The nonspecific lymph node uptake of 18F-choline in patients with prostate cancer - A prospective observational study

Abstract

The aim of this study was to observe and characterize the nonspecific ¹⁸F-choline lymph node uptake in patients with prostate cancer.
In this single center, prospective observational study which was done in University Hospital Center Zagreb between December 2012 and October 2014, 69 patients (median age 71 years; range 50-92) with prostate cancer were included. Patients underwent ¹⁸F-choline PET/CT for staging or restaging of prostate cancer. The mean follow-up period was 11.5 months. Kruskal-Wallis test was used to find out if the differences between SUV values of specific and nonspecific accumulation of the tracer are statistically significant.
Nonspecific accumulation of ¹⁸F-choline in lymph nodes was found in 36 patients (52.7%). Most of these findings (n = 24) were nonspecific accumulation of the tracer in mediastinal lymph nodes. Other sites of nonspecific tracer uptake were pulmonary hila (n = 20), inguinal lymph nodes (n = 15), and axillary lymph nodes (n = 10). Mean SUV values for mediastinal lymph nodes, pulmonary hila, axillary and inguinal lymph nodes were 4.8, 4.3, 3.1 and 4.1, respectively. Mean SUV value of nonspecific sites of tracer accumulation was lower (not significantly; (p = 0.2) than tracer uptake values measured in metastases sites (bone metastases mean SUVmax value - 13.2, metastatic lymph nodes mean SUVmax value - 9.2).
¹⁸F-choline PET/CT is a valuable and an established functional diagnostic imaging method for staging and restaging prostate cancer. However, nonspecific uptake of the tracer can often be seen in lymph nodes not related to primary disease. Patient history, clinical examination, laboratory tests and correlation with other imaging methods, must be taken into consideration when interpreting ¹⁸F-choline PET/CT findings.

Full text

56
Nuclear Medicine Review 2015, 18, 2: 56–60
DOI: 10.5603/NMR.2015.0015
Copyright © 2015 Via Medica
ISSN 1506–9680
Original
Correspondence to: Anja Tea Golubić, MD
Department of Nuclear Medicine and Radiation Protection
University Hospital Center Zagreb
Kišpatićeva 12, 10000 Zagreb, Croatia
Tel: +385 1 2388 587
Fax +385 1 2376 040
E-mail: anja.tea.golubic@gmail.com
The nonspecic lymph node uptake
of
18
F-choline in patients with prostate
cancer — a prospective observational
study
Anja Tea Golubić
1
, Andrea Mutvar
1
, Marijan Žuvić
1
, Dražen Huić
1, 2
1
Department of Nuclear Medicine and Radiation Protection, University Hospital Center Zagreb, Zagreb, Croatia
2
School of Medicine, Zagreb, Croatia
[Received 26 I 2015; Accepted 7 V 2015]
Abstract
BACKGROUND: The aim of this study was to observe and characterize the nonspecific
18
F-choline lymph node uptake in
patients with prostate cancer.
MATERIAL AND METHODS: In this single center, prospective observational study which was done in University Hospital Cen-
ter Zagreb between December 2012 and October 2014, 69 patients (median age 71 years; range 50–92) with prostate cancer
were included. Patients underwent
18
F-choline PET/CT for staging or restaging of prostate cancer. The mean follow-up period
was 11.5 months. Kruskal-Wallis test was used to find out if the differences between SUV values of specific and nonspecific
accumulation of the tracer are statistically significant.
RESULTS: Nonspecific accumulation of
18
F-choline in lymph nodes was found in 36 patients (52.7%). Most of these findings
(n = 24) were nonspecific accumulation of the tracer in mediastinal lymph nodes. Other sites of nonspecific tracer uptake were
pulmonary hila (n = 20), inguinal lymph nodes (n = 15), and axillary lymph nodes (n = 10). Mean SUV values for mediastinal
lymph nodes, pulmonary hila, axillary and inguinal lymph nodes were 4.8, 4.3, 3.1 and 4.1, respectively. Mean SUV value of
nonspecific sites of tracer accumulation was lower (not significantly; (p = 0.2) than tracer uptake values measured in metastases
sites (bone metastases mean SUVmax value — 13.2, metastatic lymph nodes mean SUVmax value — 9.2).
CONCLUSIONS:
18
F-choline PET/CT is a valuable and an established functional diagnostic imaging method for staging and
restaging prostate cancer. However, nonspecific uptake of the tracer can often be seen in lymph nodes not related to primary
disease. Patient history, clinical examination, laboratory tests and correlation with other imaging methods, must be taken into
consideration when interpreting
18
F-choline PET/CT findings.
KEY words:
18
F-choline, prostate cancer, false positive uptake, pitfalls
Nuclear Med Rev 2015; 18, 2: 56–60
Background
Prostate cancer is the most common malignancy in men in
Europe and the US [1, 2]. Diagnostic procedure from clinical sus-
picion to diagnosis includes determination of PSA serum value,
transrectal ultrasound (TRUS) with or without biopsy, magnetic
resonance imaging (MRI), computerized tomography (CT) and
bone scintigraphy in patients with highly elevated PSA values [3–5].
Defining the Gleason score, evaluating local disease extent,
locoregional lymph node involvement and presence of distant
metastases is crucial in patient management and deciding on
correct follow-up modality. Increasing demands for correct disease
characterization and extent, as well as variable biological behavior
of prostate cancer, have led to the extensive use of functional
imaging, positron emission tomography coupled with computed
tomography (PET/CT). PET/CT imaging is most often used as a re-
staging modality, especially after completed primary radiotherapy or
radical prostatectomy followed by an increase of PSA levels [6, 7].
Because of prostate cancer low avidity for the currently most used
radiopharmaceutical,
18
F-uorodeoxyglucose (
18
F-FDG), as well
as its urinary tract elimination and accumulation in the urinary blad-
der, other radiopharmaceuticals have been developed. In use today
are
18
F and
11
C-labeled choline and
11
C-acetate. In growing tumor

