An Appraisal and Update of Fluorodeoxyglucose and Non-Fluorodeoxyglucose-PET Tracers in Thyroid and Non- Thyroid Endocrine Neoplasms
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Aadil Adnan, MBBS, MDa,b, Shobhana Raju, MBBS, MD“, Rakesh Kumar, MBBS, DRM, DNB, MNAMS, PhDC, Sandip Basu, MBBS, DRM, DNB, MNAMSa,b,*
KEYWORDS
. Differentiated thyroid carcinoma . Aggressive variant of papillary thyroid carcinoma
· Thyroglobulin elevated negative iodine scintigraphy (TENIS)
. Anaplastic (undifferentiated) thyroid carcinoma . Medullary thyroid carcinoma
. Pheochromocytoma & Paraganglioma . Adrenocortical carcinoma . Parathyroid neoplasm
KEY POINTS
· Endocrine malignancies are composed of a spectrum characterized by differentiated, hormone- producing tumors to poorly differentiated and nondifferentiated carcinomas. These neoplasms have a cellular population, which is actively involved in synthesis and packaging of bioactive hor- mones, their transport to target cells and tissues and receptor-mediated target cell activity.
· The fact that these cells synthesize hormones and are stimulated or inhibited through specific re- ceptors is the core principle and can be exploited for various targeted approaches for diagnosis and treatment. Hence, functional molecular imaging provides opportunities for highly sensitive and specific targeted theranostic interventions.
· With increasing knowledge of pathogenesis, implicated genetic pathways, phenotypic expression, and overall tumor biology, demand for a specific target and corresponding radiotracers for better evaluation with potential for accurate clinical decision making is the need of the hour.
. The nuclear medicine fraternity has responded proportionately with many novel tracers evaluating various aspects of tumor biology, which are continuously being conceptualized and developed. Albeit the presence of several novel radiotracers and targets are on the horizon evaluating specific pathways in tumorigenesis, the importance of fluorodeoxyglucose as a prognostic marker cannot be undermined.
· The availability of a multitude of novel radiotracers and therapeutic targets mandates personaliza- tion of their use and is a significant challenge to the attending clinicians with respect to their deploy- ment at different stages of disease course, so as to ensure maximum clinical benefit. In the present communication, therefore, on the basis of the authors’ clinical experience and available literature, they have proposed recommendations for their appropriate use.
a Radiation Medicine Centre (B.A.R.C), Tata Memorial Centre Annexe, Parel, Mumbai, India; b Homi Bhabha National Institute, Mumbai, India; ” Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
* Corresponding author. Radiation Medicine Centre (B.A.R.C.), Tata Memorial Hospital Annexe, Jerbai Wadia Road, Parel, Mumbai 400012, India.
E-mail address: drsanb@yahoo.com
https://doi.org/10.1016/j.cpet.2022.03.010
INTRODUCTION
Endocrine neoplasms and malignancies are a group of tumors with varied clinical, histopatholog- ic, and functional features. These tumors may vary from sporadic to hereditary, isolated entities to multiple neoplastic syndromes, unifocal locally invasive, and advance to multifocal tumors with disseminated distant metastases. The presence of various specific biomarkers and specific recep- tor targets serves as a valuable tool for diagnosis, prognosis, and management. Nuclear medicine techniques using the historical rectilinear scanners and planner gamma camera imaging for a long time have been incorporated in the management of endocrine neoplasms. With technological ad- vancements and development of novel radio- tracers, PET-computed tomography (CT) has recently moved to the forefront of diagnosis, met- astatic workup, treatment planning, response assessment, and prognostication of these malignancies.
This article enumerates the current uses and po- tential clinical scenarios where PET could have a role in disease management of thyroid, parathy- roid, and adrenal neoplasms with particular emphasis on relative advantages of fluorod-eoxy- glucose (FDG) versus non-FDG-PET tracers. Furthermore, where applicable, a sequence of introducing these imaging modalities for better re- sults and accuracy has been proposed.
FLUORODEOXYGLUCOSE AND NON-FLUORODEOXYGLUCOSE-PET TRACERS IN THYROID NEOPLASMS Fluorodeoxyglucose-PET/Computed Tomography in Differentiated Thyroid Carcinoma
Differentiated thyroid carcinomas (DTCs) are indo- lent malignancies with a relatively better overall prognosis relative to anaplastic and medullary thy- roid carcinomas (MTC) and other head and neck malignancies (Figs. 1 and 2).1,2 The 10-year sur- vival rates are 93% for papillary, 85% for follicular, and 76% for Hürthle cell carcinomas.3 As such, there is no routine well-defined role of FDG or non-FDG-PET/CT in the initial diagnosis of DTCs, and no guidelines recommend the same. Soelberg and colleagues in their meta-analysis confirmed that approximately one-third (~35%) of all FDG- avid thyroid nodules proved to be cancerous. Various studies have reported a high negative pre- dictive value (close to 90%) of FDG-PET-CT in pre- operative evaluation of thyroid nodules and hence can effectively reduce unnecessary diagnostic surgeries in the presence of indeterminate
cytology.4-6 In recurrent DTCs, 2015 American Thyroid Association (ATA) guidelines recommend performing FDG-PET/CT for patients with sup- pressed thyroglobulin (Tg) levels greater than 10 ng/mL.
In Hürthle cell thyroid carcinoma (HTC or onco- cytic thyroid carcinoma), a relatively rarer form of DTC characterized by poor prognosis owing to more aggressive tumor biology, there is a higher incidence of locoregional and distant metastases, and most patients show negative radio-iodine scan (~80%). FDG-PET is found to be an effec- tive tool for both detection and prognostication.7 Pryma and colleagues8 recommended FDG-PET to be the imaging modality of choice in Hürthle cell carcinoma and reported a sensitivity of 95.8% and specificity of 95% for FDG-PET in 44 patients. They also reported a 6% increase in mortality with every 1-unit increase in maximum standardized uptake value (SUVmax) and showed that FDG SUVmax less than 10 was associated with 5-year survival of 92%; FDG SUVmax greater than 10 was associated with 5-year survival of just 64%.8 Plotkin and colleagues9 in a limited meta-analysis of 35 patients demonstrated a sensitivity of 92% and specificity of 80%. This increased FDG uptake in oncocytic tumors is attributed to inherent constitutive activation of glycolytic pathways rather than poorly differenti- ated phenotype and is because of mitochondrial dysfunction. 10
Also, thyroid tumors are composed of both differentiated and undifferentiated cells; hence, FDG-PET and radio-iodine scans are complemen- tary to each other and increase the accuracy. Furthermore, FDG-PET remains the only diag- nostic tool in detecting persistent disease after thyroidectomy, where tumor cells do not secrete Tg. Nascimento and colleagues11 in their study evaluating the potential role of FDG-PET/CT in DTC with aggressive histopathologies observed FDG-PET/CT to be more sensitive than radio- iodine scan for detection of individual lesions (69% vs 59%). They also inferred that both the im- aging modalities are complementary, with 41% of lesions detected only by FDG-PET/CT and 32% detected only by radio-iodine scan. Hence, both of these scans should be routinely performed in such patients,11 and tumor sites are missed in only 7% cases. 124I PET/CT is used mainly for dosimetric studies, and its role in diagnosis and staging is limited.
Recommendations
. There is no definitive role of FDG-PET/CT in DTC at baseline or at follow-up in
conventional case scenarios. However, FDG- PET/CT could be useful in certain situations.
· Patients with high risk of surgery or thyroid nodules with indeterminate cytology can be evaluated for metabolic activity.
· Planning completion surgery after hemithyroi- dectomy in very low to low-risk disease in pa- tients not fit/not willing for surgery.
· Recurrent DTCs exist with high-serum Tg (cutoff >10 ng/ml); however, better yields are seen at still higher and stimulated Tg levels that can potentially direct/modify the plan of treatment.
· Persistent disease after thyroidectomy can be detected, in which tumor cells do not secrete Tg.
· Hürthle cell carcinoma showing negative ra- dio-iodine scan can be detected.
. Both radio-iodine scan and FDG-PET/CT are complementary to each other in aggressive histopathologies.
