Published online May 28, 2026. doi: 10.4329/wjr.v18.i5.120146
Revised: March 5, 2026
Accepted: April 1, 2026
Published online: May 28, 2026
Processing time: 99 Days and 6.2 Hours
Medullary thyroid carcinoma (MTC) arises from thyroid C-cells and secretes calcitonin. Conventional anatomical imaging frequently fails to identify small lesions and biochemically recurrent tumors, necessitating phenotype-guided positron emission tomography (PET) evaluation. This article summarizes three mainstream PET tracers - 18F-fluorodihydroxyphenylalanine (FDOPA), gallium-68-labelled somatostatin receptor (SSTR) analogues, and 18F-fluorodeoxyglucose (FDG) - across initial staging, biochemical recurrence, and restaging settings. Meta-analyses confirm 18F-FDOPA achieves the highest sensitivity for recurrent or persistent MTC, with detection improved by elevated calcitonin levels and shorter doubling times. Increased FDG uptake indicates aggressive, dedifferentiated disease, while SSTR PET shows lower overall detection rates in MTC but remains valuable for assessing bone involvement and selecting candidates for PRRT. Current guidelines recommend a biology-driven imaging strategy: 18F-FDOPA is the first-choice tracer for biochemical recurrence when available; FDG is reserved for high-grade progressive disease, and SSTR PET guides pre-PRRT evaluation. Routine PET is not recommended for initial staging, though selective use is reasonable in high-risk patients combined with conventional imaging. This study proposes an evidence-based imaging algorithm for radiologists according to serum markers, tracer advantages and theranostic needs. Further prospective trials, standardized SSTR thresholds and investigations of novel tracers are still required to fill existing research gaps.
Core Tip: Selecting the right positron emission tomography tracer in medullary thyroid carcinoma depends on tumour biology. This article synthesizes evidence from five databases indicating that fluorodihydroxyphenylalanine remains the most sensitive tracer for recurrent disease, whereas fluorodeoxyglucose better captures aggressive, dedifferentiated tumours. Somatostatin receptor imaging, though less sensitive overall, is indispensable for identifying candidates for peptide receptor radionuclide therapy. We propose an expert-informed, biology-guided algorithm linking biomarker kinetics to tracer choice and highlight cholecystokinin-2 receptor and fibroblast activation protein as promising emerging targets.
- Citation: Ahmed FW, Ahmed F. Positron emission tomography tracers in medullary thyroid carcinoma: Current evidence and emerging targets. World J Radiol 2026; 18(5): 120146
- URL: https://www.wjgnet.com/1949-8470/full/v18/i5/120146.htm
- DOI: https://dx.doi.org/10.4329/wjr.v18.i5.120146
Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer arising from the parafollicular C-cells of the thyroid gland and accounts for 3%-5% of all thyroid cancers[1]. The disease produces two key biomarkers, calcitonin (Ctn) and carcinoembryonic antigen (CEA), both of which serve as indicators of tumour burden and recurrence[2]. Unlike differentiated thyroid cancers, MTC does not concentrate radioiodine, which limits treatment options and places greater emphasis on complete surgical resection and accurate staging.
Ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) form the backbone of initial MTC staging and surveillance. However, these anatomic modalities may miss small-volume disease, particularly in biochemically recurrent cases in which Ctn rises but standard imaging shows no abnormality[1,3]. Functional positron emission tomography (PET) imaging addresses this blind spot.
Three principal PET tracers are currently used in MTC, each targeting a different aspect of tumour biology. 18F-fluorodihydroxyphenylalanine (18F-FDOPA) exploits amino acid uptake and decarboxylation, which is a hallmark of neuroendocrine differentiation. 18F-fluorodeoxyglucose (18F-FDG) reflects glycolytic activity, which is often elevated in aggressive, dedifferentiated tumours. Gallium-68 (68Ga)-labelled somatostatin receptor (SSTR) analogues bind to SSTRs expressed by MTC cells to varying degrees.
