Original article Non-malignant FDG uptake in infradiaphragmatic adipose tissue: a new site of physiological tracer biodistribution characterised by PET/CT Rachel Bar-Shalom1, Diana Gaitini2, 3, Zohar Keidar1, Ora Israel1, 3 1 Department

of Nuclear Medicine, Rambam Medical Center, Haifa, Israel of Diagnostic Imaging, Rambam Medical Center, Haifa, Israel 3 The School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel 2 Department

Received: 17 November 2003 / Accepted: 17 February 2004 / Published online: 9 March 2004 © Springer-Verlag 2004

Abstract. The purpose of this study was to characterise a benign pattern of infradiaphragmatic 18F-fluorodeoxyglucose (FDG) uptake in cancer patients using PET/CT. Infradiaphragmatic foci of FDG uptake, localised by PET/CT in regions of normal fat tissues, were demonstrated, in conjunction with fatty uptake in the neck and shoulders, in 9 of 1,241 (0.7%) patients. The imaging and clinical characteristics of this pattern and its possible clinical significance were assessed. PET/CT precisely localised infradiaphragmatic fat uptake (IDFU) within normal retroperitoneal fatty tissue of the perirenal space (nine patients) and in the paracolic or parahepatic space (four patients). Perirenal uptake was bilateral in five patients and focal in six. Paracolic and parahepatic uptake was bilateral in three patients and linear in all four patients. There was no evidence of malignancy at any of the sites during a follow-up period of 9–21 months. IDFU was significantly more prevalent in young patients assessed for monitoring response to therapy, and was always associated with the benign supradiaphragmatic uptake pattern, although its prevalence was significantly lower. There were no significant differences between the clinical characteristics of these two patterns of benign fatty FDG uptake. It is concluded that PET/CT allows for precise identification of increased FDG uptake in abdominal fatty tissue and further exclusion of disease at such sites. This benign uptake may represent increased glucose consumption in activated brown adipose tissue, similar to the mechanism suggested for supradiaphragmatic uptake. Recognition of this benign IDFU pattern is important for correct interpretation of abdominal PET findings in cancer patients.

Rachel Bar-Shalom (✉) Department of Nuclear Medicine, Rambam Medical Center, 35254 Haifa, Israel e-mail: [email protected] Tel.: +972-4-8543009, Fax: +972-4-8542928

Keywords: PET/CT – FDG – Biodistribution – Abdomen – Cancer Eur J Nucl Med Mol Imaging (2004) 31:1105–1113 DOI 10.1007/s00259-004-1506-0

Introduction Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) plays an important role in the evaluation of cancer [1]. Although highly sensitive for the detection of malignancy, FDG uptake in physiological and benign processes is well documented [2]. Recognition of unusual patterns of FDG biodistribution is important in order to avoid misinterpretation of PET [3]. Hybrid PET/CT imaging provides accurate co-registration of morphological and metabolic information, enabling precise localisation of FDG uptake within distinct anatomical structures [4, 5, 6]. Based on PET/CT, areas of increased symmetrical FDG uptake in the cervical region and the shoulder girdle have been suggested to represent activated brown adipose tissue [7, 8], rather than physiological activity in tense muscles, as previously thought. The purpose of this study was to describe a pattern of infradiaphragmatic benign FDG uptake, observed in cancer patients in conjunction with the previously reported supradiaphragmatic uptake in fatty tissues. This infradiaphragmatic fatty uptake (IDFU) pattern of FDG was precisely localised and characterised by hybrid PET/CT imaging. Materials and methods Infradiaphragmatic increased FDG uptake was found to be located in fatty tissue at various abdominal sites in 9 out of 1,241 cancer patients who had FDG PET/CT in our institution between January

