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Positron Emission Tomography in Urology
Igle J. de Jong a,*, Anthonius J. Breeuwsma a,b, Jan Pruim b
a
Department of Urology, University Medical Center Groningen, University of Groningen, PO Box 30001,
NL 9700 RG Groningen, The Netherlands
b
Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen,
University of Groningen, PO Box 30001, NL 9700 RG Groningen, The Netherlands
Article info
Abstract
Keywords:
Urology
Oncological urology
Molecular imaging
PET
Positron Emission Tomography has rapidly become available in many
institutes throughout Europe during the last years. Also the clinical
indications for PET have increased in this period, especially in the field
of oncology and based on FDG PET. In this review paper an overview on
the principles and an update on the developments of PET is given.
Emphasis on the spectrum of current and newly developed radiopharmaceuticals in particular the possibilities on targeted imaging is discussed. Next we provide a brief summary of the current literature on the
clinical results of PET in oncological urology (prostate, bladder, kidney,
testicular and penile cancer) and non-oncological urology (neuroimaging
in bladder dysfunction).
# 2007 European Association of Urology and European Board of Urology.
Published by Elsevier B.V. All rights reserved.
* Corresponding author.
E-mail address: [email protected] (I.J. de Jong).
1.
Introduction on Positron Emission
Tomography (PET)
PET is a technique in which an image of a molecular
process is obtained. For this purpose a radioactively
labeled substance, a radiopharmaceutical, is administered to a patient. The substance will participate
in a metabolic or (patho-)physiologic process, and
accumulate at the sites the process is most active.
Since the substance is radioactively labeled the
accumulation, and thus the distribution of the
radiopharmaceutical, can be viewed on the outside
of the body and be followed in time. So far, there is
no difference with conventional nuclear medicine
techniques.
The main difference of PET versus conventional
nuclear medicine is the type of (radio) isotope used.
In conventional nuclear medicine, these radioisotopes are gamma-ray emitters. The energy of the
gamma-rays is a characteristic of each radioisotope. The most well known of these isotopes
is 99mTc (technetium), bound to a large number of
substances, e.g. to a diphosphonate. With the
resulting 99mTc-labeled diphosphonate bone scans
are being made, e.g. in the work-up of patients with
cancer.
In positron emission tomography a different type
of radioisotopes is used, viz. positron emitters.
These isotopes are characterized by a surplus of
positive charge in the nucleus, creating an unstable
1871-2592/$ – see front matter # 2007 European Association of Urology and European Board of Urology. doi:10.1016/j.eeus.2007.01.002
Published by Elsevier B.V. All rights reserved.
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eau-ebu update series 5 (2007) 93–104
nucleus. Stability is regained by either capturing an
electron (=negative charge) into the nucleus, or by
emitting the surplus positive charge in the form of a
positron. The positron is a particle with the mass of
an electron, but with a positive charge. It should be
considered the ‘anti-matter’ of an electron.
The positron is expulsed from the nucleus with a
certain kinetic energy and migrates through the
tissue for a few millimeters, losing its kinetic energy
when traveling. The distance traveled is depending
on the isotope used. When the positron has come to
a complete standstill it will form a positronium.
Together with an electron in its vicinity the
positronium will be annihilated instantly, a process
in which the available mass of the particles is
converted into energy following Einstein’s formula
E = mc2. It has been calculated that the energy
present in this system is 1022 kilo-electron Volts
(keV). However, in order to fulfill the law on
conservation of momentum, this energy is released
as 2 gamma-photons with energy of 511 keV which
are expulsed diametrically. In clinical practice the
most often used positron emitters are relatively
short-lived, cyclotron-produced. Examples are 18F,
15
O, 13N, and 11C. The last few years also other, often
generator-produced, positron emitters are being
introduced as 68Ga, 82Rb, 89Zr, and 124I.
The radiation resulting from this annihilation
event can be detected with conventional gammacameras, but nowadays dedicated PET-cameras are
widely available. The principal difference between
conventional cameras and PET-cameras is the
presence of coincidence electronics. As stated, an
annihilation event produces 2 photons released in
opposite directions. This means that when an event
is detected in a detector, the other event should be
detected within a short time-frame in an opposing
detector. Based on these principles modern day
cameras consist of a large number of detectors with
coincidence electronics, spanning an axial length of
15 cm or more. The newest cameras have detector
and electronics characteristics that are thus fast that
the time difference between the detection of the 2
photons can be taken into account to locate the
exact position of the annihilation. These machines,
so-called ‘time-of-flight’ machines, will undoubtedly be the future of PET-cameras.