This narrative review compares the current evidence for these three tracers across initial staging, biochemical recurrence, and restaging. We present a biology-guided imaging algorithm that brings together serum markers, tumour kinetics, and theranostic considerations. We also discuss emerging tracers, including cholecystokinin-2 receptor (CCK2R)/minigastrin analogues and fibroblast activation protein inhibitor (FAPI), that may reshape MTC imaging in the coming years.
We searched PubMed/MEDLINE, Ovid MEDLINE, EMBASE, Cochrane CENTRAL, and Scopus on January 15, 2026. Search terms combined medical subject headings and free-text keywords for MTC, PET, specific tracers, Ctn, and PRRT. We also hand-searched reference lists of included studies and major guidelines from the American Thyroid Association, European Society for Medical Oncology, European Association of Nuclear Medicine (EANM), and National Comprehensive Cancer Network. Articles were selected based on relevance, methodological rigour, and impact on clinical practice. From approximately 1400 unique records after deduplication, we selected 29 core references for this narrative synthesis.
18F-FDOPA is a radiolabelled amino acid analogue and precursor for dopamine synthesis. The large neutral amino acid transporter mediates its uptake, after which aromatic L-amino acid decarboxylase converts it to dopamine. MTC cells, by virtue of their neuroendocrine origin, tend to exhibit high aromatic L-amino acid decarboxylase activity. This biochemical property is what makes 18F-FDOPA a particularly well-suited tracer for this tumour.
Among available tracers, 18F-FDOPA PET offers the highest sensitivity and specificity for recurrent MTC, especially when patients present with biochemical relapse. Treglia et al[4] conducted a foundational meta-analysis showing pooled detection rates of 66% per patient and 71% per lesion. When Ctn exceeded 1000 pg/mL, sensitivity rose to 86%. Detection also improved with shorter Ctn doubling times.
A network meta-analysis by Lee et al[5] compared five PET radiopharmaceuticals; 18F-FDOPA was superior for patient-based detection. More recently, Zhang et al[6] published the largest single-centre dataset to date, comprising 109 patients followed over a 15-year period. Their reported patient-level sensitivity was 95%, specificity 93%, and overall accuracy 94%. Additionally, both standardised uptake value maximum (SUVmax) and metabolic tumour volume on 18F-FDOPA PET were found to have prognostic significance. The EANM 2020 practice guideline recommends 18F-FDOPA as the first-line PET tracer when serum Ctn exceeds 150 pg/mL[7]. A summary of key diagnostic performance metrics for all three tracers is provided in Table 1.
| Tracer | Ref. | Patient-based detection rate (sensitivity) | Lesion-based detection rate | Key correlate/finding |
| 18F-FDOPA | Treglia et al[4], 2012 | 66% (pooled) | 71% (pooled) | Sensitivity rises to 86% with Ctn |
| Lee et al[5], 2020 | Highest among 5 tracers (network meta-analysis) | N/A | Ranked 1 for patient-level detection | |
| Zhang et al[6], 2024 | 95% (single-centre cohort, n = 109) | N/A | High specificity (93%) and accuracy (94%) | |
| 18F-FDG | Cheng et al[13], 2012 | 68-69% (pooled) | N/A | General performance in recurrent/metastatic MTC |
| Treglia et al[14], 2012 | 75% (with Ctn > 1000 pg/mL) | N/A | Sensitivity rises to 91% with CEA DT | |
| Verbeek et al[15], 2012 | 77% positivity in patients with Ctn DT < 24 months | N/A | Strong correlation with aggressive disease | |
| 68Ga-SSTR | Treglia et al[17], 2017 | 63.5% (pooled) | N/A | Lower than FDOPA; comparable to FDG |
| Hayes et al[18], 2021 | 26% show sufficient uptake for PRRT | N/A | Highlights limited PRRT eligibility | |
| Castroneves et al[19], 2018 | 100% for bone metastases | N/A | Superior to bone scintigraphy (44%) for bone lesions |
Biochemical recurrence: The principal indication for 18F-FDOPA is localising disease when Ctn rises postoperatively, but anatomic imaging shows nothing. This role is now well established in clinical guidelines[7,8]. Several studies have demonstrated that 18F-FDOPA outperforms both 18F-FDG and 68Ga-SSTR PET for neck and liver metastases[9,10].