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1106 and December 2002. The precise localisation of increased FDG uptake to fatty tissue on fused PET/CT images was defined and documented prospectively during the original review of the study. The files of all patients who had FDG PET/CT during the study period were retrospectively reviewed to retrieve data of patients with documented infradiaphragmatic fatty tissue uptake of FDG, for further characterisation. The institutional review board approved the retrospective review of patient data for assessment of the clinical significance of PET/CT studies. Imaging technique. All patients had a combined PET/CT scan (Discovery LS, GE Medical Systems, Milwaukee, USA). Patients fasted for at least 4 h and blood glucose was verified to be less than 11 mmol/l prior to the injection of 370–555 MBq of FDG. Patients were kept quiet and comfortable for 60 min after the injection. No muscle relaxants were administered. PET/CT acquisition included an initial head to pelvis four-slice spiral CT scan with acquisition parameters of 140 kV, 80 mAs, 0.8 s per rotation, 6:1 pitch and slice thickness of 4.25 mm, performed during normal breathing. This was followed by a PET acquisition of the same axial range for 5 min per field of view. Data obtained from the CT acquisition were used for low-noise attenuation correction of PET emission data, and for fusion of attenuation-corrected PET images with the corresponding CT images. PET images were reconstructed with and without CT-based attenuation correction. Both sets of uncorrected and CT-attenuation corrected PET, CT and fused PET/CT images were displayed on an Entegra workstation (GE Medical Systems, Milwaukee, USA). Image characterisation. The routine PET/CT review protocol consists of initial review of both non-corrected and CT attenuationcorrected PET images with prospective localisation and characterisation of findings, followed by the review of combined PET/CT data for final study interpretation. Attenuation-corrected PET and fused PET/CT images were also evaluated for the presence of respiratory motion artefacts and areas of resulting misregistration. The review of sites of IDFU was performed in correlation with the patient clinical history and the results of previous imaging studies. Increased FDG uptake was defined as benign when related to the physiological biodistribution of FDG or to a known non-malignant process. Any area of focal FDG activity of an intensity higher than that of surrounding tissues and not related to known normal physiological or benign FDG uptake was defined as malignant. Any other area of increased FDG uptake that could not be clearly characterised as malignant or benign according to its intensity, location or pattern was defined as an equivocal site on PET. The precise localisation of increased FDG uptake in infradiaphragmatic fatty regions was evaluated on the PET/CT studies, and its symmetry and focality were recorded. The association of IFDU with benign supradiaphragmatic FDG uptake was evaluated. The prevalence and clinical characteristics of the two uptake patterns in fatty tissue above and below the diaphragm were assessed and compared. Clinical characterisation. Clinical characterisation of the infradiaphragmatic uptake pattern was performed by a retrospective review of the clinical records. The possible association of the IDFU pattern with clinical factors including patient age, gender, body mass index, tumour histology and therapy status at the time of imaging was assessed. The clinical significance of fatty uptake at infradiaphragmatic sites was evaluated by further follow-up for at least 9 months (range 9–21 months), including clinical assessment, repeat CT in

all nine patients and repeat FDG PET/CT in eight patients. The prevalence of this pattern and the relationship between IDFU and clinical patient characteristics was evaluated in the whole study group of 1,241 patients and in a subgroup of 34 patients presenting with FDG uptake in supradiaphragmatic fatty tissue. Chi-square test was used to determine the significance of the association of IDFU with each of the clinical factors evaluated, and independent t test was used for assessment of mean age differences. P values smaller than 0.05 were considered statistically significant. Multiple logistic regression analysis was performed in order to assess the clinical factors most significantly associated with IDFU.