Second, the specific way of decay allows for a full
correction of attenuation of the signal. One can
imagine that a signal coming from the deep will be
attenuated more than a signal coming from the
surface as e.g. the skin. Attenuation can be measured by introducing an external radiation source in
the gantry of the camera and comparing the counts
obtained in an empty gantry with those obtained
with the counts obtained with the patient present. A
disadvantage is the relatively long time such a
transmission scan for attenuation correction takes
(approximately 50% of the whole procedure).
In the past few years a second development
occurred, that already has had great impact in
clinical routine, viz. the combined PET-CT cameras.
In these machines a CT-camera and a PET-camera
are combined to one functional unit. In 1 session
patients will undergo a CT-scan and a PET-scan
directly after each other and thus both anatomical
and metabolic information are obtained. The great
advantage of these machines is that the metabolic
process can be pinpointed to a certain anatomical
location. Moreover, the CT-data can replace the
transmission scanning for attenuation correction.
Since CT-data are obtained in less than a minute,
scanning time per patient can be reduced by
approximately 50%. However, one has to realize
that the CT and the PET-scan are obtained sequentially (be it with a short time interval), not
simultaneously. Consequently, there is still the
possibility of artifacts due to movement of the
patient in between scans. A general tendency in
tracer development is the search for more specific
tracers, while not loosing on sensitivity. The drawbacks of such tracers, viz. problems in locating the
tumor, are overcome with the new PET-CT
machines. Consequently, the development of these
machines itself will form a boost for radiopharmaceutical development.
1.1.
Radiopharmaceuticals
1.1.1.
18
F-FDG
The most commonly used radiopharmaceutical for
PET in oncology is 2-[18F]fluoro-2-deoxy-d-glucose,
also called fluorodeoxglucose or FDG. FDG is an
analogue of glucose. It is taken up by the cell by
glucose transporters (mainly glut-1) and phosphorylized to FDG-6-phosphate by the enzyme glucose6-phosphokinase. Whereas glucose-6-phosphate
finds itself on a crossroads of a vast number
of metabolic processes such is not the case of
FDG-6-phophate. Because of the introduction of the
fluor-atom, the three-dimensional structure of the
molecule changes after phosphorylation changes in
such a way that FDG-6-phosphate is not a substrate
for other enzymes anymore. As a result, the FDG is
trapped in the cell, at least on the time-frame of a
normal PET-scan.
The use of FDG in oncology is based on the
observation that most cancer cells have a high
expression of glut-1 transporters in the cell membrane [1]. It’s use has been established in variety of
eau-ebu update series 5 (2007) 93–104
carcinomas, e.g. lung cancer, colorectal cancer, and
malignant lymphomas [2–4].
Despite the promising results of FDG, the substance also has some drawbacks. First, FDG is also
taken up in inflammatory tissue, macrophages in
particular [5]. This phenomenon may hamper
interpretation of images obtained and results in a
reduction of specificity. Second, as FDG is not equal
to glucose, the substance is not re-absorbed by the
kidneys. As a result, accumulation of FDG in the
bladder occurs, causing a high radiation dose to
the bladder wall, and hampering interpretation of
the pelvic areas. Bladder irrigation or forced diuresis
in combination with an indwelling catheter only
could solve a part of this problem of FDG PET.
1.1.2.
11
C-choline and analogues
As it was shown that FDG is not suitable for clinical
practice of prostate cancer, alternative tracers were
developed. The first of these showing clinical
potential was 11C-labeled choline. Choline is one
of the components of phosphatidylcholine, which in
itself is an essential element of phospholipids in the
cell membrane. Cancer is associated with cell
proliferation and up regulation of choline kinase
(the enzyme which catalyzes the phosphorylation of
choline), providing the rationale for the use of
choline in oncological PET [6].
A major disadvantage of 11C-choline is the short
half-life of 20.4 minutes. This short half-life will
prohibit a widespread use of the tracer, as it is
depended on the presence of an on-site cyclotron for
the production of 11C. This has led to the development of 18F-labeled analogues as 18F-methyl-choline
and 18F-ethyl-choline.
1.1.3.
11
C-acetate
The mechanism of increased 11C-acetate accumulation in cancer cells is yet unclear. It has been
reported that increased 11C-acetate uptake in malignant tissue is caused by accelerated lipid synthesis.