Initial staging: Routine 18F-FDOPA PET at initial diagnosis is not universally recommended, and this review does not advocate its use as a guideline-level endorsement. Neck ultrasound combined with contrast-enhanced CT or MRI remains the standard workup for most patients, consistent with both the ATA and European Society for Medical Oncology guidelines[11].
The only prospective dataset evaluating F-DOPA at initial diagnosis is the single-centre study by Brammen et al[3], who performed preoperative ultrasound and F-DOPA-PET/CT in 50 consecutive MTC patients. For the primary tumour, ultrasound was slightly more sensitive than F-DOPA (92% vs 86%). For lymph node metastases, both modalities performed poorly: F-DOPA sensitivity was 57% overall (28% for central nodes, 75% for lateral nodes). The authors concluded that surgical strategy could not be reliably determined by either modality alone[3].
Where F-DOPA did provide incremental value over conventional imaging was in detecting disease beyond the neck. Mediastinal lymph node metastases were identified exclusively by F-DOPA in 3/50 patients (6%), leading to the addition of mediastinal dissection. Distant metastases (liver, lung, bone) were similarly diagnosed only by F-DOPA in a further 3/50 patients (6%), prompting a shift to a less extended, palliative surgical approach. Notably, all six patients in whom F-DOPA changed management had pre-operative basal Ctn levels ≥ 500 pg/mL[3].
On this basis, selective use of F-DOPA PET/CT at initial staging may be considered in patients with high-risk features, which we define as: (1) Pre-operative Ctn > 500 pg/mL, consistent with both the Brammen data and the ATA guideline threshold for cross-sectional imaging[3,11]; (2) Imaging-suspected extrathyroidal extension or distant spread on conventional modalities; or (3) Highest-risk RET genotype (codon M918T/ATA-HST category). This recommendation is based on limited data from a single prospective cohort and retrospective series, and no study has yet demonstrated that adding PET at initial staging improves long-term survival compared with conventional imaging alone.
Prognostic value: 18F-FDOPA findings also carry prognostic weight. In a multicentre study, Caobelli et al[12] assessed the prognostic and predictive value of 18F-FDOPA PET/CT in recurrent MTC. They found that both the extent of tracer-avid disease and the intensity of uptake were associated with clinical outcomes.
18F-FDG is a glucose analogue taken up by metabolically active cells. Its uptake reflects the rate of glycolysis, which is often elevated in malignant tumours. In MTC, FDG uptake typically signifies more aggressive, dedifferentiated disease, that is, tumours that have lost their neuroendocrine features and shifted towards a glycolytic phenotype.
The diagnostic yield of 18F-FDG PET in MTC is generally lower than 18F-FDOPA, particularly for well-differentiated or low-volume disease. Cheng et al[13] reported a pooled sensitivity of 68%-69% in a systematic review. However, detection rates rise sharply in aggressive disease: Treglia et al[14] found FDG sensitivity of 75% when Ctn exceeded 1000 pg/mL and 91% when CEA doubling time was under 24 months.
Aggressive disease and prognostication: The real clinical niche for FDG PET lies in aggressive disease. When Ctn or CEA doubling time drops below 24 months, this is generally taken as a sign that the tumour is behaving aggressively, and FDG imaging becomes clinically relevant. Verbeek et al[15] observed that 77% of FDG-positive patients had Ctn doubling times of less than 24 months, compared with only 12% of FDG-negative patients.
This observation gives rise to what has been termed a “flip-flop” phenomenon, whereby FDOPA-avid tumours tend to be FDG-negative and vice versa (Figure 1). The pattern reflects the underlying tumour biology and carries prognostic implications, as FDG positivity is associated with worse overall survival.
