Non-FDG PET/CT in Diagnostic Oncology: a pictorial review

Positron emission tomography/computed tomography (PET/CT) is currently one of the main imaging modalities for cancer patients worldwide. Fluorodeoxyglucose (FDG) PET/CT has earned its global recognition in the modern management of cancer patients and is rapidly becoming an important imaging modality for patients with cardiac, neurological, and infectious/inflammatory conditions. Despite its proven benefits, FDG has limitations in the assessment of several relevant tumours such as prostate cancer. Therefore, there has been a pressing need for the development and clinical application of different PET radiopharmaceuticals that could image these tumours more precisely. Accordingly, several non-FDG PET radiopharmaceuticals have been introduced into the clinical arena for management of cancer. This trend will undoubtedly continue to spread internationally. The use of PET/CT with different PET radiopharmaceuticals specific to tumour type and biological process being assessed is part of the personalised precision medicine approach. The objective of this publication is to provide a case-based method of understanding normal biodistribution, variants, and pitfalls, including several examples of different imaging appearances for the main oncological indications for each of the new non-FDG PET radiopharmaceuticals. This should facilitate the interpretation and recognition of common variants and pitfalls to ensure that, in clinical practice, the official report is accurate and helpful. Some of these radiopharmaceuticals are already commercially available in many countries (e.g. 68Ga-DOTATATE and DOTATOC), others are in the process of becoming available (e.g. 68Ga-PSMA), and some are still being researched. However, this list is subject to change as some radiopharmaceuticals are increasingly utilised, while others gradually decrease in use.

humans. The vast clinical application of F-compounds has led to the development of efficient automated production methods of F-18 tracers for clinical use.
Gallium-68 has a T1/2 of 67.7 min, and is usually obtained from a germanium-68 generator. Due to the T1/2 of 271 days of the parent isotope, 68Ge, the generator can be used for in-hospital production of Ga-68.

