Over several years, functional tumour imaging has often relied on abnormal patterns of specific metabolic pathways or the overexpression of tumour specific receptors. Initial observations that demonstrated the alterations in Kennedy pathway in cancerous tissues fueled the development of radiolabelled choline and exploration of its uptake patterns in tumour cells. Subsequently, several trials and research studies established the invaluable role of choline-based radiotracers in accurate detection of biochemical relapse in patients of prostate cancer, following initial definitive treatment.

Although preliminary studies linked the increased phosphocholine (PCho) levels in tumour cells to increased cell membrane turnover and thus to proliferative activity, it was only subsequently realised to be due to overexpression of the choline transporters (e.g. CLT-1) and the key enzyme, choline 1-α-kinase. Several molecules were developed to target these mechanisms; however, only 11C-choline, 18F-methylcholine (FCH) and 18F-ethylcholine garnered widespread utilisation [1]. Since 11C-choline is biochemically indistinguishable from natural choline and shows similar kinetics, it is believed to follow the pathways of naturally occurring choline. Although its favourable imaging characteristic of limited urinary clearance had the advantage in urological malignancies, the short half-life of 11C (20 minutes) restricted its utilisation only to centres equipped with an on-site cyclotron. Flourine-18 methylcholine (FCH) was subsequently developed by DeGrado et al., which demonstrated slightly slower rates of incorporation than choline and higher rates of urinary clearance than 11C-Choline. However, better image quality and longer half-lives provided logistic advantage over 11C-choline [2]. Currently, both these tracers are in use depending on their availability and validation in various regions.

Several authors have previously reported and reviewed the several pitfalls of PET imaging with radiolabelled choline derivatives [3, 4]. In this chapter, we review the physiological distribution and pitfalls of FCH PET/CT imaging that a clinician should be aware of during the interpretation.

8.1 Physiological Tracer Distribution

After intravenous administration, significant fraction of radiolabelled choline is rapidly cleared from the circulation within 10 min, after which the plasma concentration reaches a plateau. Physiological uptake of tissues is noted most prominently in the liver, pancreas, followed by salivary glands, spleen and lacrimal glands. Mild diffuse tracer uptake is noted in the bone marrow and muscles. A recent multicentre evaluation demonstrated no significant difference in the extra-prostatic distributions of 11C-choline, 18F-methylcholine (FCH) and 18F-ethylcholine [1]. Table 8.1 lists the organs with physiological uptake graded as per the degree of uptake.

Table 8.1 Physiological distribution [1]
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8.2 Applications

Although choline labelled radiotracers were utilised in evaluating patients with several malignancies (including brain tumours, oesophageal cancer, hepatocellular carcinoma [5] and several others), the most important clinical application is prostate cancer imaging [6] (Fig. 8.1). Incidental detection of parathyroid adenoma in patients imaged for prostate cancer evaluation led to recent studies in evaluating its utility in evaluation of patients with primary hyperparathyroidism (Fig. 8.2). Table 8.2 lists the various malignancies evaluated using radiolabelled choline PET/CT imaging and various indications in prostate cancer.

Fig. 8.1
figure 1

58 year-old-man with incidentally detected elevated S. PSA—2000 ng/mL. Trans-rectal ultrasound guided biopsy from the prostate was done, which showed adenocarcinoma (Gleason’s score 4 + 4 = 8). 18F-Choline PET/CT done for staging showed multiple foci of increased tracer avidity in the thoracic region, abdomen and pelvis in the maximum intensity projection image (a). Transaxial CT and fused PET/CT images showed increased tracer avidity in a heterogeneously enhancing lesion in the entire prostate (b, c—arrow; SUVmax 5.4), multiple tracer avid bilateral lung nodules (d, e) with SUVmax 14.5 and tracer avid sclerotic lesion in the sacrum (f, g) with SUVmax 11. The patient was put on androgen deprivation therapy with anti-androgen therapy and concurrent docetaxel based chemotherapy

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Fig. 8.2
figure 2

45 year-old-man with history of renal stone disease. Biochemical examination showed elevated serum levels of calcium (12.2 mg/dL) and intact parathyroid hormone (270 pg/mL). Ultrasound of neck did not reveal any abnormality. Sestamibi scan done for detection of parathyroid adenoma did not reveal any abnormality. 18F-Choline PET/CT showed a well-defined tracer avid (SUVmax 11.4) lesion postero-inferior to the right lobe of thyroid gland (~1.7 × 1.2 cm) (maximum intensity projection image—(a), transaxial CT—(b), fused PET/CT—(c), arrow). The patient underwent surgical resection of the lesion with the histopathology confirming the parathyroid adenoma