Prediction of tyrosine kinase inhibitor response: In a recent study, Jager et al[16] examined whether pre-treatment PET metrics could predict response to tyrosine kinase inhibitor (TKI) therapy in a cohort of 25 patients. They found that patients with higher metabolic tumour volume and total lesion activity on 18F-FDG PET/CT had better structural responses to TKI treatment (P < 0.001). This raises the possibility that FDG PET could serve a role in selecting patients for systemic therapy. It is worth noting that 68Ga-labelled DOTA-Tyr3-octreotate (DOTATATE)-derived metrics, by contrast, showed no predictive value in the same cohort.
Complementary role to 18F-FDOPA: In the setting of biochemical recurrence, 18F-FDG PET serves as a valuable com
68Ga-labelled somatostatin analogues (DOTATATE, DOTA-Tyr3-octreotide, DOTA-1-Nal3-octreotide) bind SSTRs, particularly SSTR2, which are expressed on many neuroendocrine tumours. Although SSTR expression is a defining feature of well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumours (NETs), MTC cells express these receptors more variably. This heterogeneity largely explains the lower diagnostic yield of SSTR PET in MTC when compared with typical NETs.
SSTR PET detects fewer lesions than 18F-FDOPA in MTC but adds complementary information. Treglia et al[17] conducted a meta-analysis reporting a pooled detection rate of 63.5% (95% confidence interval: 49%-77%), substantially lower than the 96% observed in GEP-NETs. Hayes et al[18] published the largest multicentre 68Ga-DOTATATE study in metastatic MTC, finding that only 26% of patients showed sufficient uptake to qualify for PRRT. Castroneves et al[19] demonstrated that SSTR PET was superior to other modalities for detecting bone metastases.
18F-SiTATE is a novel 18F-labelled SSTR-directed radiotracer offering practical advantages over 68Ga-compounds: Longer half-life (110 minutes vs 68 minutes), cyclotron-based large-batch production, and superior spatial resolution. Kunte et al[20] reported the first clinical experience in thyroid carcinoma, including 10 MTC patients. Disease burden correlated with Ctn levels (r = 0.771, P = 0.002).
The area in which SSTR PET arguably adds the most clinical value in MTC is PRRT patient selection. This is an important consideration for patients with progressive disease who have already failed TKI therapy or who develop intolerable side effects, as 177Lu-DOTATATE PRRT represents one of the few alternative treatment options available to them.
The largest PRRT series in MTC to date was published by Parghane et al[21], who treated 43 patients and observed a median progression-free survival of 24 months and a median overall survival of 26 months. Of note, response rates reached 61% by PET Response Criteria in Solid Tumors and 62% by Response Evaluation Criteria in Solid Tumors criteria. Maghsoomi et al[22] conducted a systematic review of PRRT in 220 MTC patients, finding radiological disease control in 65.7%.
The evidence for PRRT in MTC remains limited and is almost entirely retrospective. No randomized controlled trial has compared PRRT with best supportive care or TKI therapy in this disease. The response rates reported in MTC (disease control 61%-66%)[21,22] are notably lower than the approximately 80% disease control rates observed in the NETTER-1 trial for midgut neuroendocrine tumours, reflecting the more variable and often lower SSTR expression in MTC compared with well-differentiated GEP-NETs[17]. Furthermore, the Krenning score threshold of ≥ 3 used to determine PRRT eligibility in MTC is borrowed directly from NET practice and has never been independently validated in a dedicated MTC cohort. No standardised uptake value cutoff for PRRT candidacy in MTC currently exists. The finding that only approximately 26% of metastatic MTC patients demonstrate sufficient uptake for PRRT eligibility[18] further underscores that this remains a niche application. Accordingly, SSTR PET for PRRT planning in MTC should be regarded as a promising but incompletely validated theranostic pathway rather than an established standard of care. It is worth noting that only approximately one quarter to one third of MTC patients demonstrate sufficient SSTR uptake for PRRT eligibility. The combination of high SSTR uptake with low FDG avidity appears to best predict favourable PRRT outcomes[18,21].
