Medullary thyroid carcinoma (MTC) is a slow-growing neuroendocrine tumor originating from parafollicular C cells. MTC accounts for approximately 5% of thyroid carcinomas, occurring in either sporadic (75% of cases) or familial forms (25% of cases). This tumor is frequently aggressive; most frequent sites of metastatic disease are cervical and mediastinal lymph nodes, lungs, liver, and bone. The main treatment for MTC is surgical resection that is the only strategy for potential cure; in patients with metastatic disease therapeutic options are limited as this tumor does not concentrate radioiodine and shows poor response to chemotherapy and radiation therapy [
Serum calcitonin represents the most sensitive and accurate tumor marker in the postoperative management and surveillance of MTC. In about one third of patients with MTC lesions also carcinoembryonic antigen (CEA) levels may be increased and this finding has prognostic significance, as increased CEA levels are characteristic of advanced forms when the tumor tends to dedifferentiation. Serum calcitonin and CEA doubling times are efficient tools for assessing tumor progression and are useful prognostic factors of survival in patients with MTC [
The early detection of recurrence represents an important step in the management of patients with MTC, because identifying recurrent tumor tissue impacts in patient outcome [
Fluorine-18-Fluorodeoxyglucose (FDG), a glucose analog, accumulates in neoplastic cells allowing scintigraphic visualization of tumors that use glucose as an energy source. FDG uptake in neoplastic cells correlates with poor differentiation and high proliferative activity. Neuroendocrine tumors usually show an indolent course, and consequently low FDG uptake [
Dihydroxyphenylalanine (DOPA) is an amino acid that is converted to dopamine by aromatic amino acid decarboxylase (AADC). Fluorine-18-DOPA (FDOPA) is taken up through ubiquitous transmembrane amino acid transporter systems that are significantly upregulated in neuroendocrine tumors, including MTC. This upregulation is presumably secondary to the increased activity of metabolic pathways involving the enzyme AADC which is a specific property of neuroendocrine tumors.
The aim of this paper is to perform an overview of the literature about the role of PET and PET/CT using different radiopharmaceuticals in patients with recurrent MTC based on biochemical findings (increased tumor marker levels after primary surgery).
A comprehensive computer literature search of the PubMed/MEDLINE, Scopus and Embase databases was carried out to find relevant published articles on the role of PET or PET/CT using different radiopharmaceuticals in patients with recurrent MTC. We used a search algorithm based on a combination of the terms: (a) “PET” or “positron emission tomography” and (b) “medullary” or “thyroid”. No beginning date limit was used; the search was updated until February 29th 2012. To expand our search, references of the retrieved articles were also screened for additional studies. No language restriction was used.
Only those studies or subsets in studies that satisfied all of the following criteria were included: (a) PET or PET/CT performed in patients with suspected recurrent MTC after primary surgery; (b) sample size of at least 6 patients with MTC. The exclusion criteria were (a) articles not within the field of interest of this paper; (b) review articles, editorials or letters, comments, conference proceedings; (c) case reports or small case series (sample size of less than 6 patients with recurrent/residual MTC); (d) possible data overlap (in such cases the most complete article was included).
For each included study, information was collected concerning basic study (author names, journal, year of publication, and country of origin), patient characteristics (number of patients with suspected recurrent MTC performing PET or PET/CT, mean age, and sex), technical aspects (study design, device used, radiopharmaceutical used, injected dose, time interval between radiopharmaceutical injection and image acquisition, acquisition protocol, image analysis, and reference standard used), and diagnostic performance data (sensitivity and specificity). Patients evaluated with PET or PET/CT before primary surgery were excluded from the analysis. Only patients with a postoperative PET imaging were included.
Twenty-nine articles comprising 714 patients with suspected recurrent MTC were retrieved using the above cited criteria [
Basic study and patient characteristics.