Thyroglobulin Elevated Negative Iodine Scintigraphy
Thyroid tumor cells usually retain many of the characteristics of their normal progenitor cells, such as, capacity to concentrate iodine, capacity to synthesize thyroid hormone, and capacity to secrete Tg; hence, radio-iodine scan is well estab- lished in the management of thyroid malignancies, provided the original tumor cells are well differen- tiated and have the ability to concentrate radio- iodine. About one-third (30%) of DTC develop recurrent disease in the long run, and most of these recurrences are non-iodine-avid, as they tend to lose natrium-iodide (Na/I) symporter (NIS) owing to dedifferentiation of cells leading to decreased expression of NIS and increased GLUT1 expression, referred to as the “Flip-Flop” phenomenon, as defined by Feine and col- leagues12-15 in 1996. As a result, the whole-body scan shows no radio-iodine concentration despite high-serum Tg; this clinical situation was recently named thyroglobulin elevated negative iodine scintigraphy (TENIS) syndrome (ie, Tg elevated negative iodine scan) by Silberstein15 in 2011.
TENIS is a rare entity, reported somewhere be- tween 2% and 13% in available literature15 and is challenging in terms of diagnosis and manage- ment. TENIS usually develops late in the course of disease in very few cases even after complete treatment, and 15% to 20% of recurrent DTC may become dedifferentiated, fail to concentrate radio-iodine, and is attributable mostly to mutation in the NIS gene.16 The loss of iodine avidity is associated with aggressive disease pattern, and this dedifferentiation affects approximately one- third of patients with disseminated DTC.14
Diagnostic approach for thyroglobulin elevated negative iodine scintigraphy
Diagnosis of TENIS is challenging, and certain fac- tors need to be ruled out before a definitive diag- nosis of TENIS could be made: (a) interference with stable iodine needs to be effectively ruled out (the most common reason behind negative iodine scintigraphy and proper preprocedure counseling and a thorough history taking just before the procedure could alleviate this); (b) poor imaging characteristics of 131I as against 123I, which could lead to radio-iodine uptake on posttherapy scan in cases with negative prether- apy (diagnostic) radio-iodine scan. Hence,
empirical radio-iodine therapy is of special impor- tance here; (c) false-positive elevated Tg level owing to heterophile antibodies and anti-Tg anti- bodies (less common phenomenon than false negative); and (d) nodal recurrence should be ruled out (as these lymph nodes are negative for NIS and therefore do not show up on radio-iodine scan). Hence, the usual initial investigation should be (a) a reliable new ultrasonography (USG) to rule out/ conform nodal recurrence, and (b) a whole-body FDG-PET/CT scan for disease mapping.
Imaging in Thyroglobulin Elevated Negative Iodine Scintigraphy
Fluorodeoxyglucose-PET/computed tomography in thyroglobulin elevated negative iodine scintigraphy
The initial imaging of choice in TENIS is high- resolution USG of the neck by a trained radiologist preferably with experience in head and neck USG, which is important in determining localized dis- ease and which can be surgically treatable or amenable to external beam radiotherapy. Howev- er, in most cases, a whole-body FDG-PET/CT scan is required for metastatic workup and poten- tially can change the line of management. Further- more, an FDG-PET/CT scan is the most important imaging/investigation in TENIS for disease map- ping, prognostication, and response to systemic/ localized therapy with the reported sensitivity ranging from 70% to 94% in the literature.17 Özde- mir and colleagues18 demonstrated overall sensi- tivity, specificity, and diagnostic accuracy of 68.8%, 78.8%, and 71.9% respectively, of FDG- PET/CT in TENIS, and when analyzed according to stimulated Tg values, FDG-PET/CT was nega- tive in those with stimulated Tg less than 5 ng/ mL, whereas it was true positive in 70% of patients with stimulated Tg greater than 20 ng/mL. Sensi- tivity of FDG-PET/CT for detecting radio-iodine negative recurrent disease was reported to be 63% to 98%.19-21 Sensitivity and accuracy in- crease with high-serum thyrotropin (TSH). Deichen and colleagues22 demonstrated that TSH in- creases FDG uptake by thyrocytes in vitro, and Fil- etti and colleagues23 demonstrated that TSH increases GLUT1 expression in cultured rat thyroid cells and hence increases FDG uptake.
The sensitivity of FDG-PET/CT scan improves with increasing values of Tg: Na and colleagues21 in a series of 60 patients of TENIS inferred that sensitivity of FDG-PET/CT scan increases with an increase in stimulated Tg levels, 28.6% when stimulated Tg between 2 and 5 ng/ml, 57.1% when stimulated Tg between 5 and 10 ng/mL, 60% when stimulated Tg between 10 and 20 ng/
mL, and 85.7% when stimulated Tg greater than 20 ng/mL. Trybek and colleagues24 reported 100% sensitivity and specificity for FDG-PET/CT to detect metastases at stimulated Tg cutoff value of 28.5 ng/ml in 19 patients of TENIS. Vural and colleagues in their study on 105 TENIS patients showed that highest accuracy of FDG-PET/CT was reached at suppressed Tg greater than 1.9 ng/ml and stimulated Tg greater than 38.2 ng/mL25. In a study on 40 patients with unde- tected Tg and high anti-Tg antibodies (>40 IU/mL), Asa and colleagues demonstrated the value of FDG-PET/CT in detecting recurrent/metastatic disease in this group of patients.
Non-Fluorodeoxyglucose-PET Tracers in Differentiated Thyroid Carcinoma
Somatostatin receptor analogue
Pazaitou-Panayiotou and colleagues26 in their study demonstrated increased expression of all types of somatostatin receptor subtypes (SSTRs) in human nonmedullary thyroid carcinoma tissues, whereas the expression of SSTRs was low in non- neoplastic thyroid tissues obtained from the same operation material, and SSTR subtypes 2, 3, and 5 appeared to be most abundantly expressed and were located both in the cytoplasm and at plasma membrane of thyroid cells. Pisarek and col- leagues27 demonstrated that in TENIS syndrome, SSTR1 is the most commonly expressed subtype (88.8% of patients) followed by SSTR 3, 2, 5, and 4 in 55.5%, 44.4%, 33.3%, and 11.2% of patients, respectively. Of all the DOTA conjugates, DOTA- NOC PET/CT identified most lesions, as DOTA- NOC is the only radio-tracer having affinity for SSTR 2, 3, and 5 and moderate affinity for SSTR4.28 Mourato and colleagues29 demon- strated that SSTR-based PET/CT could detect disease in approximately 17% of patients with negative FDG-PET/CT. Binse and colleagues30 showed that SSTR-based PET should be consid- ered in radio-iodine and FDG-PET-negative DTC patients with elevated and rising Tg levels. This SSTR positivity in thyroid malignancies, especially in diagnostically and therapeutically challenging TENIS syndrome, opens potential avenues for diagnosis and treatment (with 177Lu to 90Y), known as peptide receptor radionuclide therapy (PRRT). One recent study by Basu and colleagues31 has placed PRRT concurrently or ahead of tyrosine ki- nase inhibitors in the management of TENIS, in eligible patients (showing high-grade SSTR expression, Krenning 3 or 4). In an early study, Jois and colleagues32 had endeavored to analyze the percentage of TENIS patients who are suitable for PRRT and came to a conclusion that although
63% of patients showed SSTR-positive lesion expression demonstrating uptake ranging from grade I to IV, only 16% showed high enough up- take to qualify for the PRRT.
Prostate specific membrane antigen
Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein receptor and a zinc-dependent peptidase having glutamate carboxypeptidase/folate hydrolase enzymatic ac- tivity.33 Derlin and colleagues,34 Chang and col- leagues,35 Bychkov and colleagues,36 and Gordon and colleagues37 demonstrated that PSMA is significantly expressed on the endothe- lium of the neovasculature of tumor cells in the solid tumors (and not in the blood vessels of normal tissue), except in prostate carcinoma, where it is expressed in cytoplasm and membrane of the epithelium. Bertagna and colleagues38 in their review article stated that classical papillary thyroid carcinoma, follicular thyroid carcinoma, and radioactive iodine refractory thyroid carci- nomas demonstrated the highest percentage of PSMA staining and was greater in distant metasta- ses than lymph nodal metastases. Moore and col- leagues39 demonstrated that compared with normal thyroid tissue PSMA is significantly overex- pressed in the neovasculature of DTC, especially in radio-iodine refractory type. Although 68Ga- PSMA and 177Lu-PSMA could form a potential theranostic pair in patients with TENIS where there is a paucity of diagnostic and therapeutic options and few such endeavors are done, a well- structured study with statistically significant sam- ple size and critical analysis is needed to effec- tively draw any conclusions. 40
Iodine 124
The main use of 124I PET/CT in DTC has been for dosimetric studies for determining an accurate and personalized therapeutic dose of radio- iodine.41 There are 2 ways to determine the dose of 131I activity to be administered by dosimetry planning: (a) the most efficient absorbed dose in the tumor to reach tumor lysis (100 Gy to distant metastases), and (b) by giving the greatest 131I ac- tivity limited by the threshold toxicity in normal tis- sues (2 Gy to bone marrow). Its role in TENIS where there is no significant radio-iodine uptake in tumor cells is not well defined and theoretically inappropriate. In DTC,124I PET/CT shows better sensitivity than gamma camera-based radio- iodine scan because of better resolution of the PET system, and there are highly variable results on comparing 124I PET and 131I after therapy whole-body scan. Furthermore, thyroid hormone withdrawal significantly enhanced the sensitivity
of 124I PET/CT than rhTSH stimulation. Khorjekar and colleagues42 demonstrated that a negative 124| PET failed to rule out the need for empiric radionuclide therapy, as 10/12 patients with nega- tive 124I PET showed suspicious foci on 131I after therapy whole-body scan.