With three tracers targeting three distinct biological pathways, the practical question becomes which tracer to use and when. Published meta-analyses offer a degree of guidance on this question.
The network meta-analysis by Lee et al[5], which compared five PET radiopharmaceuticals, placed 18F-FDOPA at the top for both patient-level and lesion-level detection rates. Asa et al[9] compared 18F-FDOPA and 68Ga-DOTATATE directly in 46 patients. FDOPA sensitivity was at 86.8%, slightly ahead of DOTATATE at 84.2%, with the difference most apparent in lymph node and liver metastases. An umbrella review by Trimboli et al[23], which pulled together all existing meta-analyses on MTC diagnostic tests, reached the same conclusion: 18F-FDOPA remains the strongest PET option for picking up recurrent disease.
Each tracer has particular strengths depending on the anatomical site involved. A network meta-analysis by Li et al[10] specifically examined sensitivities across the four most common metastatic locations in MTC (Table 2). Their results showed that 18F-FDOPA had the best performance for neck/Lymph node disease and liver metastases, while 68Ga-SSTR PET was the most sensitive modality for bone metastases[19,10]. ¹¹C-methionine showed the highest sensitivity for lung lesions, though its clinical availability remains limited.
| Metastatic site | 18F-FDOPA | 68Ga-SSTR | 18F-FDG | 11C-methionine | Best performing tracer |
| Neck/Lymph nodes | 85.7% | 68.2% | 61.5% | 83.3% | 18F-FDOPA |
| Liver | 90.9% | 75.0% | 66.7% | 88.9% | 18F-FDOPA |
| Bone | 84.2% | 94.7% | 78.9% | 89.5% | 68Ga-SSTR |
| Lung | 78.6% | 71.4% | 71.4% | 92.9% | ¹¹C-methionine |
The EANM 2020 guideline[7] and Treglia et al[8] recommend a phenotype-driven sequence. Drawing on this evidence, we propose the following practical, radiology-centric algorithm (Figure 2).
In the setting of biochemical recurrence (Ctn > 150 pg/mL with slow doubling time), 18F-FDOPA PET/CT should be the starting investigation. Its high sensitivity for differentiated disease makes it well-suited to this common clinical presentation. When disease behaviour appears aggressive (rapid Ctn/CEA doubling time < 24 months), 18F-FDG PET/CT should be prioritised, either as the initial test or following a negative 18F-FDOPA scan. FDG positivity in this context flags aggressive tumour biology and a worse prognosis[15]. For theranostic planning or when bone metastases are suspected, 68Ga-SSTR PET/CT is the appropriate choice. SSTR imaging is a prerequisite before PRRT and detects bone metastases with greater accuracy than other tracers[17-19]. Matching tracer choice to expected tumour phenotype improves diagnostic yield.
The Ctn and doubling-time thresholds that inform each branch of this algorithm are drawn from the published literature and can be summarised as follows. For 18F-FDOPA, the EANM guideline recommends its use when serum Ctn exceeds 150 pg/mL[7]. Detection sensitivity rises with increasing Ctn: Pooled rates approximate 66% overall[4], rising to 86%-95% when Ctn exceeds 1000 pg/mL[4,6], and reaching 100% when Ctn exceeds 150 pg/mL in the Brammen initial-staging cohort[3]. For 18F-FDG, the clinical trigger is aggressive biomarker kinetics: Ctn or CEA doubling time shorter than 24 months is the threshold most consistently associated with FDG avidity, with sensitivity reaching 75% when Ctn exceeds 1000 pg/mL and 91% when doubling time is under 24 months[14,15]. The ATA guidelines note that FDG-PET is most informative when Ctn exceeds 500-1000 pg/mL and has limited sensitivity below this range[11]. For 68Ga-SSTR PET, no Ctn threshold has been validated for predicting sufficient uptake. The Krenning score ≥ 2 criterion used to determine PRRT eligibility[21] is borrowed from NET practice and has not been independently validated in MTC. It is important to note that these thresholds derive from retrospective analyses with variable inclusion criteria and assay methods; they are not uniformly standardised across studies and should be interpreted as practical guidance rather than rigid decision rules.
