aggressive histologic subtypes of thyroid cancer are less frequent and have a worse prognosis than well - differentiated thyroid carcinoma ( dtc ) .
most important aggressive subtypes of thyroid cancer are hrthle cell carcinoma ( hctc ) and anaplastic and poorly differentiated carcinoma ( atc and pdtc ) .
now , it is included in aggressive histologic subtypes , because of its biological behaviour .
atc could be a de novo tumour or arising from dedifferentiation of dtc . during this process
, thyroid cancer could be found in an intermediate differentiation pattern , classified as pdtc .
both atc and pdtc have a poor prognosis and efficient diagnostic tools are needed to improve survival . after those about dtc and medullary thyroid cancer ( mtc ) [ 1 , 2 ] , american thyroid association ( ata ) recently published guidelines for the management of patients with atc .
fluorine-18-fluorodeoxyglucose ( fdg ) , a glucose analogue , is the most used positron emission tomography ( pet ) tracer in oncology .
although fdg - pet and pet / ct have a moderate sensitivity for early - stage , well - differentiated thyroid malignancy , they are currently used in dtc , particularly in postthyroidectomy patients with high serum thyroglobulin ( tg ) levels and a negative radioiodine whole - body scan , as prognostic tool in patients with metastases , for the measurement of posttreatment response , and as selection tool in patients not eligible to radioiodine therapy [ 57 ] .
fdg - pet or pet / ct is also used in recurrent mtc and in thyroid nodules with indeterminate or nondiagnostic fine needle aspiration biopsy ( fnab ) . during dedifferentiation process ( from dtc to atc ) , an inverse relationship between radioiodine ( i-131 ) and fdg uptake in thyroid cancer cells was observed ( the so - called flip - flop phenomenon ) .
a recent study highlights that thyroid cancer dedifferentiation is characterized by glucose transporters ( glut1 ) upregulation and reduced expression of sodium - iodide symporter ( nis ) .
this is the rationale to propose fdg - pet or pet / ct as efficient diagnostic tools in atc , pdtc , and other aggressive subtypes of thyroid cancer .
the aim of this paper is to perform an overview of the literature about the role of fdg - pet or pet / ct in aggressive histological subtypes of thyroid cancer .
initially , hctc was included in dtc group , but it has a different oncogenic expression and is now considered as different histological and clinic disease .
hctc has a 10-year disease - free survival of 40% and mortality of 51% , worse than dtc .
in fact , hctc is associated with a high risk of distant and lymph nodal metastases having a worse prognosis compared to dtc .  
only few studies about the role of fdg - pet or pet / ct in hctc have been published in the literature .
some authors suggested a good sensitivity of fdg - pet in hctc [ 13 , 14 ] and hrthle cell adenoma .
overall , hctc seems to be unable to concentrate i-131 , but it is an fdg - avid tumour .
there were 24 positive and 20 negative fdg - pet scans giving a sensitivity of 95.8% and a specificity of 95% .
these authors suggested that fdg - pet could be indicated in patients with hctc in postoperative staging and as followup in patients with an increase of tg or recurrent disease .
lowe et al .   studied 14 fdg - pet scans in patients with hctc .
pet findings were positive in all but 1 of patients with known disease , with a sensitivity of 92% .
moreover , in 7 out of 14 pet scans , a disease not diagnosed by other techniques was demonstrated . in 7 patients ,
so , these authors concluded that fdg - pet improves staging and disease management in patients with htct .
a , patients with an elevated tg level were included ( n = 13 ) , and in 10 cases pet scans were true positive . in subgroup b ,
patients with a suspect morphologic imaging were included ( n = 4 ) , and pet scans were true negative in three cases .
overall , fdg - pet demonstrated a sensitivity of 92% , a specificity of 80% , a positive predictive value of 92% , a negative predictive value of 80% , and an accuracy of 89% in hctc .
overall , fdg - pet or pet / ct seems to be useful functional imaging methods in initial staging or restaging of hctc ( figure 1 ) , presenting high diagnostic accuracy in this setting ( table 1 ) .
atc is a rare and aggressive tumour , representing less than 5% of all thyroid carcinomas and originating by thyroid follicular cells
atc is often diagnosed in older patients and usually has a rapid growth and an extensive local invasion [ 2123 ] .
