MTC. Median calcitonin levels of patients were calculated as 757.5 (min-max: 28.5-7911) pg/mL. Nine patients and 5 patients had undergone ultrasound and contrast-enhanced computed tomography (ceCT) of the neck, respectively, before PET/CT imaging. Eight patients had ⁶⁸Ga- DOTATATE and 7 patients had ¹⁸F-FDG PET/CT within 3 months period before ¹⁸F-DOPA PET/CT. Results were confirmed histopathologically in 7 patients. Clinical follow-up results were used for confirmation in 7 patients. Four of these patients showed no sign of recurrence, and in 3 patients, progression was recorded on radiological examinations [CT and/or magnetic resonance imaging (MRI)] in the follow-up. Patient characteristics, details of PET/CT and follow-up results are given in Table 1.

¹⁸F-FDG PET/CT Findings

¹⁸F-FDG PET/CT was normal in 5 patients. In 1 patient, ¹⁸F-FDG PET/CT revealed cervical metastatic lymph node, and in 1 patient ¹⁸F-FDG was positive in both cervical and mediastinal lymph nodes. In these 2 patients, ¹⁸F-FDOPA PET/CT was negative for lymph node metastasis and ⁶⁸Ga PET/CT was not available.

⁶⁸Ga-DOTATATE PET/CT Findings

⁶⁸Ga-DOTATATE was negative in 5 patients. In patients with a positive ⁶⁸Ga-DOTATATE PET/CT, cervical lymph nodes were detected in all 3 of them, mediastinal lymph nodes in one patient, and pathological uptake was recorded in the thyroid bed in 1 patient. In 1 patient with cervical lymph node metastasis, ¹⁸F-FDOPA PET/CT was negative and ¹⁸F-FDG PET/CT was not performed.

¹⁸F-FDOPA PET/CT Findings

¹⁸F-FDOPA PET/CT was normal in 5 patients. ¹⁸F-FDOPA PET/CT revealed pathological uptake on the thyroid bed, lymph nodes and distant organs in 3, 5, and 2 patients, respectively. Median SUV_max for the recurrent lesions were calculated as 6.4 (min-max: 1.9-18.4). Although not statistically significant, serum calcitonin levels in ¹⁸F-FDOPA PET/CT-positive patients were higher than ¹⁸F-FDOPA PET/CT-negative patients (800 pg/mL min: 47, max: 7911 vs. 98.2 pg/mL, min: 28.5,  max: 800, respectively, p=0.30).

¹⁸F-FDOPA PET/CT detected recurrent disease in 4 of 5 and 2 of the 5 patients who had negative ¹⁸F-FDG PET/CT and negative ⁶⁸Ga-DOTATATE PET/CT, respectively. In 5 patients with negative ¹⁸F-FDG PET/CT, ¹⁸F-FDOPA was positive in the thyroid bed in 2 patients, in regional lymph nodes in 2 patients, and in lung metastasis in 1 patient. In 2 patients with a negative ⁶⁸Ga-DOTA PET/CT scan, ¹⁸F-FDOPA was positive in the thyroid bed (Figure 1). The sensitivity of ¹⁸F-FDOPA PET/CT in the detection of recurrent disease was calculated as 64%.

Discussion

Medullary thyroid cancer is a relatively rare malignancy of the thyroid. Disease progression is usually slow, and overall survival rates are acceptable if an effective surgical resection at the time of diagnosis could be achieved. However, calcitonin recurrence or persistence is observed in up to 80% of the patients. Detection and accurate localization of structural diseases in patients with biochemical recurrence is important for further therapies (6). Reoperation aims to total resection of recurrent or persistent malignant tissues and to achieve undetectable calcitonin levels. Even with experienced operators and excellent surgeries, complete remission could be maintained in only 30% of patients (7). Thus, imaging studies are expected to detect insignificant- volume diseases with high accuracy for differentiating candidates of surgery/local therapies or systemic therapy (8).

¹⁸F-FDOPA has gained importance in medullary thyroid cancer recently. In a meta-analysis, the patient-based and lesion- based detection rates of ¹⁸F-FDOPA in patients with increased tumor markers were calculated as 66% and 71% respectively. The performance of ¹⁸F-FDOPA PET/CT was related to serum calcitonin levels. The detection rate of ¹⁸F-FDOPA was found 86% in patients with serum calcitonin levels >1000 pg/mL (9). In another study comparing the diagnostic utility of ¹⁸F-FDOPA and ¹⁸F-FDG PET/CT, the sensitivity of ¹⁸F-FDOPA was significantly higher in patients with serum calcitonin levels >150 pg/mL compared to <150 pg/mL (90.9% vs. 28.6%; p=0.013) (10). In our study, compatible with the literature, patient-based sensitivity of ¹⁸F-FDOPA PET/CT in medullary thyroid cancer patients with elevated serum calcitonin levels was found to be 64%. Serum calcitonin levels were relatively higher in ¹⁸F-FDOPA PET/CT-positive patients compared to others (800 pg/mL vs. 98.2), but this difference could not be proved statistically due to the very small number of patients in the subgroups.