Several important caveats apply to this algorithm. First, it is expert-informed and evidence-synthesised, drawing on the pooled findings of retrospective cohorts, meta-analyses, and published guideline recommendations[7,8]; it has not been prospectively validated in a multicentre trial, and the underlying data are heterogeneous in design, patient selection, and Ctn thresholds. Second, the algorithm assumes access to 18F-FDOPA, which requires either an on-site cyclotron or a reliable regional supply chain. In many countries and centres, FDOPA is not routinely available. Where FDOPA cannot be obtained, a reasonable alternative is to begin with 18F-FDG PET/CT (particularly if biomarker kinetics suggest aggressive disease) and to add 68Ga-SSTR PET/CT when theranostic planning or bone metastasis assessment is required. Third, the Ctn and doubling-time thresholds cited within this algorithm are drawn from retrospective analyses and are not uniformly defined across studies; they should be interpreted as practical guidance rather than rigid decision rules. Prospective, multicentre trials are needed to validate this imaging sequence and to determine whether algorithm-guided tracer selection translates into improved patient outcomes.
Two emerging platforms deserve attention (Table 3).
| Tracer platform | Target | Key advantage(s) | Ref. | Key finding(s) |
| CCK2R/minigastrin | CCK2R | Expressed in about 92% of MTCs | Günther et al[24], 2024 | Proof-of-concept PET imaging with high tumour uptake (SUVmax 7.4) |
| Complete theranostic platform (68Ga, 177Lu, 225Ac) | Holzleitner et al[25], 2025 | Preclinical 225Ac alpha therapy showed 4.5-fold survival benefit | ||
| FAPI | FAP | Targets tumour stroma, not tumour cells | Kong et al[27], 2025 | Head-to-head vs FDG: 98% vs 66% detection rate; SUVmax 11.7 vs 2.6; changed management in 32% of patients |
| Very high tumour-to-background contrast | ||||
| Novel SSTR | SSTR | 18F-labelling overcomes 68Ga generator limitations | Kunte et al[20], 2025 | 18F-SiTATE PET burden correlated with calcitonin levels (r = 0.771) |
| Improved logistics and potentially higher resolution |
The CCK2R is expressed in approximately 92% of MTC tumours, making it the most consistently expressed targetable receptor in this disease[24]. The first clinical proof-of-concept was provided by Günther et al[24], who imaged 2 MTC patients with 68Ga-DOTA-CCK-66 PET/CT. Tumour uptake was in a similar range to 18F-FDOPA (SUVmax of 7.4 compared with 7.0), and tumour-to-background ratios were approximately 2-fold higher than those reported with older minigastrin compounds. On the therapeutic side, Holzleitner et al[25] tested 225Ac-DOTA-CCK-66 in preclinical models and reported a 4.5-fold survival benefit over controls; this exceeded the 3-fold benefit seen with 177Lu-labelled beta therapy. A phase I/IIA pilot study by von Guggenberg et al[26] subsequently demonstrated the clinical feasibility of 68Ga-DOTA-MGS5 in a cohort of 12 patients. What makes the CCK2R platform particularly compelling is its potential to serve as a complete theranostic system for MTC: 68Ga for diagnostic PET imaging, 177Lu for beta therapy, and 225Ac for alpha therapy, all directed at the same receptor.