Radiopharmaceuticals
Acetate Names: CH 3 [ 11 C]O 2 , 11 C-acetate Biodistribution and metabolism ( Fig. 1) After injection 11 C-acetate is dispersed in many human tissues including the pancreas, bowels, liver, kidneys, and spleen. The tracer is not excreted in urine under normal circumstances. 11 C-acetate is typically incorporated into the cellular membrane in proportion to the cellular proliferation rate or alternatively oxidised to carbon dioxide and water. 11 C-acetate may also be converted into amino acids (Seltzer et al. 2004;Karanikas and Beheshti 2014).
Scan acquisition The main clinical application of 11 C-acetate is the detection of non 18 F-FDG-avid neoplasm, such as differentiated hepatocellular carcinoma and renal cell carcinomas (Hain and Maisey 2003;Ho et al. 2003;Park et al. 2008). Some other applications of 11 C-acetate PET are brain tumours (Liu et al. 2006) and lung carcinomas, while in the past the tracer has been used in prostate cancer (Sandblom et al. 2006).
Scan acquisition Treatment with oestrogen receptor antagonists (e.g. tamoxifen, fulvestrant, faslodex, oestrogens) should be suspended for at least 5 weeks prior to performing the scan. Aromatase inhibitors and luteinizing hormone releasing hormone agonists may be continued No fasting is required Clinical indications in oncology (Figs. 5 and 6) 18 F-fluoroestradiol is a valuable tracer for the studies of the oestrogen receptor status of primary and metastatic breast or ovarian cancers (Venema et al. 2016;van Kruchten et al. 2013a;van Kruchten et al. 2012;van Kruchten et al. 2013b;Peterson et al. 2011;Linden et al. 2011 • 4-5 MBq\Kg of 18 F-FET iv • Dynamic one bed brain acquisition for 40 min or static one bed brain acquisitions at 10 and 40-50 min. after injection, for 10 min. Clinical indications in oncology (Figs. 8,9,and 10) Diagnosis of central nervous system tumours (very low background in healthy brain) (Galldiks et al. 2015;Albert et al. 2016;Unterrainer et al. 2016;Kunz et al. 2011;Poulsen et al. 2017).
FLT Names: 3′-deoxy-3′-[ 18 F]-fluorothymidine; 18 F-fluorothymidine Biodistribution and metabolism (Fig. 11) 18 F-FLT is an analogue of the nucleoside thymidine; however, substitution of the 3′-F atom prevents from further entering the regular biochemical pathway. FLT is transported from the blood into cells by active transport and phosphorylated by thymidine kinase I without incorporation into the DNA. The conjugated FLT is cleared via the kidneys and excreted in the urine. The accumulated activity in the cells is proportional to thymidine kinase 1 activity as well as cellular proliferation (Grierson and Shields 2000;Oh et al. 2004;Shankar 2012;Turcotte et al. 2007;Vesselle et al. 2003).  (2011), ER+, presenting with an 18-mm brain lesion on MRI (a). Biopsy was not possible due to location. PET/CT findings: solitary lesion with increased ER expression in the brain in MIP (b), located in the left occipital lobe on fused images (c), suggesting brain metastasis from breast cancer C-Methionine, an essential amino acid, enters the cells by various aminoacid transporters and is involved in the synthesis of proteins and lipids, as well as in the regulation and synthesis of DNA and RNA (Davis et al. 1982;Deloar et al. 1998;Harris et al. 2013).
Scan acquisition • Fasting for at least 2 h • 3 MBq/kg of 11 C-Methionine iv • Injection immediately before the start of the emission Clinical indications in oncology (Figs. 16, 17, and 18) 11 C-Methionine is used in the detection of brain tumours, primarily gliomas. The gliomas present an increased protein metabolism and capture 11 C-Methionine through specific carriers, in contrast to normal tissues that show low uptake.
[11C]CH, 11 C-choline 2. [ 18 F]CH, 18 F-fluorocholine Biodistribution and metabolism ( Fig. 19) After injection, the tracer rapidly clears from the circulation (< 3 min), with high clearance by liver and kidneys. Increased metabolism will lead to an increased uptake of choline in the cell membranes and tissues. 11 C-choline distributes mainly to the pancreas, kidneys, liver, spleen, and colon. Based upon the relatively low urinary excretion of radioactivity, renal distribution is predominantly to the organ itself, rather than via formation of urine.  The urinary excretion of 18 F-fluorocholine has been reported to be about 5% of the administered activity in female patients and 2% in male patients within 60 min after injection (Mitterhauser et al. 2005;DeGrado et al. 2001;DeGrado et al. 2002).
Scan acquisition • Fasting of 4 h is suggested • 4 or 5 MBq\Kg of 11 C-choline iv/300 MBq 18 F-fluorocholine iv Physiological bio-distribution and normal variants of 11 C-choline 2-5 min after administration: main findings. a Normal biodistribution but a small amount of radioactive urine is present in the bladder; mild uptake in the thyroid. b The presence of intense uptake in the vessels in which the tracers has been injected is a relatively common finding; some mild thyroid uptake is present. c Moderate uptake in the bowel may be present. d Some diffuse faint uptake in the bone marrow may be present especially after treatments as a bone marrow rebound The main clinical application of choline is in prostate cancer patients for staging and restaging the disease in case of biochemical recurrence after primary treatment (Kryza et al. 2008;Evangelista et al. 2013).  Clinical indications in oncology (Figs. 26,27,28,29,30,31,32,33,34,35,36,and 37) The main clinical application of 68 Ga-PSMA is in prostate cancer patients, namely initial diagnosis (Fendler et al. 2017), nodal staging (Schneider et al. 2016), restaging in case of biochemical recurrence (Calais et al. 2018;Maurer et al. 2016), and theranostic in case of 177 Lu-PSMA treatment (Mottet et al. 2011;Zamboglou et al. 2016), or alfa emitters such as 225 AcPSMA (Maurer et al. 2016). is metabolised in the striatum, but also in peripheral tissues such as liver, kidneys, and lung (Rahbar et al. 2017). Scan acquisition • Fasting for more than 4 h • 2-3 MBq/Kg of 18 F-DOPA iv • Uptake time 60 min for extra-cranial tumours. An additional acquisition of 10 min after injection is suggested in medullary thyroid cancer. • Uptake time 10 min for primary brain tumours.
Clinical indications in oncology (Fig. 39, 40, 41, 42, and 43) 18 F-DOPA is used in the detection of neuroendocrine tumours. It is the PET tracer of choice for recurrence detection in patients with medullary thyroid cancer and may play a role in the management of patients with pheochromocytoma and neuroblastoma. 18 F-DOPA PET/CT is also used in recurrent glioma Chondrogiannis et al. 2013;Soussan et al. 2012;Amodru et al. 2018).

Conclusion
The constant growth of PET/CT including the increasing use of novel non-FDG PET/ CT radiopharmaceuticals in cancer patients creates a need for training in the proper interpretation of complex imaging studies with compounds that have very different biodistribution, normal variants, and pitfalls. In addition, the use of several of these non-FDG PET radiopharmaceuticals, such as 68 Ga-PSMA and 68 Ga-DOTA peptides, constitutes an integral part of the evaluation of patients with cancer for theranostics. As this further increases the radiopharmaceuticals' clinical relevance, there is also the need for accurate interpretation of non-FDG PET/CT studies.