57
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Anja Tea Golubić et al., The nonspecic lymph node uptake of
18
F-choline in patients with prostate cancer
Original
tissue, increased lipid synthesis is found, as well as the increased
activity of choline kinase enzyme activity which increases choline
uptake. On the cell level imported choline becomes part of the cell
membrane, as phosphatidylcholine [8]. Physiological tracer uptake
is found in the liver and pancreas, spleen, salivary and lachrymal
glands. Variable uptake can be present in the bone marrow, the
small and large intestines kidneys, urinary bladder and ureters [9].
18
F-choline has been recognized as a valuable imaging method
for prostate cancer evaluation, notably after primary treatment
has been done [10–12]. As with each diagnostic tool, apart from
all the benets and relevant data it provides, some drawbacks have
been noticed. Nonspecic uptake of
18
F-choline is seen in lymph
nodes, whether a low-grade lymphoma or, more often, inammatory
altered inguinal, axillary or mediastinal lymph nodes, as has been
reported by some scientic groups [9, 13].
The purpose of this study was to observe and characterize
nonspecic lymph node uptake of
18
F-choline in order to expand
the awareness of broader physiological
18
F-choline uptake.
Material and methods
Design and setting
This prospective observational study was done in University
Hospital Center Zagreb from December 2012 till October 2014.
Participants
Sixty nine patients underwent
18
F-choline PET/CT for staging
or restaging of their disease. The patients have been referred from
their oncologists mostly because of increased PSA values observed
after primary therapy.
Their median age was 71 years, range 50–92 years. The me-
dian PSA value was 5.3 ng/ml (doubling time less than 6 months in
9 patients). PSA values exceeding 0.2 ng/ml for patients with radi-
cal prostatectomy and 2 ng/ml higher than the lowest known PSA
value for patients with only radiotherapy treatment were considered
as biochemical relapse. PSA values that doubled in less than
6 months previous to PET/CT scan and the increase of 1 ng/ml of
prostate specic antigen over the past year were also considered
as clinically relevant. In 38 patients radical prostatectomy was per-
formed, 18 of which had received hormonal therapy. Twenty three
patients underwent radiotherapy, and in 12 it had followed radical
prostatectomy. Thirty four patients have received hormonal therapy,
while 13 patients received no therapy before
18
F-choline PET/CT
examination (Table 1).
18
F-choline PET/CT examination
All patients fasted 6 hours before the examination. Mean
administered activity was 183 MBq (4.9 mCi) of
18
F-choline
(2 MBq/kg, IASOcholine was purchased from IASON GmbH A-8054
Graz-Seiersberg, Austria). The whole-body PET/CT was acquired
20 minutes after the intravenous F-choline administration (Sie-
mens Biograph mCT, Siemens Medical Solutions USA, Inc., USA
PET/CT; 3 minutes per bed position).
The follow-up was at least 6 months, median 11, range
6–22 months.
Interpretation of
18
F-FDG PET/CT scans
All PET/CT scans were interpreted by two board-certied nu-
clear medicine physicians (DH, AM). An increased uptake was de-
ned as focal activity higher than that of surrounding background
tissue not located in areas of physiological
18
F-choline uptake,
without similar activity seen on the contralateral side. SUV value
was calculated for each lesion. A normal uptake was dened as no
abnormal
18
F-choline uptake.
As true positive were considered patients with clearly visible
increased uptake in the lymph nodes or bone structures in the
regions where prostatic cancer metastases can be often found
(pelvis, central skeleton). Those patients received further treatment
(most often radiotherapy or hormonal therapy) suggested by their
referring physicians.
Reference standard
In patients with increased tracer uptake in easily reachable
lymph nodes a ne needle aspiration cytology (FNAC) or biopsy
was performed. A true negative nding was noted if the FNAC or
biopsy analysis reported a benign lesion or the follow-up period
was at least 6 months without any disease progression observed.
Ethics
Signed informed consent was obtained from all patients for
imaging and using patient data for further research.
Statistical analyses
Kruskal-Wallis test was used to determine differences between
SUV values of specic and nonspecic accumulation of the tracer.
Results
Specific accumulation of the tracer
True positive focal uptake in prostate bed (local recurrence)
was found in 6 (9%) patients, with a mean SUVmax value of 10.2.
Bone metastases were found in 15 patients (21.7%; SUVmax mean
value 13.2, range 4.7–21.3). True positive ndings in the abdominal,
retroperitoneal (Figure 1) and iliac lymph nodes were noted in 27
patients (39.1%, SUVmax mean value 9.2, range 3.9–16.1) (Table2).
Pulmonary metastases have been observed in two patients with
the SUVmax values of 6.8 and 2.3. All of our patients with positive
ndings and tracer uptake in abdominal lymph nodes, bone and
lung metastases were scheduled for subsequent treatment, mostly
radiotherapy.
Nonspecific accumulation of the tracer
Nonspecic tracer uptake to the lymph nodes was observed in
36 patients (52.7%). Most of the false-positive lymph nodes were
identied in the mediastinum (24 patients; mean SUVmax value
of 4.8) (Figure 2), and pulmonary hila (20 patients, mean SUVmax
Table 1. Prostate cancer patient population therapy modalities before
18
F-choline PET/CT exam
Procedures performed Patients (n = 69)
Radical prostatectomy (RP) 38 (55.1%)
Radiotherapy (RT) with or without RP 23 (33.3%)
Hormonotherapy with or without RP and RT 34 (49.3%)
Orchidectomy 10 (14.5%)