Based on the assumption that this increased lipid
metabolism rate is associated with the accelerated
cell membrane synthesis due to tumor growth, 11Cacetate may be an indicator of this metabolic
pathway in cancer tissue [7].
1.2.
Radioimmunology and PET
Immuno-PET involves radio labeled monoclonal
antibodies bound to an antigen on tumor cells.
Targeting of tumor antigens in the treatment of
cancer is rapidly progressing. The new classes of
biological anticancer agents probably work only in
subpopulations of patients, in whom the specific
95
tumor antigens (target) are expressed. Immuno-PET
will likely play a greater role in patient selection and
tailoring of treatment, monitoring of dosage and
response to treatment. Several radio-immunoconjugates are currently studied in for instance prostate
cancer, renal cell cancer, colorectal and ovarian
cancer. The optimum uptake of such antibody
conjugates in tumors is normally several days for
the intact immunoglobulin. The half-life of common
PET isotopes like 11C and 18F is therefore too short for
clinical use with antibodies. Positron emitters with
longer half-lives are better suited to the slow
pharmacokinetics of radio labeled monoclonal
antibodies. For this purpose the radioisotopes 89Zr
and 124I with physical half lives of 78 and 100 hours
are commonly used although the ideal radioisotope
has not been defined [8].
2.
PET in oncological urology
2.1.
Bladder cancer
The mainstay of patients with transitional cell carcinoma of the bladder present with non-invasive form
of the disease. Local therapy combined with adjuvant installations of chemo- or immunotherapeutic
agents prevent progression in terms of recurrence
and grade. Optimal treatment for invasive bladder
cancer without (lymph node) metastases is surgery.
Apart from transurethral resection to determine
depth and grade, computerized tomography is
mainly used to determine presence of lymph node
metastases. This technique relies on anatomic
distortion for instance enlargement. However is
has been shown that although metastases are
present enlargement does not have to occur. It
has been proposed that metabolic imaging through
PET could provide extra information on the presence
of metastatic sites even outside local lymph node
regions. One of the first tracers to be studied that did
not excrete into urine was 11C-methionine. However, the initial results using this radiopharmaceutical were poor, only tumors of more than 1 cm in
diameter being visualized with PET [9]. It was also
shown that L-methyl-11C-methionine PET was
unsuitable for monitoring of neo adjuvant chemotherapy in bladder cancer [10].
Although a commonly applied tracer in oncology,
FDG has very limited application in bladder cancer.
The rapid excretion via the kidneys into the urinary
tract hampers evaluation of the pelvic region and
in particularly the bladder For this reason FDG PET
was not useful in local staging [11,12]. Recently
Drieskens et al. studied FDG PET for detection
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eau-ebu update series 5 (2007) 93–104
of nodal or distal metastases in a large series of
patients comparing FDG PET with PET CT using
histology as reference. FDG PET/CT was superior to
CT alone for the diagnosis of metastatic disease with
a sensitivity, specificity and accuracy of PET/CT of
60%, 88% and 78%, respectively. Diagnostic discordances between PET/CT and CT alone were found
in 9/40 patients, among whom PET was correct in
six (15%): three with true-positive and one with
true-negative distant metastases, and two with
true-negative lymph nodes. The authors concluded
that metabolic imaging using FDG PET added to the
diagnostic accuracy but the sensitivity of 60%
needs to be improved before routine clinical use [13].
11
C-choline PET has already shown potential for
the detection and staging of tumors in areas where
FDG lacks sensitivity, such as the brain and the
prostate. In a pilot study by de Jong et al. 18 patients
with invasive bladder cancer were studied with
11
C-choline PET. All 10 patients with residual
tumor were identified by 11C-choline PET. One
false-positive scan was attributed to an indwelling
catheter. Pre-malignant and non-invasive tumors
were not visualized [14]. Pichio et al studied
11
C-choline PET in 27 patients with bladder cancer
prior to cystectomy and confirmed the high detection rate of residual tumor. Next 11C-choline PET
was slightly superior to CT in identifying nodal
metastases with a detection rate of 5/8 for PET/CT vs
4/8 for CT only [15]. In a recent study by Gofrit et al.
in 18 patients using 11C-choline PET/CT, all 6
patients with proven lymph node metastases
were detected by PET/CT [16]. Larger studies on
pre-operative staging are lacking at present. Thus
the clinical value of PET in bladder cancer still has to
be determined. With the present data PET does not
have a role in the primary diagnosis or in local
staging of bladder cancer.