Authors | Year | Country | MTC patients performing PET for suspected recurrence | Mean age (years) | % Male | Tracers used for PET or PET/CT |
---|---|---|---|---|---|---|
Treglia et al. [ |
2012 | Italy | 18 | 53 | 33% | FDG, FDOPA, and Gallium-68-DOTANOC/DOTATOC |
Kauhanen et al. [ |
2011 | Finland | 19 | 52 | 53% | FDG and FDOPA |
Ozkan et al. [ |
2011 | Turkey | 33 | 50 | 27% | FDG |
Gómez-Camarero et al. [ |
2011 | Spain | 31 | 56 | 45% | FDG |
Palyga et al. [ |
2010 | Poland | 8 | 56 | 50% | Gallium-68-DOTATATE |
Jang et al. [ |
2010 | Korea | 16 | 51 | 56% | FDG and Carbon-11-methionine |
Luster et al. [ |
2010 | Germany | 28 | 48 | 46% | FDOPA |
Skoura et al. [ |
2010 | Greece | 32 (38 scans) | 52 | 31% | FDG |
Marzola et al. [ |
2010 | Italy | 18 | 51 | 44% | FDG and FDOPA |
Bogsrud et al. [ |
2010 | USA and Norway | 29 | 50 | 55% | FDG |
Conry et al. [ |
2010 | UK and Singapore | 18 | 54 | 72% | FDG and Gallium-68-DOTATATE |
Beheshti et al. [ |
2009 | Austria | 19* | 59 | 38% | FDG and FDOPA |
Faggiano et al. [ |
2009 | Italy | 26 | NR | 49% | FDG |
Koopmans et al. [ |
2008 | The Netherlands | 21 | 56 | 48% | FDG and FDOPA |
Rubello et al. [ |
2008 | Italy | 19 | 53 | 42% | FDG |
Oudoux et al. [ |
2007 | France | 33 | 53 | 64% | FDG |
Giraudet et al. [ |
2007 | France | 55 | 56 | 62% | FDG |
Czepczyński et al. [ |
2007 | Poland and Italy | 13* | 50 | 57% | FDG |
Beuthien-Baumann et al. [ |
2007 | Germany | 15 | 56 | 53% | FDG and FDOPA |
Ong et al. [ |
2007 | USA | 28 (38 scans) | 59 | 64% | FDG |
Iagaru et al. [ |
2007 | USA | 13 | 48 | 46% | FDG |
Gotthardt et al. [ |
2006 | Germany and the Netherlands | 26 | 45 | 58% | FDG |
De Groot et al. [ |
2004 | The Netherlands | 26 | 51 | 58% | FDG |
Szakáll et al. [ |
2002 | Hungary | 40 | 48 | 45% | FDG |
Diehl et al. [ |
2001 | Germany | 85 (100 scans) | 53 | 47% | FDG |
Hoegerle et al. [ |
2001 | Austria | 10* | 57 | 55% | FDG and FDOPA |
Brandt-Mainz et al. [ |
2000 | Germany | 17 | NR | 65% | FDG |
Adams et al. [ |
1998 | Germany | 8 | 49 | 50% | FDG |
Musholt et al. [ |
1997 | USA and Germany | 10 | 36 | 70% | FDG |
NR: not reported; FDG: fluorine-18-fluorodeoxyglucose; FDOPA: fluorine-18-dihydroxyphenylalanine; *patients evaluated before primary surgery were excluded from the analysis.
Twenty-seven articles evaluating the role of FDG-PET or PET/CT in patients with recurrent MTC were selected and retrieved from the literature (Tables
Technical aspects of the studies which used FDG-PET or PET/CT for detecting recurrent medullary thyroid carcinoma.