Results Imaging characterisation of abdominal fat FDG uptake Infradiaphragmatic foci of FDG uptake were demonstrated on PET images and localised by PET/CT in regions of fat tissues in 9 (0.7%) out of 1,241 cancer patients assessed between January and December 2002. Increased perirenal FDG uptake was seen on the PET images in all nine patients, either in the superior (eight patients) or the inferior perirenal region (one patient). Uptake was bilateral in the suprarenal region in five of the nine patients. Uptake was focal in six and linear in three patients with perirenal uptake. In four of the nine patients, there were additional sites of uptake involving the lateral aspect of the upper abdomen. Uptake at these sites was bilateral in three of the four patients and linear in all four. No other areas of abnormal FDG uptake below the diaphragm were seen in these nine patients. These foci were seen on both the non-corrected and the attenuation-corrected PET images in all patients. No significant respiratory artefacts were demonstrated in any of the studies. These findings were therefore considered of non-artefactual aetiology. In the absence of correlative abnormalities in the same regions on CT, these areas of increased FDG uptake were defined as equivocal following the interpretation of the PET studies. The differential diagnosis of the increased perirenal FDG uptake included physiological tracer activity in renal calices or bowel, as well as tumour involvement in the adrenals, liver, regional lymph nodes or bowel. In the lateral abdominal region the increased FDG uptake was considered to represent either physiological abdominal muscles activity or tumour involvement of the abdominal wall. Hybrid PET/CT images localised all foci of infradiaphragmatic FDG uptake to areas of normal abdominal fatty tissue (Table 1). Perirenal uptake was localised to retroperitoneal fat in the upper or lower perirenal space (Figs. 1, 2). Lateral abdominal uptake was localised to extraperitoneal parahepatic or paracolic fat (Fig. 3). All nine patients also showed multiple foci of symmetrical increased FDG uptake in the neck, shoulder girdle and paravertebral regions bilaterally. Fused images localised these areas to normal fatty tissue on CT in all patients.

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1107 Table 1. Patient characteristics and imaging findings Patient

Gender, age (yrs)

Diagnosis

PET findings

PET/CT localisation

Follow-up (months)

1

M, 27

Hodgkin’s disease

Bilateral linear uptake, suprarenal region Bilateral linear uptake, lateral abdomen

Retroperitoneal upper perirenal fat Extraperitoneal parahepatic and paracolic fat

NED (10)

2

M, 24

Non-Hodgkin’s lymphoma

Bilateral linear uptake, suprarenal region Bilateral linear uptake, lateral abdomen

Retroperitoneal upper perirenal fat Extraperitoneal paracolic fat

NED (10)

3

M, 14

Non-Hodgkin’s lymphoma

Bilateral focal uptake, suprarenal region Unilateral linear uptake, lateral abdomen

Retroperitoneal upper perirenal fat Extraperitoneal parahepatic fat

NED (21)

4

F, 16

Hodgkin’s disease

Bilateral focal uptake, suprarenal region

Retroperitoneal upper perirenal fat

NED (12)

5

F, 17

Hodgkin’s disease

Bilateral focal uptake, suprarenal region

Retroperitoneal upper and posterior perirenal fat

NED (9)

6

F, 29

Hodgkin’s disease

Unilateral focal uptake, suprarenal region

Retroperitoneal upper perirenal fat

NED (9)

7

M, 38

Seminoma

Unilateral focal uptake, suprarenal region Multiple lung foci

Retroperitoneal upper perirenal fat Lung nodules

NED (12) (Lung toxicity following chemotherapy)

8

M, 17

Non-Hodgkin’s lymphoma

Unilateral focal uptake, infrarenal region Anterior mediastinal uptake

Retroperitoneal lower perirenal fat Hyperplastic thymus

NED (11)

9

F, 18

Hodgkin’s disease

Bilateral linear uptake, suprarenal region Bilateral linear uptake, lateral abdomen Uptake in right neck and mediastinum

Retroperitoneal upper perirenal fat Extraperitoneal parahepatic and paracolic fat Cervical and mediastinal adenopathy

NED at these sites (13)

(Lymphoma sites)

NED, No evidence of disease

Additional PET findings included pathological uptake in right cervical and upper mediastinal adenopathy representing lymphomatous involvement in one patient assessed before therapy, increased FDG uptake in a hyperplastic thymus after treatment in a second patient, and several hypermetabolic lung lesions related to bleomycin lung toxicity in a third patient. Clinical characteristics of the patient population with abdominal fat FDG uptake Of the nine patients with infradiaphragmatic FDG uptake in normal fatty tissues, five were men (56%) and four women (44%). Their mean age was 22 years (range 14–38). Body mass indices ranged between 18 and 25 and were within the normal gender- and age-adjusted values for all nine patients.