Fibroblast activation protein is highly expressed in the tumour stroma of many epithelial cancers, including MTC. Kong et al[27] published what can be considered a landmark first-in-class clinical trial comparing 68Ga-CTR-FAPI PET/CT with 18F-FDG PET/CT in 50 MTC patients. The results were striking: Patient-based detection was 98% vs 66% (P = 0.0002), mean SUVmax was 11.71 vs 2.55 (P < 0.0001), pathology-validated diagnostic accuracy reached 96.7%, and management was changed in 32% of patients.
CTR-FAPI uses covalent targeted radioligand technology, achieving > 80% irreversible fibroblast activation protein binding with 257% greater tumour uptake and 13-fold increased retention compared with standard FAPI compounds. A phase II trial (NCT06277180) is now evaluating CTR-FAPI PET/CT-guided precision surgery.
The findings of this review reinforce the notion that no single PET tracer can adequately characterise MTC in all its clinical presentations. The disease is biologically heterogeneous, and this heterogeneity has direct consequences for imaging. A well-differentiated, Ctn-secreting tumour recurrence behaves very differently from a dedifferentiated, rapidly progressing lesion, and the tracer that works well for one may fail for the other. Recognising this is, in our view, the most important practical takeaway for clinicians.
The evidence base for 18F-FDOPA in recurrent MTC is now reasonably mature. Multiple meta-analyses and a large single-centre series spanning 15 years consistently place it at the top for patient-level detection[4,5,6,23]. However, it is worth acknowledging that much of this literature comes from retrospective, single-centre cohorts. Prospective, mul
It is also important to acknowledge that FDOPA’s position as the first-line PET tracer, while well-supported by current literature, may be conditional rather than universal. Several factors temper the strength of this recommendation. First, there is considerable heterogeneity between the studies pooled in the FDOPA meta-analyses[4,5,23]. Inclusion criteria vary in the Ctn thresholds used for patient selection (some studies enrolling patients with Ctn > 150 pg/mL, others > 500 pg/mL or > 1000 pg/mL), scanner technology has evolved across the study period, and reference standards differ. This heterogeneity inflates apparent pooled performance in some analyses and limits direct comparability. Second, sample sizes in the FDOPA literature are frequently small; the largest single-centre series comprises 109 patients[6], while most individual studies include 20 patients to 50 patients. The meta-analyses by Treglia et al[4] and Lee et al[5] necessarily pool these small cohorts, and no formal assessment of publication bias (such as funnel plot analysis) has been reported across the FDOPA literature in MTC specifically. Studies reporting high sensitivity are more likely to be published, which may overestimate the true diagnostic yield. Third, geographic availability and regulatory access represent a practical barrier. FDOPA requires a cyclotron-based production facility or a reliable supply chain, and it is not approved or routinely accessible in many countries, including large parts of the Middle East, Asia, South America, and some centres in the United States and Europe. Algorithms that default to FDOPA as first-line are therefore not universally applicable, and the alternative sequence of FDG combined with SSTR PET must be considered for centres where FDOPA is unavailable. Finally, FDOPA’s sensitivity advantage is most pronounced in well-differentiated, Ctn-secreting disease with high serum Ctn levels (> 500-1000 pg/mL); in low-Ctn recurrence or dedifferentiated tumours, its advantage over FDG narrows considerably or may be reversed entirely, as the flip-flop phenomenon demonstrates[15].
The “flip-flop” phenomenon between FDOPA and FDG uptake has important clinical implications that go beyond tracer selection[15]. It effectively serves as a non-invasive biomarker of tumour differentiation (Figure 1). When a patient’s disease shifts from FDOPA-avid to FDG-avid over time, this may indicate biological progression that should prompt a reassessment of the management strategy[7,8]. Whether serial dual-tracer imaging can detect such transitions early enough to influence outcomes is an open question and one that warrants formal study.