Recommendations
. FDG-PET/CT is the imaging method of choice for TENIS if high-resolution USG is negative. High stimulated Tg increases the sensitivity and specificity of the scan and is greater than 90% in reported literature when stimu- lated Tg is greater than 20 ng/ml and anti- Tg antibodies are greater than 40 IU/mL.
· Somatostatin receptor analogue (SSA)-based PET/CT may be considered in patients with negative FDG-PET/CT, especially in the setting of TENIS syndrome and while planning patients for PRRT. PSMA-PET/CT showed PSMA expression in radio-iodine refractory metastatic thyroid carcinoma, especially in osseous lesions, and could be considered in radio-iodine refractory disease with high Tg and negative conventional imaging.
· In a vast majority of patients, however, the SSTR and PSMA expression is either absent or low and not suitable for targeting radionu- clide therapy.
· 124| is used for dosimetric studies and has bet- ter image resolution and sensitivity than 131I- and 123I-based gamma camera scans.
Fluorodeoxyglucose and Non- Fluorodeoxyglucose-PET Tracers in Aggressive Variants of Differentiated and Poorly Differentiated Thyroid Carcinoma
Aggressive variants of papillary thyroid carcinoma include tall cell, columnar cell, solid, and diffuse sclerosing types and tend to show a more aggres- sive behavior than classical papillary thyroid carci- noma. Some have included these aggressive variants of papillary thyroid carcinoma with poorly differentiated thyroid carcinoma (PDTC), but this could not be justified. The term poorly differentiated thyroid carcinoma was introduced by Sakamoto and colleagues43 in 1983 based on the presence of nonglandular components with a solid, trabec- ular, and/or scirrhous growth pattern and includes insular and other large cell types. 44 PDTC results from dedifferentiation of well-differentiated thyroid carcinoma and is mostly regarded as an intermedi- ate stage in the oncogenesis of anaplastic (undiffer- entiated) thyroid carcinoma from well-diff- erentiated thyroid carcinoma. 45,46 In the process of dedifferentiation, there is progressive loss of
function: mainly sodium-iodide symporter expres- sion; in relatively smaller cases, there is loss of Tg formation, and BRAF is the most important gene implicated.47
Aggressive variants of DTC retain the ability for concentrating radio-iodine; hence, whole-body ra- dio-iodine scan should be considered in all cases for metastatic workup and guides treatment strat- egy for a patient. At present, there have been few published accounts on the importance and bene- fits of FDG in aggressive DTC, but in the authors’ clinical experience and according to few published case reports and small case series evaluating the patients with tall cell,48 diffuse sclerosing, 49 solid/trabecular,50 and insular51 variants, FDG- PET is useful in staging and restaging of these tumors.
PDTC falls midway between well differentiated and anaplastic thyroid carcinoma (ATC). Albeit they show limited NIS expression and can produce some Tg, radio-iodine scan and Tg are not consid- ered useful for disease assessment, prognostica- tion, and management. FDG-PET scan has been a reliable tool in such patients because of interme- diate GLUT1 (glucose transporter 1) expression more than NIS expression and demonstrates a “flip-flop” phenomenon between radio-iodine and FDG, and PDTC often shows considerable FDG- PET positivity than radio-iodine uptake and TSH increases FDG uptake in PDTC cells.52
No studies or guidelines suggest or deal with the utility of non-FDG-PET in aggressive variants of DTC and PDTC.
Recommendations
· FDG-PET/CT is an important tool in staging and restaging of PDTC, as radio-iodine scin- tigraphy and Tg are both unreliable in disease assessment, prognostication, and treatment and show considerable FDG positivity.
· Role of FDG-PET/CT is not as well defined in cases of DTC with aggressive histology, but FDG-PET/CT is useful in staging and restag- ing when radio-iodine scan is either negative or discordant to Tg levels.
Fluorodeoxyglucose and Non- Fluorodeoxyglucose-PET Tracers in Anaplastic (Undifferentiated) Thyroid Carcinoma
ATC is a follicular cell-derived thyroid malignancy and is characterized by rapidly proliferating cells with an extremely aggressive tumor biology that is associated with the highest mortality for any thy- roid tumor, but accounts for only a small fraction of overall thyroid cancer cases, approximately 1.3% to 9.8% (median, 3.6%).53,54 ATC patients have a
historical median survival of about 5 months and a 1-year overall survival of 20%.55 FDG-PET/CT is particularly useful in ATC for disease staging, restaging, metastatic workup, and treatment response evaluation and is the most reliable mo- dality because undifferentiated cells do not ex- press NIS and do not produce Tg, but they abundantly express GLUT1 responsible for avid FDG uptake.56,57 Approximately 10% of patients present with intrathyroidal tumor, whereas 40% have extrathyroidal invasion and/or lymph nodal metastases, and the remaining patients present with distant metastases; accurate rapid staging is a prerequisite for the most effective treatment planning.58,59
Recent ATA guidelines of 2021 recommend FDG- PET/CT as the best modality for staging to classify the disease as IVA, IVB, or IVC and are particularly valuable in identifying the metastatic sites that are sometimes not appreciated on conventional cross-sectional imaging, like CT or MR imaging, especially osseous and marrow involvement.54,56 FDG-PET/CT has higher sensitivity for detecting metastatic lesions than CT alone (99.6% vs 62% in identifying 265 individual lesions in 18 patients, P <. 002).56 Furthermore, FDG-PET/CT findings can potentially alter the management recommenda- tions in approximately 25% to 50% of patients. 54,56 FDG-PET/CT scan scores better than CT scan in treatment response evaluation in ATC patients. Poisson and colleagues56 demonstrated discor- dant findings between FDG-PET/CT and CT scan in 45% of the cases, and in each such case, FDG- PET/CT findings were more informative than change in size, as determined by CT scan.
No studies or guidelines suggest or deal with the utility of non-FDG-PET in anaplastic (undifferenti- ated) thyroid carcinoma.
Recommendations
· FDG-PET/CT is the best modality for staging ATC and classifying as stage IVA, IVB, and IVC.
· FDG-PET/CT is more sensitive than conven- tional imaging for detecting metastatic lesions and can potentially alter the management rec- ommendations in approximately 25% to 50% of patients (Fig. 3).
· FDG-PET/CT is also better in treatment response evaluation of ATC.
Fluorodeoxyglucose and Non- Fluorodeoxyglucose-PET Tracers in Medullary Thyroid Carcinoma
MTC is a neuroendocrine tumor originating from the neural crest-derived para-follicular “C cells”
of the thyroid gland and accounts for about 1% to 2% of thyroid malignancies.59,60 Most of the MTC are sporadic, and about one-third are hered- itary and are associated with multiple endocrine neoplasia (MEN) 2A or 2B syndromes or familial MTC based on specific autosomal dominant germline mutations in rearrangement during trans- fection (RET) proto-oncogene.61 MTC frequently has an aggressive clinical course; only about half (48%) of the patients present with localized dis- ease, whereas 35% have locally advanced and invasive disease to lymph nodal metastases and approximately 13% have distant metastases to lungs, liver, or bones.62 The prognosis depends on the extent of primary tumor: 10-year survival is 90% when the tumor is confined to the thyroid and drops drastically to 70% and 20% with lymph nodal and distant metastases, respectively. Calci- tonin and carcinoembryonic antigen (CEA) are sensitive tumor markers, especially calcitonin and CEA doubling times and correlates well with disease/tumor burden. Gradually increasing tumor markers mandate imaging workup to look for re- sidual/recurrent and metastatic disease (Figs. 4 and 5).