three main histological subtypes of atc are reported : spindle cell , pleomorphic giant cell , and squamous cell subtype . in over 70% of the patients
the tumour infiltrates surrounding tissues , and median survival time is about 68 months . in differential diagnosis , it is important to distinguish atc and pdtc .
in fact , proportion of atc , pdtc , or dtc characterizing the thyroid tumour can change prognosis and clinical management .
this aggressive thyroid tumour is not able to uptake iodine and to produce tg [ 19 , 20 , 24 , 25 ] .
conversely , atc has a high glucose metabolism and high fdg uptake [ 5 , 9 ] .
ata recommended fdg - pet and pet / ct in evaluating metastatic patients , especially bone lesions .
moreover , fdg - pet may be useful in distinguishing atc from dtc metastases because of the higher fdg uptake of atc .
other indications described about fdg - pet or pet / ct in atc were resectability evaluation and followup , with a higher sensitivity than ct alone .
fdg - pet is also recommended 36 months after therapy in patients with no disease or in persistent structural disease as a guide to therapy .
few original studies have been published about the role of fdg - pet in atc ( table 1 ) .
poisson et al .   studied 20 consecutive atc patients with fdg - pet / ct for initial staging and during followup .
authors analysed progression on imaging followup ( ct or pet / ct ) . per lesion ,
maximal standardised uptake value ( suvmax ) and functional volume were a predictive factor for survival .
conversely , in bivariate analysis , only functional volume was a prognostic factor . early evaluation of treatment has been done in 4 out of 11 patients in whom pet and ct were both registered .
after treatment with combined radiotherapy and chemotherapy , a negative fdg - pet / ct scan confirmed a complete long - term remission .
finally , authors suggested the use of fdg - pet / ct in atc during initial staging . among other imaging modalities , only preoperative ct should be requested .
fdg - pet / ct could be also recommended in both early and long - term followup and in the assessment of treatment response .
pet data were compared with other diagnostic tools ( ct , ultrasound , magnetic resonance imaging , bone scan , and histology ) and with clinical follow - up .
in all 16 patients included , pet records resulted true positive for primary tumours . in 50% of patients
these authors concluded that fdg - pet could improve disease staging changing the clinical management of patients with atc .
overall , fdg - pet or pet / ct should be used in patients with atc in initial staging and in the followup after surgery to evaluate metastatic disease ( figure 2 ) . in selected cases
, these functional imaging methods may be helpful in directing treatment and in evaluating the efficacy of therapy .
new studies are needed to investigate the role of fdg - pet or pet / ct in detecting the proportion of dtc , atc , and pdtc in the same tumour .
pdtc is an intermediate histological subtype between dtc and atc and may be a transition form .
conversely to atc , pdtc preserves some markers of differentiation , such as tg and thyroid transcription factor 1 ( ttf1 ) , and does not represent a de novo tumour . in dedifferentiation process ,
pdtc and atc present a growing number of chromosomal alteration , such as ras , braf , tp53 , and b - catenin mutations [ 3 , 11 ] .
activation of the pten / pi3 kinase / akt / mammalian target of rapamycin pattern and mutation of the akt or pik3ca genes are more common in pdtc and atc than dtc [ 2629 ] .
these metabolic pathways could be related to the different fdg - pet pattern in different subtypes of thyroid cancer .
pdtc has an intermediate glut1 expression and fdg uptake between atc and dtc , because of  flip - flop  phenomenon [ 9 , 30 ] .
more often pdtc is an fdg - pet positive tumour [ 5 , 9 ] .
an in vitro study suggested that thyrotropin ( tsh ) increases fdg uptake in pdtc cells ; so , fdg - pet scans under tsh stimulation may be more efficient .
surgery and radiotherapy could be indicated in treatment of pdtc but not radioiodine treatment , because of poor radioiodine uptake .
some authors suggested the use of fdg - pet or pet / ct in staging patients with pdtc ( figure 3 ) , especially in postthyroidectomy staging of high - risk patients .
some authors studied the role of fdg - pet in all thyroid cancer subtypes but included only few cases of pdtc in their analysis , not sufficient to conclude that fdg - pet is efficient for this histological tumour type .
more preclinical and clinical studies are needed about fdg - pet or pet / ct in pdtc to demonstrate the clinical usefulness of fdg - pet in pdtc .