The role of SSTR PET in MTC is narrower than in GEP-NETs, and this should be communicated clearly to referring physicians. The pooled detection rate of 63.5% is significantly lower than the 96% reported in typical NETs[17]. That said, the theranostic potential of SSTR PET in MTC, while clinically meaningful for a selected subset of patients, should not be equated with the robust evidence base that supports PRRT in well-differentiated GEP-NETs. For the subset of patients who do express sufficient SSTR, PRRT offers a meaningful therapeutic option, and the imaging step is essential for patient selection[18,21]. The challenge lies in the fact that only about a third of MTC patients will show adequate uptake. The development of standardized uptake thresholds for PRRT eligibility remains an unmet need.
The emergence of CCK2R and FAPI as novel imaging targets is encouraging, though caution is warranted. The CCK2R data, while biologically compelling, come from a handful of patients[24-26]. Similarly, the CTR-FAPI results reported by Kong et al[27] are impressive (98% detection) but derive from a single trial at a single centre. Larger, independent validation studies are necessary before these tracers can be incorporated into routine practice. Nevertheless, the theranostic potential of CCK2R, which could offer a single-receptor platform for diagnosis and both beta and alpha therapy, is a development worth watching closely.
A further point that deserves emphasis is the integration of serum biomarkers with imaging. Ctn and CEA doubling times are not merely triggers for ordering a PET scan; they should actively guide which tracer is selected[2,7]. This review and the EANM guideline both advocate for a biology-driven algorithm (Figure 2), but real-world implementation will require better education and closer collaboration between endocrinologists, surgeons, and nuclear medicine physicians[8,29].
Finally, several limitations of the current evidence should be acknowledged. The majority of studies included in this review are retrospective[28]. Sample sizes are frequently small, and there is considerable heterogeneity in the Ctn thresholds and imaging protocols used across studies. Geographic variation in tracer availability further complicates the generalisability of published algorithms[7,8]. These factors underscore the need for well-designed, prospective, multicentre trials.
18F-FDOPA PET is the first-line functional imaging modality for localizing disease in patients with biochemical recurrence of MTC (serum Ctn > 150 pg/mL) and slow biomarker kinetics (doubling time > 24 months). 18F-FDG PET is essential for prognostic stratification and should be prioritised in patients with aggressive disease, as indicated by rapid Ctn or CEA doubling times (< 24 months). High FDG uptake signifies a poor prognosis. 68Ga-SSTR PET holds a unique theranostic role and should be performed to document sufficient SSTR expression before PRRT. It is also the most sensitive modality for detecting bone metastases. A dual-tracer approach (18F-FDOPA and 18F-FDG) is often necessary to capture the full heterogeneity of MTC and provides more comprehensive disease assessment than either tracer alone. Anatomic imaging (ultrasonography, CT, MRI) remains foundational for initial staging. PET imaging plays a selective role in high-risk patients at diagnosis but is primarily used for restaging recurrent or metastatic disease. Always integrate serum biomarker levels (Ctn, CEA) and their doubling times with imaging findings to guide management.
PET has fundamentally changed how clinicians manage MTC, particularly in the recurrent and metastatic settings. The accumulated data favour a biology-driven, multimodal approach that plays to the individual strengths of each tracer. For the majority of patients presenting with biochemical recurrence, 18F-FDOPA should remain the first-line tracer. When there is clinical suspicion of aggressive disease, whether based on rapid marker kinetics or high-grade histology, 18F-FDG PET provides critical prognostic information and may reveal dedifferentiated lesions that FDOPA would miss. SSTR PET occupies an essential theranostic niche, both in determining PRRT eligibility and in its superior detection of bone metastases.
Important gaps in the evidence remain. Prospective head-to-head trials are still needed to establish the optimal imaging sequence and to measure the real-world impact of PET-guided management on patient outcomes. Standardized SSTR PET thresholds for PRRT patient selection also require validation. On the horizon, CCK2R and FAP tracers appear promising: CTR-FAPI achieved 98% detection in early trials, and CCK2R analogues may ultimately provide a comprehensive theranostic platform tailored to MTC. Ultimately, linking tracer selection to tumour phenotype should sharpen the way imaging informs both surgical planning and systemic treatment decisions.
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