Authors | Study design | Device | Injected activity | Time between tracer injection and image acquisition (min) | PET acquisition protocol | Image analysis | Reference standard | Sensitivity of FDG-PET or PET/CT* | Specificity of FDG-PET or PET/CT* |
---|---|---|---|---|---|---|---|---|---|
Treglia et al. [ |
Retrospective multicenter | PET/CT | 259–407 MBq | 60 | Static acquisition | Qualitative | Histology and/or clinical/imaging followup | 17% | NC |
Kauhanen et al. [ |
Prospective multicenter | PET/CT | 377 MBq | 60 | Static acquisition (3 min per bed position) | Qualitative and semiquantitative | Histology and/or clinical/imaging followup | 53% | NC |
Ozkan et al. [ |
Retrospective single center | PET/CT | 296–370 MBq | 60 | Static acquisition (4 min per bed position) | Qualitative and semiquantitative | Histology and/or clinical/imaging followup | 93% | 68% |
Gómez-Camarero et al. [ |
Retrospective single center | PET and PET/CT | 333–434 MBq | 60 | Static acquisition | Qualitative and semiquantitative | Histology and/or clinical/imaging followup | 88% | 85% |
Jang et al. [ |
Prospective single center | PET/CT | 370 MBq | 60 | Static acquisition (4 min per bed position) | Qualitative | Histology and/or clinical/imaging followup | 63% | NC |
Skoura et al. [ |
Retrospective single center | PET/CT | 370 MBq | 60 | Static acquisition (4 min per bed position) | Qualitative and semiquantitative | Histology and/or clinical/imaging followup | 47% | NC |
Marzola et al. [ |
NR; multicenter | PET/CT | 2.2 MBq/kg | 60 | Static acquisition (3 min per bed position) | Qualitative and semiquantitative | Histology | 61% | NC |
Bogsrud et al. [ |
Retrospective single center | PET and PET/CT | 740 MBq | 60–75 | Static acquisition (5 min per bed position) | Qualitative | Histology and/or clinical/imaging followup | 45% | 93% |
Conry et al. [ |
Retrospective multicenter | PET/CT | 195–550 MBq | 50–75 | Static acquisition (1.5/5 min per bed position) | Qualitative and semiquantitative | Histology and/or clinical/imaging followup | 78% | NC |
Beheshti et al. [ |
Prospective single center | PET/CT | 370 MBq | 60 | Static acquisition (4 min per bed position) | Qualitative and semiquantitative | Histology and/or clinical/imaging followup | 58% | NC |
Faggiano et al. [ |
Retrospective multicenter | PET | 222–370 MBq | 60–90 | Static acquisition (4 min per bed position) | Qualitative | Histology and/or clinical/imaging followup | 50% | NC |
Koopmans et al. [ |
Prospective single center | PET | NR | NR | Static acquisition(5 min per bed position) | Qualitative | Histology and/or clinical/imaging followup | 24% | NC |
Rubello et al. [ |
Prospective multicenter | PET/CT | 5.5 MBq/kg | 60–90 | Static acquisition (4 min per bed position) | Qualitative and semiquantitative | Histology | 79% | 100% |
Oudoux et al. [ |
Prospective multicenter | PET/CT | 310–450 MBq | 60 | Static acquisition | Qualitative and semiquantitative | Histology and/or clinical/imaging followup | 76% | NC |
Giraudet et al. [ |
Prospective single center | PET/CT | 5 MBq/Kg | 60 | Static acquisition | Qualitative and semiquantitative | Histology and/or clinical/imaging followup | 32% | NC |
Czepczyński et al. [ |
NR; single center | PET | NR | NR | Static acquisition | Qualitative | Histology and/or clinical/imaging followup | 58% | NC |
Beuthien-Baumann et al. [ |
Retrospective single center | PET | 370 MBq | 60 | Static acquisition | Qualitative | Histology and/or clinical/imaging followup | 47% | NC |
Ong et al. [ |