2.2.
Prostate cancer
The incidence of prostate cancer increases yearly.
This can be mainly attributed to increased use of
sensitive diagnostic tools such as prostate specific
antigen (PSA). 75% of patients present with localized
disease. Prognosis is dependent on accurate staging
and treatment selection. Widely used transrectal
ultrasound in combination with sextant biopsies
gives accurate diagnosis and grading. However
determination of capsular penetration and metastases detection has remained a challenge with
current imaging modalities. CT and magnetic resonance imaging (MRI) has been used with variable but
reproducible results [17,18]. With addition of an
endocoil and ultra small super paramagnetic iron
oxide particles an increased sensitivity of MRI in
local staging and detection of lymph nodes was
achieved [19].
2.2.1.
18
Staging primary prostate cancer
F-FDG – Prostate cancer is the most researched
urological tumor with PET. FDG is the most applied
tracer in the oncological field. Its accumulation is
dependent on the glycolytic activity of the tumor.
However prostate cancer displays little glycolytic
activity. The added effect of urinary excretion makes
it very difficult to determine uptake of FDG in
primary prostate cancer. Even under continuous
bladder irrigation FDG was not able to distinguish
between scar tissue, BPH and prostate carcinoma
[20–22]. The detection of metastases of prostate
cancer with FDG varies (20–65%) but uptake of FDG
seems to signify progression of disease [22,23]. At
the moment FDG does not seem to be the tracer of
choice in the primary staging of prostate cancer.
11
C-acetate – Oyama and co-workers reported in a
series of 22 patients that all primary prostate
carcinoma could be visualized [24]. The main
advantage over FDG is that prostate imaging could
be achieved without hindrance by urinary excretion.
In the same group of patients five presented with
lymph node metastases detected with Acetate
against 2 positive with FDG. However there seems
to be an overlap in patient with uptake of acetate
due to BPH and prostate carcinoma [24].
11
C-choline – Several studies have confirmed that
11
C-choline with PET is able to visualize carcinoma
of the prostate although there is ‘non specific’
uptake observed in both benign hyperplasia as well
as in high grade prostatic intraepithelial neoplasia
[25–28].
11
C-choline has several advantages over FDG.
Although bowel uptake can disturb reading, generally there is intense and clear uptake of choline in
primary and metastatic prostate cancer. There is
hardly any urinary excretion and its serum clearance is fast. The short half life of 11C does limit the
application of this tracer to institutions with
production systems. The application of 18F with
choline could overcome this problem. However
urinary excretion of 18F poses challenges in determining uptake of choline in urinary tumors. In a
group of 67 patients preoperative staging revealed
that of 15 patients positive on PLND 12 had a positive
choline PET scan (sensitivity 80%). The 3 falsenegative findings are thought to be on the basis of
micro metastases [29]. This inability to detect
metastases is that the spatial resolution of current
PET scanning is approximately 5 mm due to physical
restraints of modern PET scanning.
eau-ebu update series 5 (2007) 93–104
11
C-methionine – At first the uptake of 11CMethionine could be demonstrated in patients
with prostate cancer [30]. In a more recent study in
twenty patients with elevated PSA (average 9,36 ng/
mL) a sensitivity in detection of tumor could be
demonstrated in 75% of patients with repeat negative
biopsies. In 5 patients with negative PET findings no
carcinoma could be shown on biopsy [31].
18
F-Fluorodihydrotestosteron (FDHT) – Ongoing
research must further elucidate the knowledge of
the role of the androgen receptor in prostate cancer.
In an initial study performed in 7 patients a lesion to
lesion comparison with FDG PET. FDHT showed 78%
of lesions whereas FDG detected 97%. However an
uptake decrease was noticed in patients with
hormonal therapy which might indicate a use in
therapy monitoring [32]. In another study of twenty
patients, nineteen patients that had known metastases of which 12 patients showed positive scans
(sensitivity 63%). These patients showed decreased
uptake on flutamide administration with repeat PET
scan [33]. These results probably indicate that FDHT
PET can be used to distinguish androgen dependent
prostate cancer and undifferentiated forms. This
could have implications for tailoring treatment in
near future.
2.2.2.
Recurrent prostate cancer
PSA relapse most commonly preludes clinical manifestations of recurrent or residual prostate cancer.