limited experience exists about the role of fdg - pet or pet / ct in patients with more aggressive histological subtypes of dtc , including case reports or small case series in patients with tall cell , diffuse sclerosing [ 3335 ] , solid / trabecular   and insular variant   of dtc .
these articles underlines that fdg - pet or pet / ct seem to be very useful tools for the staging and restaging of such tumours .
radioactive iodine - refractory ( rair ) fdg - pet positive thyroid carcinomas represent the major cause of deaths from thyroid carcinomas and are therefore the main focus of novel target therapies .
although the majority of primary thyroid carcinomas leading to rair fdg - pet positive metastatic disease are pdtc , dtc can also be responsible for rair disease .
histologic characterization of metastases / recurrence in 70 rair fdg - pet positive thyroid carcinoma patients revealed that 47.1% had pdtc , 20% had tall - cell variant of papillary thyroid carcinoma , 22.9% had well - differentiated papillary thyroid carcinoma ( including classic and follicular variants ) , 8.6% had hctc , and 1.4% had atc .
dtc presenting fdg uptake on pet scan and histological features such as necrosis should be considered aggressive differentiated cancers and fdg uptake in these tumours is highly prognostic for survival .
from this overview of the literature about the usefulness of fdg - pet or pet / ct in aggressive subtypes of thyroid tumours , we conclude the following : the role of fdg - pet or pet / ct in patients with hctc is clear in initial staging or followup of invasive and metastatic tumours;fdg - pet or pet / ct is recommended in staging , followup , and posttreatment restaging of atc , especially in metastatic disease , as published in ata guidelines;further evaluations are needed to investigate the role of fdg - pet or pet / ct in pdtc , because of the difficulties connected to define the biological behaviour of this aggressive subtype of thyroid cancer;limited experience suggests the usefulness of fdg - pet or pet / ct in patients with more aggressive histological subtypes of dtc;dtc presenting as rair and fdg - pet positive should be considered aggressive tumours with poor prognosis .
the role of fdg - pet or pet / ct in patients with hctc is clear in initial staging or followup of invasive and metastatic tumours ; fdg - pet or pet / ct is recommended in staging , followup , and posttreatment restaging of atc , especially in metastatic disease , as published in ata guidelines ; further evaluations are needed to investigate the role of fdg - pet or pet / ct in pdtc , because of the difficulties connected to define the biological behaviour of this aggressive subtype of thyroid cancer ; limited experience suggests the usefulness of fdg - pet or pet / ct in patients with more aggressive histological subtypes of dtc ; dtc presenting as rair and fdg - pet positive should be considered aggressive tumours with poor prognosis .
 aggressive histological subtypes of thyroid cancer are rare and have a poor prognosis . 
 the most important aggressive subtypes of thyroid cancer are hrthle cell carcinoma ( hctc ) and anaplastic and poorly differentiated carcinoma ( atc and pdtc ) . 
 the american thyroid association recently published guidelines for the management of patients with atc , but no specific guidelines have been done about hctc . 
 we performed an overview of the literature about the role of fluorine-18-fluorodeoxyglucose positron emission tomography or positron emission tomography / computed tomography ( fdg - pet or pet / ct ) in aggressive histological subtypes of thyroid cancer . only few original studies about the role of fdg - pet or pet / ct in hctc , pdtc , and atc 
 have been published in the literature . 
 fdg - pet or pet / ct seems to be useful in staging or followup of invasive and metastatic hctc . 
 fdg - pet or pet / ct should be used in patients with atc in initial staging and in the followup after surgery to evaluate metastatic disease . 
 some authors suggest the use of fdg - pet / ct in staging of pdtc , but more studies are needed to define the diagnostic use of fdg - pet / ct in this setting . 
 limited experience suggests the usefulness of fdg - pet or pet / ct in patients with more aggressive histological subtypes of dtc . 
 however , dtc presenting as radioiodine refractory and fdg - pet positive should be considered aggressive tumours with poor prognosis . 
1. Introduction
2. FDG-PET in Hrthle Cell Thyroid Carcinoma (HCTC)
3. FDG-PET in Anaplastic Thyroid Carcinoma (ATC)
4. FDG-PET in Poorly Differentiated Thyroid Carcinoma (PDTC)
5. FDG-PET in More Aggressive Histological Subtypes of DTC
6. Noniodine Concentrating Metastases of DTC
7. Conclusions