Lymphoma was the primary malignancy in eight of the nine patients (five patients had Hodgkin’s disease and three had non-Hodgkin’s lymphoma), while one patient had a testicular seminoma. FDG PET was performed after initiation of therapy in eight patients (to assess response to therapy in six patients, or during followup in two patients), and for initial staging in one patient (Table 2). The clinical significance of FDG uptake in infradiaphragmatic fatty tissue was evaluated in all nine patients. There was no history of abdominal disease in eight of the nine patients. One patient had been previously treated for metastatic retroperitoneal adenopathy. At the time of the study there was no clinical or imaging evidence for abdominal disease in eight patients. One patient with right focal suprarenal FDG uptake had a residual retroperitoneal mass on CT in the left para-aortic region.

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1108 Fig. 1A, B. Bilateral suprarenal fatty FDG uptake. A PET images in the coronal (upper row) and axial (lower row) planes show increased FDG uptake in the suprarenal region bilaterally. Note additional areas of symmetrically increased FDG uptake in the shoulder girdle and paravertebral thoracic area. B Axial (upper rows) and coronal (lower row) corresponding PET (left) and PET/CT (centre) images demonstrate localisation of FDG uptake in fatty tissue in the retroperitoneal upper perirenal space. No morphological abnormalities are seen on the corresponding CT slices (right). The patient (no. 2, Table 1) had no evidence of disease during 10 months of clinical and imaging follow-up

Routine clinical and imaging (CT) follow-up was performed for all nine patients and showed no further evidence of disease in the regions of increased FDG uptake in fatty tissues. Repeat FDG PET/CT was also per-

formed in eight patients, at a mean interval of 4.9 months (range 2–8 months). Persistent abdominal fatty FDG uptake was demonstrated on the repeated PET in one of these eight patients. Persistent benign supradia-

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1109 Fig. 2A, B. Unilateral focal perirenal fat uptake. A PET images in the coronal, sagittal and axial planes show a focus of increased FDG uptake in the right infrarenal region. B Axial (upper row) and coronal (lower row) corresponding PET (left) and PET/CT (centre) images demonstrate localisation of FDG uptake to fatty tissue in the right retroperitoneal lower perirenal space. No morphological abnormalities are seen on the corresponding CT slices (right). The patient (no. 8, Table 1) had no evidence of disease during 11 months of clinical and imaging follow-up

phragmatic fatty uptake (in the cervical, shoulder girdle and upper paravertebral region) was seen in five patients. The eight patients assessed during or after therapy remained without evidence of disease for a follow-up period of 9–21 months. The lymphoma patient evaluated for staging before therapy achieved complete remission and was without evidence of disease after 9 months. A comparative analysis of the clinical characteristics in the nine patients with IDFU and the total study population of 1,241 patients is presented in Table 2. There were statistically significant differences between the groups with respect to age, number of patients with lymphoma and time of evaluation in relationship to treatment. Using the chi square test, IDFU was found to be significantly more prevalent in young patients, with lymphoma, and assessed for monitoring response to therapy.

The mean age of lymphoma patients with IDFU (20± 5 years) was significantly lower than that of the other lymphoma patients in the study population (48±12 years, P<0.001). Multiple logistic regression analysis did not find any clinical variable to be significantly related to the presence of IDFU. There was a significant association between IDFU and supradiaphragmatic fatty uptake. Abdominal sites of uptake were always demonstrated concomitantly with the benign supradiaphragmatic uptake pattern, appearing in nine (26%) of 34 patients with benign supradiaphragmatic uptake. Benign supradiaphragmatic fatty uptake was seen in 34 of the total of 1,241 patients, for an overall prevalence of 2%, which was significantly higher than that of IDFU (0.7%, P<0.001). Comparison of prevalence and clinical characteristics of patients presenting

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1110 Fig. 3A, B. Unilateral linear lateral abdominal fatty FDG uptake. A PET images in the coronal (upper row) and axial (lower row) planes show increased linear FDG uptake in the lateral aspect of the right upper abdomen. Note additional areas of increased FDG uptake in the suprarenal region and in the posterior shoulder girdle and the paravertebral thoracic area. B Axial (upper row) and coronal (lower row) corresponding PET (left) and PET/CT (centre) images demonstrate localisation of FDG uptake in fatty tissue in the extraperitoneal parahepatic space. No morphological abnormalities are seen on the corresponding CT slices (right). Suprarenal uptake was also localised to normal fatty tissue on PET/CT (not shown). The patient (no. 3, Table 1) had no evidence of disease during 21 months of clinical and imaging follow-up

with FDG uptake in infra- and supradiaphragmatic fatty tissue is presented in Table 3. Body mass indices of patients with supradiaphragmatic fatty uptake tissue were within the normal gender- and age-adjusted values as found in patients with IDFU. No statistically significant

differences were found between the clinical characteristics of these two patterns of benign fatty FDG uptake including gender, age, tumour histology and PET timing in relation to disease course.