Retrospective single center | PET and PET/CT | 555 MBq | Minimum 45 | Static acquisition (4 min per bed position) | Qualitative and semiquantitative | Histology and/or clinical/imaging followup | 62% | NC |
Iagaru et al. [ |
Retrospective single center | PET and PET/CT | 550 MBq | 45/60 | Static acquisition (4/5 min per bed position) | Qualitative | Histology and/or clinical/imaging followup | 86% | 83% |
Gotthardt et al. [ |
NR; multicenter | PET | 350 MBq | 60 | Static acquisition | Qualitative | Histology and/or clinical/imaging followup | 70% | NC |
De Groot et al. [ |
Prospective single center | PET | 400 MBq | 90 | Static acquisition (5 min per bed position) | Qualitative | Histology and/or clinical/imaging followup | 41% | NC |
Szakáll et al. [ |
Retrospective single center | PET | 5.55 MBq/Kg | 40 | Static acquisition (10 min per bed position) | Qualitative | Histology and/or clinical/imaging followup | 95% | NC |
Diehl et al. [ |
Retrospective multicenter | PET | 300–500 MBq | Minimum 30 | Static acquisition | Qualitative | Histology and/or clinical/imaging followup | 78% | 79% |
Hoegerle et al. [ |
Prospective single center | PET | 330 MBq | 90 | Static acquisition | Qualitative | Histology and/or clinical/imaging followup | 60% | 100% |
Brandt-Mainz et al. [ |
Prospective single center | PET | 350 MBq | 30 | Static acquisition (15–20 min per bed position) | Qualitative | Histology and/or clinical/imaging followup | 76% | NC |
Adams et al. [ |
Prospective single center | PET | 374 MBq | 60 | Static acquisition (12–15 min per bed position) | Qualitative | Histology and/or clinical/imaging followup | 87% | NC |
Musholt et al. [ |
NR; single center | PET | 370–555 MBq | 40 | Static acquisition (10 min per bed position) | Qualitative | Histology and/or clinical/imaging followup | 90% | NC |
NR: not reported; NC: not calculated; *sensitivity and specificity are reported on a per patient-based analysis.
False negative results of FDG-PET and PET/CT could be related to small lesions or to the slow growth of neuroendocrine tumors. Both factors impact the diagnostic accuracy of these imaging modalities. False positive results also occurred by using FDG-PET and PET/CT, and were typically due to inflammatory lesions [
It should be noted that a significant number of recurrent MTC, based on rising levels of tumor markers, remained unidentified using FDG-PET or PET/CT. On the other hand, it should be considered that FDG-PET and PET/CT were often performed in patients with suspected recurrent MTC after negative conventional imaging studies, affecting the surgical management of patients with recurrent MTC when hypermetabolic lesions were detected [
Based on literature findings, the diagnostic performance of FDG-PET or PET/CT in patients with recurrent MTC improved in patients with higher serum calcitonin and CEA levels [
FDG-PET or PET/CT were usually performed in the included studies if no disease sites were identified on conventional imaging in patients with biochemical evidence of MTC recurrence or if calcitonin levels were elevated out of proportion to minor disease found on conventional imaging. The diagnostic performance of FDG-PET and PET/CT in recurrent MTC increased whether patients with known lesions at conventional imaging were included in the study population, because functional abnormalities are usually detectable by FDG-PET or PET/CT when anatomical changes are already evident.
Eight articles evaluating the role of FDOPA-PET or PET/CT in patients with recurrent MTC were selected and retrieved from the literature (Tables
Technical aspects of the studies which used FDOPA-PET or PET/CT for detecting recurrent medullary thyroid carcinoma.