This group of patients has a very varied outcome and
therefore it is difficult to predict clinical significance.
Ten years after prostatectomy 30–50% of patients
show biochemical recurrence. The mean interval
between biochemical recurrence and clinical symptoms is approximately 8 years. During this period
imaging recurrent disease can be difficult [34].
97
11
C-acetate – In the 31 patients studied by Kotzerke
et al. it was shown that of the 18 patients with
recurrence 11C-acetate PET identified 15 patients
(83%) with recurrence. In the three false-negative
cases patients had small recurrent lesions (<15 mm)
[35]. These limitations were reproduced by Oyama
et al. [36]. In this study 11C-acetate was compared
with FDG PET. Fricke and co-workers showed that
11
C-acetate was able to visualize 80% of local and
distant recurrence whereas FDG demonstrated recurrence in only 66% of 25 patients. FDG (75%) was
superior to 11C-acetate in showing distant metastases
(50%) [37].
11
C-choline – In a pilot study by de Jong et al. in 36
patients with 13 of the patients with biochemical
recurrence, 11C-choline showed a sensitivity of 38%
in detecting recurrence after radical prostatectomy.
11
C-choline PET displayed a higher sensitivity in
patients with biochemical recurrence after curative
radiotherapy (7 of 9 patients) (Fig. 1). No positive
PET-scans were obtained in patients with a
serum PSA < 5 ng/ml [38]. Picchio et al. studied
100 patients with biochemical recurrence after
radiotherapy (N = 77) and radical prostatectomy
(N = 23) with 11C-choline and FDG. 11C-choline
showed greater sensitivity (47%) compared to FDG
(27%). Only one 11C-choline PET scan was falsenegative [39].
18
F-fluorocholine – Heinisch et al. studied 34
patients with prostate cancer who had undergone
initial local therapy using 18F-fluorocholine (FCH)
PET/CT during follow-up in case of demonstrable or
rising PSA levels. This study aimed at the use in
patients with low PSA levels. In eight of 17
examinations (47%) with PSA < 5 ng/ml, at least
one FCH-positive focus was detected. Follow up and
additional imaging and or histology confirmed
Fig. 1 – 11C-choline PET and PET/CT fusion images in a patient with recurrent prostate cancer after external beam
radiotherapy. A pathological lymph node is identified on PET (arrow) and corresponds with the enlarged node in the left
iliac region. Histology confirmed the nodal metastases after PLND.
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eau-ebu update series 5 (2007) 93–104
recurrent prostate cancer in 7/8 patients. In restaging patients with prostate cancer, FCH PET/CT is
able to yield true positive findings even at
PSA < 5 ng/ml [40]. But as long as the decision for
salvage radiotherapy after radical prostatectomy is
directed by a PSA at a level of 1.0 ng/ml the clinical
utility of PET/CT in stratification of patients has to be
proven in the low PSA ranges.
2.2.3.
Distant metastases
About 20% of patients presents with distant (bone)
metastases. The incidence in hormone refractory
prostate cancer patients reaches 100%. The current
standard for screening is (di)phosphonate bone
scanning. It has well-known high sensitivity and
low specificity. It is becoming increasingly clear that
as much as 17% of metastases are not seen on bone
scanning [41]. One cause could be that for a positive
bone scan there needs to be cortical involvement.
Micro metastases do not cause this reaction at that
time.
FDG - Prostate cancer is considered as a cancer
with false-negative results on FDG-PET. A limited
number of studies have looked at FDG PET and bone
metastases. In a study from Yeh et al only 18% of
bone scan lesions were positive on FDG-PET [42].
Shreve et al evaluated 34 patients in which PET was
compared with the isotope bone scan, computed
tomography (CT), and clinical follow up for the
presence of skeletal metastases. FDG-PET identified
131 of 202 untreated metastases in 22 patients with a
sensitivity of 65%. In only 1 out of 7 patients
receiving hormonal treatment FDG uptake was seen
in only 4 of the 131 metastases seen on bone scan
Fig. 2 –
18
[22]. Although the authors concluded that FDG PET
did not perform as well as bone scintigraphy in the
identification of skeletal metastases, a question can
be raised on the biological activity of FDG negative
lesions. In a recent study by Morris et al. in 17
patients with progressive metastatic prostate cancer, bone scans were compared with FDG PET. Of 134
bone lesions considered to be metastases identified
on either FDG-PET or bone scans, 95 were seen on
both FDG-PET and bone scan whereas 8 were seen
on FDG-PET only and 31 on bone scan only [43]. FDGPET had a sensitivity of 77% in this group of
progressive patients. The interest in this study
was that all but one lesion seen on bone scan alone
were ‘‘stable’’ on follow-up when compared with the
baseline bone scan, whereas all FDG-PET lesions
reflected active disease on subsequent studies. So
the authors concluded that FDG-PET can discriminate active osseous disease from quiescent lesions
on bone scintigraphy in patients with progressive
metastatic prostate cancer. Future studies will be
needed to answer the question if these FDG-PET
negative but bone scan positive lesions have
clinically relevancy.