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Table 8.2 Possible role of choline PET/CT in various malignancies
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8.3 False Positive FCH Uptake

It is not uncommon to notice incidental sites of FCH uptake that are less likely to be related to the primary aetiology of concern (usually prostate cancer) (Figs. 8.3, 8.4, and 8.5). In such cases, all suspicious findings warrant further evaluation with imaging and/or histological correlation to rule out any atypical pattern of metastatic involvement or any synchronous malignancy (Table 8.3). Also, several benign inflammatory and non-inflammatory conditions can demonstrate variable FCH uptake due to its inherent non-specific mechanism of uptake. Knowledge of these conditions will avoid potential misinterpretation of these conditions as malignant/metastatic involvement (Table 8.4).

Fig. 8.3
figure 3

45 year-old-man with an incidentally detected intracranial space occupying lesion on CT. MRI showed an extra-axial mass in the left frontal—basi-frontal region—likely meningioma. 18F-Choline PET/CT showed increased tracer uptake (SUVmax 6.1) in a hyperdense lesion (~3.2 × 3.0 cm) in the left basi-frontal region (maximum intensity projection image—(a), transaxial PET—(b), CT—(c), fused PET/CT—(d)). Mass effect was also seen in the form of effacement of frontal horn of left lateral ventricle and midline shift (maximum ~7 mm) towards the right side with significant perilesional oedema. He subsequently underwent tumour resection and the histopathology was suggestive of meningioma

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Fig. 8.4
figure 4

51 year-old-man with acromegaly. MRI examination suggestive of pituitary microadenoma. 18F-Choline PET/CT showed a tracer avid (SUVmax 5) hyperdense soft tissue lesion (~1.3 × 1.9 cm) in the pituitary fossa—likely pituitary macroadenoma (maximum intensity projection image—(a), transaxial PET—(b), CT—(c), fused PET/CT—(d), arrow). The patient underwent trans-sphenoidal resection of the tumour and had an uneventful post-operative recovery. The diagnosis on histopathologic examination of the resection specimen was pituitary macroadenoma

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Fig. 8.5
figure 5

68-year-old-man presented with complaint of headache for 1 year, gradual in onset and with increasing severity. MRI of the head was suggestive of clival chondrosarcoma. 18F-Choline PET/CT showed a tracer avid (SUVmax 4.8) lytic expansile mass (~3.6 × 6.1 × 5.2 cm) at the base of the skull (maximum intensity projection image—(a), transaxial CT—(b), fused PET/CT—(c)). The mass was seen to cause lytic destructive changes of the base of the skull, clivus and the sella with anteriorly extension to the sphenoid sinus (arrow in (b, c)). The patient underwent tumour resection with the histopathology diagnosing the tumour as clival chordoma

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Table 8.3 Various incidentally detected (synchronous) malignancies reported with positive radiolabelled choline uptake [16]
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Table 8.4 Reported literature on various benign conditions with positive choline uptake that can lead to potential false positive interpretation
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8.4 False Negative Interpretation of FCH PET/CT (Table 8.5)

Some authors have reported lower detection rates of FCH PET/CT imaging in patients treated with androgen deprivation therapy [43]. However, subsequently results contrary to initial have been reported. Hence, due to lack of conclusive evidence for or against the hypothesis, currently withholding of therapy is suggested in hormone naïve patients planned for restaging. There is also report of impaired uptake of tracer in patients taking colchicine.

Table 8.5 False negative interpretation
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Administration of furosemide enhances the rapidity of tracer clearance and improves interpretation of perivesical space and avoids focal abnormal accumulations in the ureter. However, recently Rischke et al. reported that administration of furosemide reduced the degree of choline uptake in pelvic lymph nodes [42]. Hence, an early initial imaging followed by a delayed post-diuretic regional imaging seems to be a safer alternative. Some authors also reported that similar potential false negative interpretations are possible in patients treated with erythropoietin and chemotherapeutic drugs like docetaxel and paclitaxel [7, 41].

Key Points

  • Choline labelled radiotracers were utilised in evaluating patients with several malignancies and the most important clinical application is prostate cancer imaging.

  • Flourine-18 methylcholine (FCH) demonstrates slightly slower rates of incorporation and higher rates of urinary clearance than 11C-choline.

  • Physiological uptake of tissues is noted most prominently in the liver, pancreas, followed by salivary glands, spleen and lacrimal glands.

  • There is no significant difference in the extra-prostatic distributions of 11C-choline, 18F-methylcholine (FCH) and 18F-ethylcholine.