Authors | Study design | Device | Injected activity | Time between tracer injection and image acquisition (min) | PET acquisition protocol | Image analysis | Reference standard | Sensitivity of FDOPA-PET or PET/CT* | Specificity of FDOPA-PET or PET/CT* |
---|---|---|---|---|---|---|---|---|---|
Treglia et al. [ |
Retrospective multicenter | PET/CT | 4 MBq/kg | 60 | Static acquisition (3 min per bed position)no carbidopa premedication | Qualitative | Histology and/or clinical/imaging followup | 72% | NC |
Kauhanen et al. [ |
Prospective multicenter | PET/CT | 243 MBq | 60 | Static acquisition (3 min per bed position)carbidopa premedication | Qualitative and semiquantitative | Histology and/or clinical/imaging followup | 58% | NC |
Luster et al. [ |
Retrospective single center | PET/CT | 298 MBq | 60 | Static acquisition (4 min per bed position)carbidopa premedication | Qualitative and semiquantitative | Histology and/or clinical/imaging followup | 74% | 100% |
Marzola et al. [ |
Multicenter | PET/CT | 2.2 MBq/kg | 60 | Static acquisition (3 min per bed position)no carbidopa premedication | Qualitative and semiquantitative | Histology | 83% | NC |
Beheshti et al. [ |
Prospective single center | PET/CT | 4 MBq/Kg | 30 | Static acquisition (4 min per bed position)no carbidopa premedication | Qualitative and semiquantitative | Histology and/or clinical/imaging followup | 81% | NC |
Koopmans et al. [ |
Prospective single center | PET | 180 MBq | 60 | Static acquisition; (5 min per bed position)carbidopa premedication | Qualitative | Histology and/or clinical/imaging followup | 62% | NC |
Beuthien-Baumann et al. [ |
Retrospective single center | PET | 4.8 MBq/Kg | 45 | Static acquisition carbidopa premedication | Qualitative | Histology and/or clinical/imaging followup | 47% | NC |
Hoegerle et al. [ |
Prospective single center | PET | 220 MBq | 90 | Static acquisition no carbidopa premedication | Qualitative | Histology and/or clinical/imaging followup | 60% | NC |
NC: not calculated; *sensitivity and specificity are reported on a per patient-based analysis.
Differences in technical aspects (Table
Based on literature findings, the diagnostic performance of FDOPA-PET or PET/CT in recurrent MTC improved in patients with higher serum calcitonin levels [
Comparative analyses between FDOPA and FDG have shown better results with FDOPA in terms of sensitivity and specificity and a complementary role of the two radiopharmaceuticals in the assessment of recurrent MTC. The different behavior of FDOPA and FDG in recurrent MTC can be explained by their different uptake mechanisms that, in turn, reflect the different metabolic pathways of neuroendocrine cells, including MTC cells. FDOPA is a marker of amino acid decarboxylation that is a feature of the neuroendocrine origin of MTC; so, it can be assumed that a higher FDOPA uptake is related to a higher degree of cell differentiation, whereas a higher FDG uptake is related to a high proliferative activity and a poor differentiation.
In the study of Hoegerle et al. [
In the study of Beuthien-Baumann et al. [
Koopmans et al. [
In 2009 Beheshti et al. [
Marzola et al. [
Recently, Kauhanen et al. [
Lastly, in a recent multicentric study [
Neuroendocrine tumors usually overexpress somatostatin receptors on their cell surface and this represents the rationale for using somatostatin analogues for diagnosis and therapy of these tumors. In fact, PET or PET/CT using somatostatin analogues labelled with Gallium-68 are valuable diagnostic tools for patients with neuroendocrine tumors [
However, somatostatin receptor PET could be a useful method in selecting patients for radioreceptor therapy to treat metastatic lesions showing a high expression of somatostatin receptors.
Lastly, Carbon-11-Methionine, a PET radiopharmaceutical used to evaluate the amino acid metabolism, was also used in detecting recurrent MTC, without significant advantages compared to FDG [
PET radiopharmaceuticals reflect different metabolic pathways and seem to show complementary role in detecting recurrent MTC.
There is an increasing evidence in the literature about the role of FDG-PET and PET/CT in recurrent MTC. FDG-PET and PET/CT should not be considered as first-line diagnostic imaging methods in patients with suspected recurrent MTC, but could be very helpful in detecting recurrence in those patients in whom a more aggressive disease is suspected.
To date, FDOPA seems to be the most useful PET radiopharmaceutical in detecting recurrent MTC based on rising levels of tumor markers. Nevertheless, the literature focusing on the use of FDOPA-PET or PET/CT in the detection of recurrent MTC remains still limited.
Other PET radiopharmaceuticals, such as somatostatin analogues labelled with Gallium-68, were also evaluated for this indication in a limited number of studies.
Multicenter and prospective studies investigating a larger patient population and comparing different PET radiopharmaceuticals in recurrent MTC are needed.
The authors declare that they have no conflict of intrests.