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Original
values of 4.3). The uptake in axillary lymph nodes was found in 10 pa-
tients with a mean SUVmax value of 3 and in inguinal lymph nodes in
15 patients (Figure 3), with mean SUVmax value of 4.1 (Table 3).
Median PSA value in patients with nonspecic tracer uptake
was 5.8, while it was found to be 8.8 in patients with
18
F-choline true
positive lesion (not statistically signicant, p = 0.2).
Additional ultrasound examination with ne needle aspiration
cytology of available lymph nodes was performed in 5 patients;
4 were found to have nonspecic inguinal lymph nodes enlarge-
ment where cytological analysis showed only fatty tissue or cystic
contents, while in one a relapse of CLL lymphoma was observed.
Mean SUV value of the sites of nonspecic accumulation of the
tracer (mean 4.1) was not statistically signicantly lower (p = 0.2)
than tracer uptake values measured in metastases sites (mean 11.2).
Discussion
Results of this study showed that in over half of our patient
population, nonspecic sites of tracer uptake have been observed
in lymph nodes out of the pelvis, not suggestive for prostate cancer
metastases. The obtained SUV values in those uptake sites were
lower than in metastatic sites, but not enough to be statistically
signicant. In most cases, we have observed accumulation of
18
F-choline in the mediastinal lymph nodes (35% of patients). The
main limitation of our study is that pathohistological conrmation
has not been performed, but during patient follow-up there have
been no evidence of disease progression, rise in PSA levels or
patient deaths due to prostate cancer. Additional ultrasound exami-
Figure 1. Retroperitoneal lymph node metastasis in the pelvis in
patients with prostate cancer. SUVmax value 10.2, PSA value 0.5
ng/ml, radical prostatectomy performed in December 2013, imaged
in April 2014. Radiotherapy and hormonal therapy followed PET/CT
examination; SUV — standardized uptake value, PSA — prostate-
specific antigen
Figure 2. Nonspecific
18
F-choline uptake in mediastinal lymph nodes
in patients with prostate cancer, SUVmax 8.8, PSA value 2.3 ng/ml.
Patient had radical prostatectomy in November 2010, and was imaged
in our facility in February 2014; SUV — standardized uptake value,
PSA — prostate-specific antigen
Table 2.
18
F-choline true positive focal lesions
Location Patients
(n = 35)
Mean SUVmax
value
Prostate bed (local recurrence) 6 (8.7%) 10.2
Bone metastases 15 (21.8) 13.2
Abdominal lymph node metastases 27 (39.1%) 9.2
SUV — standardized uptake value