Imaging modalities play a crucial role in thera- peutic decision making; however, there are still no comprehensive diagnostic imaging modalities to reliably detect all recurrent and metastatic le- sions. Therefore, concurrent use of several imag- ing methods is often required to provide the required information.63 Functional imaging with PET/CT scans is particularly useful, is more infor- mative than conventional imaging modalities, and provides whole-body assessment in a single mo- dality. Hybrid PET/CT scan also scores higher than other gamma camera-based nuclear medi- cine imaging owing to higher resolution of PET systems. Tumor markers, particularly serum calci- tonin, correlates well with tumor burden and effec- tively guides the extent of surgery at baseline and appropriate imaging modality in cases with sus- pected recurrence and also influences the choice of radiopharmaceuticals for PET/CT imaging. 64
Fluorodeoxyglucose-PET/Computed Tomography in Medullary Thyroid Carcinoma
FDG is the most commonly available and frequently used radiopharmaceutical in nuclear medicine with PET systems, detects hypermeta- bolic lesions, and reflects increased expression of glucose transporter proteins (GLUT), which correlate well with rapidly proliferating cells and is associated with poor prognosis. Hence, it is a marker of poor differentiation/dedifferentiation and aggressive clinical behavior. FDG is superior
in detecting biochemically progressive disease owing to poorly differentiated/dedifferentiated tu- mor cell population and has prognostic implica- tions. FDG-PET/CT is more sensitive than anatomic imaging (USG, CT, MR imaging) or SPECT (single photon emission tomography) tracers; however, unlike DTCs, there is relatively less of a role and evidence of increased GLUTs. Hence, the FDG uptake could be highly variable/ false negative with significant tumor burden and high tumor markers, and therefore, other tracers, such as fluro-dihydroxyphenylalanine (FDOPA), and different SSTR-based PET/CT have been investigated.
Verbeek and colleagues64 evaluated outcomes of FDG-PET/CT and FDOPA PET/CT with
calcitonin and CEA doubling times in 38 MTC pa- tients and demonstrated FDG-positive disease in patients with shorter calcitonin and CEA doubling times (<24 months) and reported positive and negative predictive values of 77% and 88%, respectively, for biochemically progressive dis- ease.64 Receiver operating characteristic (ROC) curve analysis showed optimal calcitonin cut off of 874 ng/L for PET positivity with a sensitivity of 69% and specificity of 70%. Ong and colleagues65 concluded that FDG-PET rarely detects disease in patients with calcitonin less than 500 pg/mL and demonstrated sensitivity of FDG-PET to be 78% and 20% for calcitonin greater than 1000 pg/mL and less than 1000 pg/mL. Overall, the reported patient-based sensitivity and specificity of FDG-
PET/CT for recurrent MTC were observed to range between 17% to 93% and 68% to 92%, respec- tively. Meta-analysis studies showed the patient- based detection rates in recurrent MTC ranged from 59% (95% confidence interval [CI], 54%- 63%) to 69% (95% CI, 64%-74%).66 Treglia and colleagues67 in their meta-analysis inferred vari- able detection rates of FDG-PET/CT in MTC ac- cording to calcitonin and CEA and their doubling times; overall suspected MTC recurrence was 59%, whereas it increased to 69% when CEA was greater than 5 ng/ml, 75% for patients with serum calcitonin greater than 1000 pg/mL; 76% for calcitonin doubling time of less than 12 months, and 91% when CEA doubling time was less than 24 months. FDG uptake is relatively more when CEA doubling time is less than calcitonin doubling time because CEA is a marker of early dedifferen- tiation and is retained in poorly differentiated MTC characterized by increased GLUT expression leading to avid FDG uptake, whereas calcitonin being a marker of terminal differentiation is expressed more avidly in well-differentiated MTC.68 Hence, FDG should not be considered as first-line diagnostic imaging modality in patients with suspected recurrent and metastatic MTC with low serum calcitonin and CEA and their longer doubling times but works well in later stages or rapidly-growing disease.
Non-Fluorodeoxyglucose-PET Tracers in Medullary Thyroid Carcinoma
Fluoro-dihydroxy phenylalanine
Fluoro-dihydroxy phenylalanine (18F-FDOPA) PET/ CT scan is by far the single best modality for detection of metastatic lesions in MTC and is particularly suitable for detecting small lymph node metastases, as small as 6 mm.69 Uptake of
18F-FDOPA depends on the L-type-amino-acid transporter system, and 18F-FDOPA is seques- tered into cells by cytosolic L-aromatic amino acid decarboxylase.7º Most of the studies have re- ported 18F-FDOPA PET/CT to be highly sensitive to stage MTC at baseline, before primary surgery and restaging MTC in suspected recurrence with better accuracy than FDG-PET/CT at relatively lower calcitonin values. 18F-FDOPA PET/CT has relatively less prognostic value, but is more accu- rate in detecting extent of disease and counted more lesions than FDG-PET/CT, especially when serum calcitonin is not very high and is particularly suitable for detection of small metastatic lymph nodes, as small as around 6 mm.69
Giovanella and colleagues71 in their recent prac- tice guidelines for PET/CT imaging in MTC inferred a consistently high specificity with wide patient- based sensitivity ranging from 45% to 93% in pa- tients with suspected recurrence. Treglia and col- leagues67 in their meta-analysis reported per- patient detection rate of 18F-FDOPA PET/CT to be 66% (95% CI, 58%-74%). The detection rate further improves in patients with higher levels of calcitonin and shorter calcitonin doubling time, reaching as high as 86% with calcitonin doubling time less than 24 months.72-74 Bovioand col- leagues evaluated outcome of FDG and 18F- FDOPA PET/CT with calcitonin and CEA doubling times in 36 MTC patients and demonstrated posi- tive and negative predictive value of 56% and 75%, respectively, in 18F-FDOPA PET-positive and -negative patients.75 In the ROC curve anal- ysis, the calcitonin cutoff was 825 ng/ml to be optimal for PET positivity, with a sensitivity and specificity of 88% and 80%, respectively.76 Ver- beek and colleagues64 also demonstrated that calcitonin and CEA significantly differed between 18F-FDOPA PET-positive and -negative patients,
but there was no significant difference in doubling times. An analysis based on whole-body meta- bolic tumor burden (WBMTB), calcitonin, and CEA levels, including 21 patients with both FDG and 18F-FDOPA PET/CT scans, found that, in PET-positive patients, WBMTB on 18F-FDOPA significantly correlated with calcitonin levels (r = 0.82, P = . 013) and CEA levels (r = 0.88, P = . 004) but not with doubling times. No signifi- cant correlation was found between FDG-PET and calcitonin and CEA and doubling times.64 In a recent review article by Kushchayev and col- leagues, 77 18F-FDOPA PET/CT was found superior to FDG-PET/CT in evaluation of metastatic/recur- rent MTC with a higher patient and lesion-based sensitivity. The patient-based detection rates improve significantly when calcitonin and CEA cut- off values of 150 pg/mL and 5 ng/ml are used, and Treglia and colleagues demonstrated the sensi- tivity of 73%.67 Recent ATA guidelines for MTC recommend 18F-FDOPA PET/CT at serum calci- tonin level greater than 150 pg/mL, and the studies found sensitivity of 18F-FDOPA PET/CT to be 79% to 100% for recurrent/metastatic MTC. The patient-based detection rates increase signifi- cantly with calcitonin levels greater than 150 pg/ mL versus less than 150 pg/mL for both 18F- FDOPA PET/CT (sensitivity 91% vs 29%) and for FDG-PET/CT (sensitivity 73% vs 14%) and with CEA levels greater than 5 ng/ml versus less than 5 ng/ml for both 18F-FDOPA PET/CT (sensitivity 81% vs 43%) and FDG-PET/CT (sensitivity 73% vs 14%). Albeit 18F-FDOPA fares better in detec- tion rates than any other imaging modality for MTC, Kauhanen and colleagues78 and Wong and colleagues79 stated that combining both 18F- FDOPA and FDG-PET/CT increases the sensitivity and hence are complementary. Apart from better sensitivity, specificity, and detection accuracy, 18F-FDOPA PET/CT has the highest sensitivity and specificity (>95%) for detecting pheochromo- cytoma and paraganglioma and hence is a one- stop shop for MTC with suspected MEN syndromes. 80
Somatostatin receptor analogue
Somatostatin is a regulatory peptide, and human tissues express SSTR 1 to 5 and can be targeted by synthetic somatostatin analogue ligands TOC, TATE, and NOC chelated by DOTA (DOTATOC, DOTATATE, and DOTANOC) with each having a unique profile of affinity for SSTRs 1 to 5 and are tagged with 68Ga for imaging and with 177Lu/90Y for therapeutic purposes. The relative affinities of SSTR analogues are DOTANOC for SSTR 2, 3, and 5, DOTATATE (SSTR 2), and DOTATOC (SSTR 2 and 5). SSA PET/CT in evaluation of
MTC is the natural evolution of octreotide scintig- raphy with 111In, and the reported data range from highly favorable to disappointing and are due in part to heterogeneous SSTR expression, differences in SSA used for PET/CT, patient selec- tion, and use of contrast-enhanced CT (CECT) scan with PET.