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1111 Table 2. Comparative analysis of clinical characteristics of patients with and without infradiaphragmatic fat uptake

IDFU, Infradiaphragmatic fat uptake; NS, not statistically significant Table 3. Comparative analysis of clinical characteristics of patients with infra- and supradiaphragmatic fat uptake IDFU, Infradiaphragmatic fat uptake; SDFU, supradiaphragmatic fat uptake; NS, not statistically significant

Patient characteristics

IDFU, n=9

No IDFU, n=1,232

P value

Gender (M/F) Age, mean±SD (years) Lymphoma PET for staging PET for treatment monitoring PET during follow-up Supradiaphragmatic fat uptake

5/4 (56%/44%) 22±8 8 (89%) 1 (11%) 6 (67%) 2 (22%) 9 (100%)

703/529 (57%/43%) 57±16 424 (34%) 215 (17%) 173 (14%) 844 (68%) 25 (2%)

NS <0.001 <0.001 NS <0.001 <0.01 <0.001

Patient characteristics

IDFU, n=9

SDFU only, n=25

P value

Gender (M/F) Age, mean±SD (years) Lymphoma PET for staging PET for treatment monitoring PET during follow-up

5/4 (56%/44%) 22±8 8 (89%) 1 (11%) 6 (67%) 2 (22%)

6/19 (24%/76%) 32±19 13 (52%) 1 (4%) 9 (36%) 15 (60%)

NS NS NS NS NS NS

Discussion Hybrid imaging provides accurate co-registration of PET and CT. Precise spatial correlation of metabolic PET information with corresponding anatomical structures on CT has improved image interpretation of FDG PET studies [4, 5]. The use of PET/CT optimises the localisation of malignant lesions, excludes cancer at sites of physiological uptake and also allows for the reassessment of previously recognised patterns of physiological tracer biodistribution [6, 7, 8]. Increased symmetrical FDG uptake in the neck, shoulder and costovertebral regions has been considered to represent physiologically increased uptake in tense muscles due to anxiety or cold stress-induced shivering [2, 9, 10, 11]. Disappearance of these findings following the administration of muscle relaxants has supported this assumption [12]. With the introduction of PET/CT it has been shown, however, that increased FDG uptake in the neck and shoulders may be localised in non-muscular fatty tissue [7, 8]. Increased muscular FDG uptake below the diaphragm has been reported only infrequently, and considered to be secondary to muscular contraction in cases of hyperventilation, nausea or vomiting [2, 13]. Physiological FDG activity in the gastrointestinal or urinary tract may be mistaken for, or may disguise, a malignant lesion in its proximity [2, 3]. The differential diagnosis of a malignant or benign aetiology of abdominal sites of increased FDG uptake is clinically significant but may be difficult. Image fusion of PET and CT improves image interpretation in the abdomen [6, 14]. The infradiaphragmatic foci of increased FDG activity in the upper abdomen, described in the present study, posed a diagnostic dilemma on PET analysis, especially when they were asymmetrical or focal or did not conform to the expected physio-