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Anja Tea Golubić et al., The nonspecic lymph node uptake of
18
F-choline in patients with prostate cancer
Original
nation with ne needle aspiration cytology of axillary and inguinal
lymph nodes with low tracer uptake has shown fatty inltration in
four patients and a relapse of low grade lymphoma in one patient.
No similar false positive, nonspecic radiotracer uptake was found
in abdominal or pelvic lymph nodes, making the interpretation
easier. In the minimal 6 month follow-up (median of 11.5 months),
no clinically apparent sign of disease progression was found,
pertaining to patients with nonspecic lymph node uptake. Other
limitations of this study were relatively small sample size and clus-
tering patients with variable disease stages and treatment options.
Also, in patients with very suggestive ndings for prostate cancer
metastases (local recurrence in pelvis, central skeleton) we didn’t
obtained nal pathology conrmation since referring physicians or-
dered a further therapy without any delay.
Variability in physiological distribution, pitfalls and image arti-
facts of F-18-FDG has been the topic of numerous articles [14,15],
and the same considerations should be made when imaging with
18
F-choline.
Up to date only one study (Rietbergen et al [13]) reported similar
percentage of patients with nonspecic choline uptake, not pertain-
ing to prostate cancer disease extent. Liu et al [16] have shown
increased choline uptake in various thoracic diseases, such as sar-
coidosis, noncaseating granuloma, tuberculosis and lymphomas.
18
F-choline accumulation is found to be specic in true positive
lesions with a prevailing morphological and statistical correlate.
Nonspecic tracer uptake will follow an increased cell membrane
production not connected to prostate cancer, but rather due to
acute or chronic inammatory process or low grade immunopro-
liferative diseases.
18
F-choline PET/CT is considered a particularly useful diagnostic
tool in several stages of patient care, with the added information
gained from revealing multiple pathophysiological processes. It
has found its role especially in restaging prostate cancer patients,
with the recommended use in patients with PSA levels > 1 ng/ml
following radical disease treatment [6]. Increasing demands of
imaging modalities have been observed in recent years because
of aging population, screening methods and growing incidence
of prostate cancer.
The need for unequivocal disease extent estimation has intro-
duced functional imaging methods, such as
18
F-choline PET/CT,
in regular clinical practice [17], and the future of prostate cancer
imaging will lie in the more specic radiotracers, such as the PSMA
tracer [18–20].
Conclusions
Although
18
F-choline PET/CT has demonstrated valuable
information in staging and restaging of prostate cancer, moder-
ate tracer accumulation in lymph nodes out of the pelvis should
be carefully evaluated since in many cases it is false positive.
Variability in physiological uptake, as well as benign causes of
accumulation, such as inammation, should be kept in mind when
interpreting unusual sites of increased uptake, with no association
with the primary disease. Recognizing the importance of patient
follow-up is crucial.
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