Souteiro and colleagues81 in their study on 13 MTC patients with residual/recurrent/metastatic disease and elevated serum calcitonin and CEA found SSA PET/CT to detect a higher number of lesions than FDG-PET/CT (sensitivity 69.2% vs 53.9% for SSA and FDG). Furthermore, they also inferred that MTC lesions are better detected by SSA PET/CT in whom calcitonin levels are comparatively higher than CEA levels, and FDG- PET/CT fared better in patients with CEA higher than calcitonin. Hence, they hypothesized 2 pro- files for metastatic MTC: a high calcitonin burden, well-differentiated, SSA PET-positive MTC with better prognosis and CEA preponderant, poorly differentiated/dedifferentiated, FDG-positive MTC with a worse prognosis. Tuncel and colleagues82 in their study on 38 MTC patients detecting clinical impact of 68Ga-DOTATATE PET/CT demonstrated it to be an essential part of MTC workup, as it out- performed conventional imaging in 14/38 (37%) patients and changed the clinical management in 13/38 (34%) patients.82 They further showed a positive correlation between tumor marker, partic- ularly calcitonin and 68Ga-DOTATATE PET positiv- ity. Castroneves and colleagues83 demonstrated that 68Ga-DOTATATE PET/CT has higher sensi- tivity (100%) for bone metastases when compared with the bone scintigraphy (44%). On a per-patient based analysis, the detection rate of SSA PET/CT is 63.5% (95% CI, 49%-77%) in suspected recur- rent MTC. Positive SSA PET/CT can modify surgi- cal management in a significant number of patients with recurrent MTC.84 Albeit 18F-FDOPA PET/CT is the most sensitive and specific imaging modality for detecting MTC lesions, SSA PET/CT has potential to identify patients for PRRT.69,85
11C-Methionine
Methionine is an essential amino acid necessary for protein synthesis; however, this tracer has considerable nonprotein metabolites, making cor- rect quantification of protein synthesis difficult.86 Jang and colleagues87 reported 11C-methionine PET/CT scan to be more sensitive than FDG- PET/CT in detecting lymph nodal metastases; however, there was no benefit as compared with USG neck and a combination of USG neck and FDG-PET/CT; moreover, 11C-methionine PET/CT scan with high physiologic uptake of tracer in the liver limits its use in hepatic metastases. Sensitivity
of 11C-methionine PET/CT scan like that of other molecular imaging modalities increases with an in- crease in calcitonin, and the cutoff was deter- mined to be 370 pg/mL.
Immuno-PET using anti-carcinoembryonic antigen antibodies
Immuno-PET using anti-CEA antibodies, using directly labeled antibodies, their fragments, or antibody-derived recombinant constructs tagged with 68 Ga, 111In, or 131I against CEA, was reported to be potentially accurate in detecting relapsing MTC; however, further studies are required.
Recommendations
· 18F-FDOPA is the single best modality for evaluating disease burden and extent of dis- ease with highest sensitivity in detecting met- astatic and recurrent lesions in MTC, reflects well-differentiated phenotype, and should be considered as first-imaging modality when serum calcitonin is greater than 150 pg/mL.
. Furthermore, 18F-FDOPA has the highest sensitivity and specificity (>95%) for detecting pheochromocytoma and paraganglioma and hence is a one-stop shop for imaging in he- reditary MTCs associated with MEN 2 syndromes.
· FDG-PET/CT positivity is a marker of poor dif- ferentiation/dedifferentiation reflecting aggressive behavior, has prognostic implica- tions, and should be considered in patients with serum calcitonin greater than 1000 pg/ mL; a shorter calcitonin and CEA doubling times (<12-24 months), and serially rising serum calcitonin and CEA levels.
· FDG-PET should not be considered as first- line diagnostic imaging modality in patients with suspected recurrence and metastases.
. SSA PET/CT should be considered in patients with high-serum calcitonin and progressive disease, especially when treatment with PRRT is under consideration.
. Combining 18F-FDOPA and FDG-PET/CT and also SSA PET/CT and FDG-PET/CT increases the sensitivity, and hence they are complementary.
FLUORODEOXYGLUCOSE AND NON-FLUORODEOXYGLUCOSE-PET TRACERS IN PARATHYROID NEOPLASMS
Parathyroid neoplasms most commonly constitute adenomas followed by hyperplasia and carcinoma, are responsible for derangements in calcium ho- meostasis owing to hypersecretion of parathyroid hormone (PTH), also known as hyperparathyroidism
(HPT), and are due to hyperfunctioning of one or more parathyroid glands. Hyperfunctioning para- thyroid glands are due to solitary adenomas most cases (75%-80%) followed by multiglandular dis- ease characterized by adenoma or hyperplasia (15%-20%), whereas parathyroid carcinoma ac- counts for less than 1% of cases.88 Parathyroid neoplasms are broadly classified as primary hyper- parathyroidism (pHPT) characterized by elevated or inappropriately normal PTH with hypercalcemia and secondary HPT characterized by elevated serum PTH owing to parathyroid hyperplasia in response to hypocalcemia, hyperphosphatemia, and hypovi- taminosis D (mainly owing to chronic renal failure). Rarely, it could be due to paraneoplastic syndrome, and in most cases, is due to overproduction and secretion of parathyroid hormone-related peptide (PTH-rp). In paraneoplastic syndrome, the serum levels of PTH are low with respect to hypercalcemia with no hyperfunctioning parathyroid glands and PTH or both PTH and PTH-rp are produced by the culprit cancer. . Most pHPT are sporadic (95%), but about 5% occur as part of hereditary syndromes of MEN 1, 2, and 4 and HPT-jaw tumor syndrome or as part of nonsyn- dromic familial pHPT.
Fluorodeoxyglucose -PET/Computed Tomography in Parathyroid Neoplasm
FDG-PET/CT is not deemed suitable for detection of hyperfunctioning parathyroid glands compared with other conventional imaging modalities, as sensitivity and specificity ranges from 0% to 94% and 62% to 100%, respectively, and varies considerably between available studies.89 Howev- er, FDG-PET/CT is a sensitive tool in imaging para- thyroid carcinoma for (a) baseline staging, (b) restaging, and (c) treatment response evaluation. Recent studies have shown choline PET tracers to be more sensitive and specific in imaging para- thyroid cancers and detected relatively more le- sions than FDG.
Non-Fluorodeoxyglucose-PET Tracers in Parathyroid Neoplasm
Choline based tracers
Recently, 11-carbon and 18-fluorine tagged with choline have shown encouraging results as compared with conventional imaging modalities. Choline is a precursor of phospholipid biosyn- thesis, which is an essential component of cell membrane. Cells with a high proliferation rate have increased demand for choline, are phosphor- ylated by enzyme choline kinase, and are retained in the cell.90 Choline PET has historically been introduced for prostate carcinoma imaging,
outperforming FDG-PET, but positive results are seen in various nonmalignant conditions as well, and incidental 11C-choline uptake was initially re- ported in parathyroid adenoma by Mapelli and col- leagues.91 18F-Fluorocholine is preferred over 11C- choline owing to its long half-life, which alleviates the need for onsite cyclotron.