logical tracer distribution. By localising these sites to normal fatty tissues, fused PET/CT images excluded malignancy and defined the benign nature of this uptake pattern. The accuracy of CT-based attenuation correction and of image co-registration on a PET/CT system is affected by differences in the respiration level that occur between the acquisition of the CT and the PET components of the study [15, 16, 17]. No significant respiratory artefacts were found in any of the nine PET/CT studies included in present report. All IDFU sites described in this study appeared outside the known areas of respiratory artefacts paralleling the diaphragmatic dome, were always demonstrated on both the non-corrected and the attenuationcorrected PET images and were always localised in fatty tissue. Tracer uptake in brown adipose tissue (BAT) has been suggested as the mechanism for the supradiaphragmatic FDG uptake in fat [7]. Although thermogenesis by BAT is a product of lipolysis and not of glucose catabolism, glucose consumption in these tissues is increased via sympathetic innervation in order to maintain the energy supply for the fatty acid oxidation process [18]. This explanation may be valid for the infradiaphragmatic FDG uptake pattern described in the cases presented here as well. Deposits of BAT, widely distributed in the body during infancy, can still be found in adults in the vicinity of cervical and intercostal vessels, in the axillary and interscapular region, along the large vessels in the thorax and abdomen, and in particular around the heart, kidneys and adrenals [18, 19, 20, 21, 22]. Peri-adrenal BAT was histologically identified in 24% of 366 adult patients at autopsy [19], and perinephric BAT was found to be more abundant in younger adults [22]. The distribution of FDG uptake in the present patients correlated with the known supra- and infradiaphragmatic

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distribution of BAT in humans. While increased supradiaphragmatic FDG uptake has been described preferentially in underweight patients, and thus has been suggested to represent increased BAT thermogenetic activity compensating for excessive heat loss through reduced subcutaneous tissues [18, 19], the body mass index of the present patients was within the normal range for their gender and age. Statistical analysis of the clinical characteristics of the patients showing IDFU revealed this pattern to be significantly more prevalent in young patients with lymphoma and in patients assessed for monitoring response to therapy (Table 2). Since the mean age of lymphoma patients with IDFU was significantly lower than that of the other lymphoma patients included in the total study population, it can be assumed that the higher prevalence of IDFU in these patients is probably related to their younger age rather than to the type of primary malignancy. The fact that no single clinical variable was found to be statistically significant for the appearance of IDFU on multiple logistic regression analysis may be due to the small size of the IDFU patient group. Nevertheless, young age and imaging during assessment of therapy response appear to be significant characteristics in patients presenting with the IDFU pattern. The possible underlying physiological process responsible for the appearance of IDFU is unclear, but may be related to alterations of adrenergic stimulation in this type of clinical scenario, with temporary BAT activation and a significant increase in its glucose uptake [19]. A significant association was found in present study between the two sites of fatty FDG uptake. The benign supradiaphragmatic fatty uptake pattern was found in all patients with, and in only 2% of patients without IDFU. The clinical characteristics of patients with supra- and infradiaphragmatic fatty FDG uptake were similar and showed no statistically significant differences. This association and the clinical similarity between patients with the two patterns of fatty FDG uptake further support the assumption of a common aetiology of FDG uptake at sites of activated BAT. Although infrequent, benign infradiaphragmatic FDG uptake in abdominal fatty tissue may represent a clinically significant pitfall in imaging of cancer patients. The presence and distribution of infradiaphragmatic fat uptake of FDG, unrecognised prior to the use of PET/CT, may result in equivocal or even erroneous definition of PET findings as malignant. The recognition and precise characterisation of this pattern as benign using PET/CT improves the accuracy of interpretation of PET images in cancer patients. When uptake in such sites is linear and bilateral, a benign aetiology may be suspected and included in the differential diagnosis of PET findings. In the presence of a single, asymmetrical or focal area of increased FDG uptake, in patients with suspected active malignancy in the same regions, PET/CT images will, however, be necessary to avoid misinterpretation.

Conclusion Benign increased FDG uptake can be seen in fatty tissues in various infradiaphragmatic sites, mainly in young patients evaluated for monitoring response to treatment. A variable pattern of focal or linear, bilateral or unilateral uptake may appear in regions such as the perirenal, paracolic or parahepatic space. PET/CT imaging is of value for precise localisation of increased FDG uptake in abdominal fatty tissues, for its benign characterisation and for exclusion of malignancy in these sites. Recognition of this benign uptake pattern as a potential pitfall will improve the specificity of FDG imaging in the assessment of cancer patients. Acknowledgement. The authors thank Drs. A. Tamir, A. Frenkel and J.A. Parker for their useful assistance and Mrs. M. Perlmutter for her help in the preparation of this paper.

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