In comparative studies with ¹⁸F-FDG PET/CT and ⁶⁸Ga-DOTATATE PET/CT, ¹⁸F-FDOPA PET/CT was reported to be superior (11,12,13). This is why the European Association of Nuclear Medicine recommends ¹⁸F-FDOPA PET/CT in the first line in medullary thyroid cancer patients with elevated serum calcitonin levels after initial treatment (14). In this study, because not all patients had ⁶⁸Ga-DOTATATE PET/CT and ¹⁸F-FDG PET/CT, no direct comparison of patient or lesion-based sensitivity or detection rates of these three modalities could be possible. In regional analysis, it is shown that ¹⁸F-FDOPA was positive in lymph nodes in 2 patients and in the thyroid bed in 2 patients with negative ¹⁸F-FDG PET/CT and in the thyroid bed in 2 patients with negative ⁶⁸Ga-DOTATATE PET/CT. However, there were 2 patients (patients 6 and 9) with ¹⁸F-FDG positive but ¹⁸F-FDOPA negative lymph node metastasis and 1 patient (patient 2) with ⁶⁸Ga-DOTATATE-positive but ¹⁸F-FDOPA negative lymph nodes. According to the literature, ¹⁸F-FDOPA has a higher performance in the neck compared to both ¹⁸F-FDG and ⁶⁸Ga-DOTATATE. This is probably due to a higher ratio of tumor/background counts compared to the other two radiopharmaceuticals. Another thing is that the uptake mechanisms of these three radiopharmaceuticals are different, and ¹⁸F-FDOPA is rather positive in relatively differentiated medullary thyroid cancer. While ¹⁸F-FDG uptake is related to dedifferentiation, ⁶⁸Ga-DOTATATE uptake is a measure of somatostatin receptor expression of the tumor cells (11,12,15,16). Our results partly confirm previous reported data, as there are patients with locoregional disease either ¹⁸F-FDG or ⁶⁸Ga-DOTATATE positive but ¹⁸F-FDOPA negative.

Regarding distant metastasis, only ¹⁸F-FDOPA was positive in a single patient with lung metastasis, which was also reported on ceCT (patient 9). Because ⁶⁸Ga-DOTATE PET/CT was not performed in this patient, a comparison between ⁶⁸Ga-DOTATATE PET/CT and ¹⁸F-FDOPA PET/CT could not be made but, this lung nodule was ¹⁸F-FDG negative. No other patients had lung metastasis detectable by any radiological or functional imaging modality. In lung metastasis, as it is the case in our study, ceCT seems adequate enough to detect lung lesions. No significant superiority of ¹⁸F-FDOPA PET/CT was reported over other imaging modalities. However, ¹⁸F-FDG PET/CT is sometimes insufficient in the evaluation of lesions with low metabolic rate or small nodules (<1cm) (17).

¹⁸F-FDOPA was found superior to ⁶⁸Ga-DOTATATE PET/CT in the detection of liver metastasis (11). There was only one patient in our study (patient 3) who had liver metastasis shown by ¹⁸F-FDOPA PET/CT. Although no comparison with ¹⁸F-FDG or ⁶⁸Ga-DOTATATE could be possible in our study, in the follow-up liver lesions showed progression on both CT and MRI and accuracy of ¹⁸F-FDOPA PET/CT was confirmed. This result was compatible with previous data in the literature (11).

Study Limitations

The major limitation of this study is that few patients were enrolled. Further statistical analysis would be possible including subgroup analysis if a larger patient population could be achieved. Another limitation is that the study was designed retrospectively. Thus, head-to-head comparison of ¹⁸F-FDOPA with ¹⁸F-FDG and ⁶⁸Ga-DOTATATE was not possible for all patients. Although patients involved in this study were scanned at 60 min, as recommended in the guideline, in recent studies, higher detection rates with the earlier acquisition for ¹⁸F-FDOPA PET/CT in medullary thyroid cancer was reported (14,18). Calculated sensitivity could have been higher if dual time point imaging could be performed. Despite these limitations, in our opinion, clinical results of a relatively specific and hard- to- reach radiopharmaceutical in a rare patient group are still valuable and would contribute to the literature.

Conclusion

¹⁸F-FDOPA PET/CT can detect recurrence in about two- thirds of the patients with elevated calcitonin levels after primary surgery for MTC. Due to variable differentiation degree, different receptor status, and clinical behavior of MTC, all three radiopharmaceuticals can be beneficial and are complementary to each other in patient management.

Ethics

Ethics Committee Approval: Ankara University Ethics Committee approval was received for this study (decision no: İ7-522-21, date: 06.09.2021).

Informed Consent: The patient consent was obtained.

Peer-review: Externally and internally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: M.K.G., Concept: Ç.S., N.Ö.K., Ö.D., Design: Ç.S., M.A., Data Collection or Processing: Ç.S., M.A., Analysis or Interpretation: Ç.S., M.A., Literature Search: M.A., Writing: M.A.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.