Quak and colleagues92 published a prospective bicentric study on 18F-fluorocholine PET/CT- guided surgery for pHPT in 25 patients in whom choline PET/CT-guided surgery in 22 patients and bilateral neck exploration could be avoided in 75% patients. In a recent head-to-head comparative study including 103 patients with pHPT, the diagnostic performance of choline PET/CT was found superior to conventional imag- ing modalities either separately or in combination, with a sensitivity of 92% for choline PET/CT, compared with 39% to 56% for conventional im- aging, and 65% for a combination of conventional methods. 93 López-Mora and colleagues94 in their prospective series of 33 patients found that 18F- fluorocholine PET/CT in an analog system could detect hyperfunctioning tissue in 22 of 33 patients, whereas a digital PET/CT system detected hyper- functioning tissue in 30 of 33 patients, and the le- sions detected only on digital systems were less than 10 mm in diameter. In view of these unique advantages with 18F-fluorocholine PET/CT, such as better detection of smaller lesions, low radiation exposure, higher resolution, and shorter acquisi- tion time, it is therefore considered the alternative first-line imaging modality for this indication95,96 (Fig. 6). Parathyroid carcinoma is also known to accumulate choline; the major limiting factors for choline PET are high cost and limited availability.
11C-Methionine
Methionine is involved in the synthesis of PTH pre- cursor and is trapped in a hyperfunctioning para- thyroid gland. Kluijfhout and colleagues97 in a meta-analysis of 14 studies found a pooled sensi- tivity of 77% and positive predictive value of 98% for detection of hyperfunctioning parathyroid glands in the correct quadrant. Other studies, however, have reported slightly lower detection rates ranging from 64% to 70% in preoperative scanning of patients with negative results on con- ventional imaging98,99 (Fig. 7). The major limita- tions of this tracer are absolute requirement of onsite cyclotron owing to short half-life of ~20 minutes and lower signal-to-noise ratio owing to higher average positron energy than 18F.
Recommendations
· Choline PET/CT should be considered as an alternative first-line imaging modality in
patients with pHPT for preoperative localiza- tion. Choline PET/CT using a digital system yields better results, especially in lesions less than 1 cm in size.
· FDG-PET/CT does not show advantage over conventional imaging modalities for detecting hyperfunctioning parathyroid glands. Howev- er, FDG-PET/CT could be considered in para- thyroid carcinoma.
· Methionine PET/CT may be useful as a second-line imaging modality in pHPT.
FLUORODEOXYGLUCOSE AND NON-FLUORODEOXYGLUCOSE-PET TRACERS IN ADRENAL NEOPLASMS AND TUMORS OF AUTONOMIC NERVOUS SYSTEM
Clinically symptomatic adrenal diseases are rela- tively rare in patients when compared with those who are diagnosed with adrenal tumor and are more frequently encountered because of a rapid increase in the use of cross-sectional imaging. The reported incidence extends up to around 5% in CT examinations, and the characterization and follow-up of these “incidentalomas” place increasing demands on health care resources. In healthy individuals, 80% of incidentally found ad- renal masses are benign, nonfunctioning ade- nomas, and even in patients with known malignancy, approximately 40% to 57% of adrenal incidentalomas are benign. These incidentalomas can be accurately classified in most cases as benign and malignant with contrast washout studies on CT scan (adrenal protocol on CECT). The workup of adrenal neoplasms should aim at establishing functional versus nonfunctional phenotype and benign versus malignant features to devise appropriate treatment plans.
USG, CT scan, and MR imaging are the first-line imaging modalities for the evaluation of adrenal neoplasms. CT scan can be used to distinguish between benign and malignant causes with a diag- nostic sensitivity of 88%, and small lesions (<4 cm) with homogeneous low HU on unenhanced CT (<10 HU) are usually benign, in which further imag- ing is not required.100 Similarly, chemical shift MR imaging identifies high intracellular lipid content with lesion intensity similar to liver on T2- weighted images, confirming benign cause; how- ever, lipid-poor adenomas representing about 30% of all adrenocortical adenomas (ACA) will remain indeterminate by anatomic imaging tech- niques. Functional imaging modalities provide an edge over anatomic imaging modalities in distin- guishing benign and malignant lesions. Metastatic lesions of adrenals should be evaluated with core- needle biopsy or fine-needle aspiration cytology
(FNAC) for ascertaining the diagnosis and then im- aging, once pheochromocytoma has been ruled out biochemically.
Tumors of Adrenal Cortex
Adrenal cortex comprises 3 distinct histologic and functional regions: zona glomerulosa, zona fascicu- lata, and zona reticularis, from outside to inside, producing mineralocorticoids, glucocorticoids, and sex steroids. Functioning neoplasms of adrenal gland constitute a smaller proportion of all detected lesions, and approximately 70% to 94% are benign, nonfunctioning adenomas; however, unsuspected adrenal malignancies can be encountered in about 21% of patients, and of these, about 32% to 73% represent metastases. 75,101,102
Fluorodeoxyglucose-PET/Computed Tomography in Adrenocortical Neoplasms
Benign ACA demonstrates low-grade to mild FDG uptake in the lesions, and hence, a lower SUVmax value points toward benign cause. Metastatic dis- ease, apart from the histopathologic findings, is the most important determinant for malignant tu- mor. The main utility of functional imaging is to distinguish benign from malignant cause, and FDG-PET/PET/CT is an important tool offering high sensitivity, specificity, and diagnostic accu- racy. Adrenocortical carcinoma (ACC) is a rare ma- lignancy with poor prognosis, and overall 5-year survival is 20% to 45% with dismal survival (<12%) in the presence of distant metastases. Pri- mary treatment is adrenalectomy with adjuvant
antimetabolite mitotane, and recurrence rate is initially high despite complete surgical resection; hence, early detection of recurrence is the key to improved survival.
A recent systemic review and meta-analysis comprising 21 studies published between 1995 and 2009 evaluating a total of 1391 lesions (824 benign and 567 malignant) in 1217 patients showed mean sensitivity of 97% (95% CI, 93%- 98%) and specificity of 91% (95% CI, 87%-94%) in differentiating benign from malignant lesions. 103 Becherer and colleagues 104 evaluated FDG-PET in 10 patients with confirmed ACC and reported sensitivity and specificity of 100% and 95%, respectively. They identified additional lesions that were not detected by anatomic imaging alone in approximately 30%, and FDG-PET modified the treatment protocol in about 20% patients. 104 Leb- oulleux and colleagues105 in their study found sensitivity for detection of distinct lesions and the diagnosis of metastases as 90% and 93%, respectively, and demonstrated that tumor SUVmax greater than 10 was found to be an adverse prognostic factor. In another study by Tessonnier and colleagues106 evaluating the role of FDG, including 37 patients of ACC, SUVmax correlated with atypical mitosis and Weiss score, but not with overall survival or disease-free sur- vival at a mean follow-up period of 49 months. FDG-PET/PET/CT is advantageous in being (a) able to distinguish effectively between benign and malignant tumors; (b) assessing the malignant potential of adrenal mass that is otherwise deemed indeterminate on anatomic imaging, especially lipid poor adenomas versus malig- nancy; and (c) having wide availability and rela- tively longer half-life, providing ease of utilization (Fig. 8).
Non-fluorodeoxyglucose-PET Tracers in Adrenocortical Neoplasms
11C-Metomidate
Metomidate (METO) is the methyl ester of “eto- midate” (ETO, an anesthetic agent), and both are inhibitors of the CYP11B enzymes: 11ß-hydroxy- lase and aldosterone synthase involved in cortisol and aldosterone synthesis, respectively. Based on high affinity to these enzymes and specific adreno- cortical binding properties, METO and ETO have been labeled with 11C and 18F and are being used as PET tracers for adrenocortical imaging. Hennings and colleagues107 in their study evalu- ated correlation with 11C-METO PET and histo- pathologic findings on 73 patients with 75 adrenal tumors (26 adenomas, 13 adrenocortical cancers, 8 hyperplasia, 6 pheochromocytoma, 3
metastases, and 19 tumors of nonadrenal origin) with varying sizes ranging from 1 to 20 cm, the sensitivity and specificity were found to be 89% and 96%, respectively, in distinguishing adreno- cortical tumors from nonadrenocortical tumors. ACCs have been shown to accumulate 11C- METO in primary neoplasm and metastases and have a sensitivity of 72%. METO PET can differen- tiate adrenal metastases and pheochromocytoma from ACC, but it cannot differentiate between ACAs and carcinoma on the basis of uptake alone as against FDG-PET.
18F-Fluoroethyl ester
Fluoroethyl ester (FETO) is another marker of 11ß-hydroxylase, and because of 18F, has a longer half-life, allows longer imaging protocols than METO, and has experimental importance.
Recommendations
· FDG-PET/CT is an important tool in distin- guishing benign from malignant lesions on a per-lesion basis.
· FDG-PET should be considered for evaluating the malignant potential of adrenal incidentalo- mas, which appear indeterminate on anatomic imaging as in lipid-poor adenoma versus malignancy (higher SUVmax values greater than 10 point toward malignancy).
· FDG-PET could detect the metastatic lesions with high sensitivity but with low specificity and cannot differentiate adrenocortical tu- mors from PPGL.
· METO and FETO PET can differentiate be- tween adrenocortical and adrenal medullary neoplasms and are of special importance in biochemically silent tumors (parasympathetic PGL).
Tumors of Adrenal Medulla and Autonomic Nervous System/Neural Crest Neoplasms
Tumors of adrenal medulla are derived from post- ganglionic sympathetic or parasympathetic neu- rons; the sympathetic postganglionic neurons are called as “chromaffin” cells (based on character- istic staining on tissue histology) and are derived from neural crest cells and hence have neuroendo- crine origin. Neural crest-derived neoplasms have a reported prevalence between 0.2% and 0.6% in patients with hypertension and in nearly 5% of pa- tients with an incidentally discovered adrenal tu- mor.108 Phenotypically, these may be sympathetic (catecholamine and dopamine secreting), in adrenal medulla and posterior mediastinum and parasym- pathetic (nonsecretory), in head and neck and ante- rior and middle mediastinum and according to location are pheochromocytoma (located in adrenal
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gland) and paraganglioma (all extra-adrenal lesions irrespective of being sympathetic or parasympa- thetic; 85% are intra-abdominal, 15% are intratho- racic, and 1%-3% are paracervical). Both can be termed together and referred to as PPGL. Differen- tial diagnosis may include other tumors of neural crest origin: neuroblastoma, ganglioneuroma, and composite tumors and metastases from these tu- mors (Figs. 9 and 10).
Most of these cells are located in the adrenal medulla or in extra-adrenal locations near the ce- liac axis. Approximately 5% to 10% of solitary pheochromocytoma are hereditary, whereas the presence of multiple pheochromocytomas or a combination of pheochromocytoma with a syn- chronous or metachronous extra-adrenal para- gangliomas is associated with germline or somatic mutation in greater than 70%. The PPGL susceptibility genes can be classified into 4 major clusters: (a) pseudohypoxia subtype (subdivided into tricarboxylic acid cycle-dependent and Von- Hippel Lindau [VHL]/EPAS-1 dependent), (b) ki- nase signaling subtype, (c) Wnt signaling subtype, and (d) cortical admixture subtype, and can be driven by either germline mutation (27%), somatic mutation (39%), or fusion gene mutation (7%).109 Albeit most PPGLs are benign, 10% to 20% are malignant (characterized by presence of distant metastases), of which 10% to 15% of patients pre- sent with metastases at diagnosis. Metastatic dis- ease is more commonly found in patients with SDHB and a-thalassemia/mental retardation syn- drome X-linked mutations, large tumors (>5 cm), extra-adrenal location, and noradrenergic and dopaminergic phenotype.
Fluorodeoxyglucose -PET/Computed Tomography in Tumors of Adrenal Medulla and Autonomic Nervous System/Neural Crest Neoplasms
Benign pheochromocytoma can show a high grade of FDG uptake, which is a unique feature for any benign tumor, and which further increases in malig- nant tumors as the tumor cells are forced to resort to anaerobic glycolysis (Warburg effect). Taieb and colleagues in their early study proposed 2 alternative explanations: an early metabolic switch related to genetic defects (pseudohypoxia model) and an adaptive response to hypoxia, and the fact that these tumors are highly vascularized is indirect evidence of hypoxia.7º Pseudohypoxia model implies a link be- tween inactivation of SDH and VHL genes and induc- tion of a hypoxic response mediated by inactivation of prolyl hydrolase and consequent stabilization of HIF-2a (hypoxia-inducible factor). 110,111 In general, in malignant cases, FDG uptake is a marker of func- tional dedifferentiation, but this phenomenon does not hold good for PPGL (as benign pheochromocy- toma are FDG avid), and the underlying mechanism could be attributed to “metabolic reprogramming” rather than tumor cell dedifferentiation.
Shulkin and colleagues76 reported sensitivity of 58% in benign pheochromocytoma and 76% in malignant pheochromocytoma, particularly in meta-iodobenzyl guanidine (MIBG) -negative tu- mors. Across the spectrum, succinate dehydroge- nase (SDH; particularly SDHB) and VHL-related tumors have higher FDG uptake as against neurofi- bromatosis and MEN-related PPGL. The main advantage of FDG-PET/CT is in patients with
metastatic PPGL related to SDH germline mutation in which FDG has a sensitivity of 100%, which exceeded that of FDOPA (88%), MIBG (80%), and SSA PET (81%), as SDH-related PPGL have larger tumor volumes, greater rates of metastases, multi- focal disease, and higher SUVs on FDG.112
Non-Fluorodeoxyglucose-PET Tracers in Tumors of Adrenal Medulla and Autonomic Nervous System/Neural Crest Neoplasms
Somatostatin receptor analogue and antagonists
PPGLs are neuroendocrine cell derivatives, hence express SSTR, particularly SSTR 2 and 3, which
can be targeted for imaging and therapeutic (thera- nostic) interventions using somatostatin analogues and antagonists (SSA). As SSTR 2A and 3 are more commonly and avidly expressed in PPGLs than SSTR 5, thus 68Ga-DOTATATE and 68Ga-DOTA- NOC are preferred agents113-115 (Figs. 11 and 12). Tracer binding and retention depend on the density of receptors on cell surface and internaliza- tion of ligand-receptor complex. SSTR antagonist NODAGA-JR 11 has recently been developed and is expected to reduce DOTA-peptide washout and hence increase the residency time despite lack of internalization, as the radiopharmaceuticals remain anchored within the cell membrane.
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Available literature is scarce on the use of SSA PET in benign pheochromocytoma and primary PPGL, whereas there are excellent results for localizing these lesions when they are malignant and/or extra-adrenal and reported to be more sensitive than MIBG scintigraphy. In a recent sys- temic review and meta-analysis, pooled detection rate for SSA PET was 93% (95% CI, 91%-95%) and was significantly higher (P <. 001 for all) than FDOPA (80%; 95% CI, 69%-88%), FDG (74%; 95% CI, 46%-91%), and MIBG scintigraphy (38%; 95% CI, 20%-59%).116 Several studies compared SSA PET with FDOPA PET and concluded that SSA PET fares better than FDOPA on a per-patient and per-lesion basis, and the sta- tistics were much better in extra-adrenal PGL (98% vs 95% and 99% vs 68%, respectively). 117 In recent noncomparative studies, SSA PET demonstrated sensitivity of 84% for pheochromo- cytoma and 100% for PGL and as compared with FDG-PET, and SSA PET was more valuable in pe- diatric patients.117 SSA PET showed lesser con- centration in PPGLs related to EPAS 1 (HIF 2%), PHD 1/2, and FH than SDHx-related PPGLs and
in areas of higher physiologic uptake (eg, liver, ad- renals).118 Furthermore, approximately 50% of metastatic PPGLs related to SDHB mutation do not concentrate MIBG owing to cellular dediffer- entiation leading to lack of norepinephrine trans- porter system but do not show significant loss of SSTR expression, and SDH-deficient tumors show avid SSTR 2A and SSTR 3 expression, making them valid theranostic targets, which has led to treatment changes in up to 60% of patients.
Fluro-dihydroxyphenylalanine
FDOPA offers high sensitivity and specificity for detecting nonmetastatic pheochromocytoma (both approaching 100%).119 FDOPA uptake in PPGL is attributed to their property to decarbox- ylate L-amino acids owing to inherent activity of L-aromatic amino-acid decarboxylase and their uptake and storage in neurosecretory vesicles through L-type amino-acid transporters (LATs), primarily LAT1.
A recent meta-analysis, including 11 studies involving 275 subjects with PPGLs, demonstrated
pooled sensitivity and specificity in lesion-based analysis of FDOPA to be 79% (95% CI, 76%- 81%) and 95% (95% CI, 84%-99%), and the most important factors are sympathetic pheno- type and being negative for SDHx mutation. 120 In several published studies, the reported patient- and lesion-based specificity of FDOPA is 94% and 100%, respectively, and for sporadic- and MEN 2-associated (almost always sympathetic) pheochromocytoma, the sensitivity for detection approaches 100%.119,120 For metastatic PPGL, FDOPA performs better in SDHB mutation nega- tive than for SDHB mutation positive (sensitivity: 93% vs 20% respectively). 119 On the other hand, FDOPA shows very high sensitivity for detection of VHL, EPAS (HIF-2%), and FH-related PPGLs, which are often multiple, recurrent, and occasion- ally exhibit high metastatic potential. The decreased sensitivity in metastatic disease related to SDHB mutation-related PPGL is probably due to dedifferentiation, which might lead to loss of specific norepinephrine transporters in these tumors.
Fluro-dopamine
Theoretically, fluro-dopamine (FDA) appears to be a promising tool for the detection of PGLs associ- ated with the sympathetic nervous system and is currently used as an experimental tracer with few preliminary studies reported to date. Timmers and colleagues121 in their prospective study on
52 patients inferred that FDA-PET is the preferred imaging modality for localizing primary PGL and to rule out metastases. For patients with known met- astatic PGL, they recommended FDA-PET in pa- tients with an unknown genotype, FDG, or FDA- PET in SDHB mutation and FDOPA or FDA-PET in SDHB mutation-negative patients.121 In various studies, the sensitivity and specificity of FDA-PET in imaging PPGL ranged from 90% to 100% and 75% to 90%, respectively.121,122
11C-Hydroxyephedrine
Hydroxyephedrine (HED) is a norepinephrine analogue that binds to the norepinephrine trans- porter, is transported to neurosecretory vesicles in presynaptic adrenergic nerve terminals, and is stored there. Vyakaranam and colleagues 123 retro- spectively evaluated 102 patients with symptoms suspicious for PPGL and showed sensitivity, spec- ificity, positive predictive value, and negative pre- dictive value of 96%, 99%, 96%, and 99%, respectively, and when correlated with histopa- thology, the respective parameters were 96%, 93%, 96%, and 93%, respectively. The study further demonstrated that HED-PET effectively ruled out PPGL in 78 patients in whom CT was inconclusive. 123 Few disadvantages associated with HED PET are shorter half-life of 11C (20 mi- nutes), which mandates the presence of an on- site cyclotron, limited availability, and that it can be used only in patients with sympathetic PGL.
124I-Metaiodobenzyl guanidine
124| is a positron-emitting isotope of iodine and holds promise for detection of primary and meta- static sites in malignant PPGLs owing to higher im- age resolution of PET systems and provides the scope to quantitate the uptake, which is valuable for dosimetric analysis and more objective treat- ment response evaluation. Few studies have been performed with 124I-MIBG, and Ott and col- leagues124 used it to predict the absorbed dose of 131I-MIBG in neural crest tumor sites of 2 pa- tients. Pre-therapeutic imaging of PPGLs to ascer- tain eligibility for 131I-MIBG therapy and dosimetry is perhaps the most attractive feature of 124I-MIBG PET imaging. Disadvantages are limited availabil- ity and a longer half-life (4 days) than other PET tracers in use for the indication and hence should be considered only when 131I-MIBG therapy is be- ing planned.
Recommendations
· Sporadic nonmetastatic pheochromocy- tomas: FDOPA PET is the most sensitive tracer, and if available, should be the preferred imaging modality. If not, SSA-PET or MIBG scintigraphy should be considered. FDG-PET can provide genotypic information linked to SDHB mutation. FDA and HED PET are of experimental status, and more data are required for their formal clinical inclusion.
· Head and neck paragangliomas (HNPGLs): SSA-PET should be considered the first imag- ing modality, as it has high detection effi- ciency for both SDHx-related and non- SDHx-related tumors, can detect very small lesions that tend to be overlooked by other imaging modalities, and has better availability, followed by FDOPA-PET. FDG has high sensi- tivity for SDHx-related HNPGLs and can com- plement SSA and FDOPA PET for detecting additional lesions. As HNPGLs are mostly parasympathetic paragangliomas, tracers tar- geting adrenergic pathways are of no signifi- cant importance.
· Retroperitoneal and other extra-adrenal non- metastatic paragangliomas: A main objective is to rule out neurogenic tumors, lymphoproli- ferative disorders, and mesenchymal tumors, and PET tracers with specific targets, SSA > FDOPA should be considered (as the former has high sensitivity and specificity for both SDHx-related and non-SDHx-related tu- mors, can detect very small lesions, and has better availability). Because most of the extra-adrenal PGLs apart from HNPGLs have sympathetic phenotype, PET tracers
targeting adrenergic pathways (FDA and HED) are valid alternatives, mainly of experi- mental importance.
· Metastatic pheochromocytomas and para- gangliomas (PPGLs): SSA PET is the imaging modality of choice owing to the above- mentioned reasons (SDHx-related and non- SDHx-related tumors, can detect very small lesions, and has better availability). FDOPA should be considered as the second-line im- aging modality in the absence of SDHB muta- tion and if the genotype is unknown. FDG-PET is an important imaging tool for SDHB- mutated lesions for detection of metastases. MIBG scintigraphy may cause significant un- derestimation of the tumor burden and conse- quent inappropriate management. 124I-MIBG PET appears promising in this setting and has theranostic implications.
· VHL and RET/MEN 2-associated PPGLs: MEN 2-associated pheochromocytomas are almost always sympathetic (adrenergic phenotype) and are exclusively adrenal; hence, FDOPA is the imaging modality of choice with the exception of larger tumors (>5 cm), which tend to become metastatic. FDG-PET fares better and should be chosen over FDOPA when aggressive metastatic PPGLs are suspected.
FUTURE DIRECTIONS Fibroblast Activation Protein Inhibitor PET
Tumor microenvironment is a complex dynamic framework that plays a crucial role in survival, pro- liferation, spread, and drug resistance of malignant cells through protumorigenic signaling path- ways.125,126 Fibroblast activation protein (FAP) is overexpressed in stroma of several tumor entities, especially in those that are characterized by a strong desmoplastic reaction, so much so that approximately 90% of the gross tumor mass con- sists of stromal cells contributed mainly by cancer- associated fibroblasts (CAF) and extracellular fibrosis, and original tumor cells are only in the mi- nority.127,128 Normal fibroblasts are present ubiq- uitously in the whole-body and show dipeptidyl peptidase 4 expression (exopeptidase activity) and very low FAP expression, whereas CAFs are specifically characterized by overexpression of FAP (both exo-peptidase and endo-peptidase ac- tivity). Hence, FAP provides a promising highly tumor-specific target, and FAP-specific inhibitors (FAPI) have been developed as anticancer drugs.
FAPI are “quinoline”-based agents attached with positron emitters (68Ga) to DOTA-containing ligands (universal bifunctional chelators) as tumor
targeting radiopharmaceuticals, and the bio- distribution suggested that FAPI may be suitable for radioligand therapy and here has over the time developed as one of the most promising theranostic agents.
Published accounts on FAPI-PET being used in endocrine malignancies are extremely deficient, and most of the work is done on metastatic thyroid carcinoma (both differentiated and in TENIS syn- drome); however, no publication could be found on FAPI PET being used in adrenal or parathyroid tumors. Wu and colleagues129 in their study compared FDG and FAPI PET/CT scans in a cohort of 35 patients and demonstrated 68Ga- DOTA-FAPI-04 detected more lymph nodal and skeletal lesions as compared with FDG (268). The specificity, accuracy, positive predictive value, and negative predictive value of 68Ga-DOTA- FAPI-04 relative to FDG for detection of metastatic lymph nodes were 84.38% versus 34.38%, 83.10% versus 60.56%, 86.49% versus 59.62%, and 79.41% versus 57.89%, respectively, and were statistically significant (P = . 05), and for skel- etal lesions, the parameters were statistically not significant (268). However, the detection rate of 68Ga-DOTA-FAPI-04 for skeletal metastases was found to be 96.0% (24/25 lesions) and was signif- icantly higher than FDG 72.0% (18/25 lesions) (P <. 05) (0.049). The detection rate for lymph nodes was also marginally higher for 68Ga-DOTA-FAPI- 04 (82.05%; 32/39) than for FDG (79.49%; 31/39) and was statistically not significant (P>.05) (0.774), and for distant metastases other than bones, 68Ga-DOTA-FAPI-04 scored 91.07% (51/ 55) versus FDG 89.09% (49/55) and was statisti- cally not significant (P>.05) (0.742). Fu and col- leagues130 in the case report on patients with TENIS syndrome reported intense uptake of 68Ga-DOTA-FAPI in metastatic lesions demon- strating its usefulness in detecting recurrent/meta- static lesions in patients with TENIS. Furthermore, 68Ga-DOTA-FAPI uptake qualifies the patients for radioligand therapy and will be a valuable addition to the limited therapeutic intervention against TENIS.
DISCLOSURE
The authors have nothing to disclose.
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