18
F-Fluoride – Sodium fluoride (NaF)can be been
used in combination with PET for imaging of bone
metastases using 18F as radioisotope (Fig. 2). EvenSapir et al. studied 18F-Fluoride PET/CT in comparison with planar and SPECT bone scintigraphy in 44
patients with high-risk prostate cancer. 18F-Fluoride
PET/CT is more sensitive and specific modality for
detection of bone metastases. It is more specific
than 18F-Fluoride PET alone and more sensitive and
specific than planar and SPECT BS. Detection of bone
F-fluoride PET showing multiple bone metastses in a patient with prostate cancer.
eau-ebu update series 5 (2007) 93–104
metastases is improved by SPECT compared with
planar bone scintigraphy and by 18F-Fluoride PET
compared with SPECT. This added value of 18FFluoride PET/CT may beneficially impact the clinical
management of patients with high-risk prostate
cancer and a negative bone scan [44].
2.3.
PET and Renal Cell Carcinoma (RCC)
2.3.1.
Tumor detection and initial staging
Only a limited number of studies have investigated
the utility of PET in the assessment of renal masses
and primary staging of RCC. The first pilot study by
Wahl et al in five patients with RCC prompted
further investigation as all primary tumor and
metastases were visualized by FDG-PET [45]. In a
second study of 29 patients by Bachor et al. PET was
compared with histology after nephrectomy. FDG
PET was true positive in 20 of 26 with confirmed
disease, but the primary tumor was missed in 6
cases. An angiomyolipoma, a pericytoma, and a
pheochromocytoma showed a false-positive PET
result [46]. In a more recent study by Ramdave et al.
PET was compared with histology and CT. The
primary RCC was identified by FDG PET in 15 of 17
patients with suspicious renal masses. There were
no false-positive results reported in this study. FDG
PET showed an accuracy of 94% which was identical
to CT in this study [47].
Kang et al. have published the largest study in
RCC so far. A total of 66 patients with renal mass
were studied with FDG PET. Sixteen patients had
proven RCC. FDG PET exhibited a sensitivity of 60%
and specificity of 100% for primary RCC tumors
which was unfavorable to abdominal CT (92%
sensitivity and 100% specificity). The authors concluded that the role of FDG PET in the detection of
RCC is limited by low sensitivity [48].
This conclusion is supported by the results from
the study of Aide et al. In a subgroup of 35 patients
FDG PET studies were performed for both characterization and staging of a suspicious renal mass. A
high rate of false negative FDG PET results was
observed, leading to a sensitivity, specificity and
accuracy of 47%, 80% and 51% respectively, versus
97%, 0% and 83% respectively for CT [49].
Results on immuno-PET have to be awaited but
could lead to improved results on primary staging
targeting hypoxia using 18F-Fluoride-misonidazole
[50] or carbonic anhydrase- IX activity using the
G250 monoclonal antibody.
In general FDG PET has not shown any advantage
over CT for the characterization of renal masses,
initial staging and treatment planning of renal cell
carcinoma.
2.3.2.
99
Recurrent and metastatic disease
Metastatic disease is a strong predictor of poor
survival in patients with RCC [51] Patients with
advanced metastatic disease have a 0% to 2% 5-year
survival rate whereas solitary metastases can be
resected surgically in selected patients, with a 5year survival rate of approximately 30% [52]. Early
detection and management of metastases has the
potential to improve prognosis and quality of life.
Currently CT, sometimes supplemented by a bone
scan if indicated, is the most commonly used
imaging test for follow-up of patients with RCC.
Although FDG-PET did not appear to contribute
much to the initial staging of RCC, the detection of
local recurrence or metastases should not be
affected by some of the FDG-inherent limitations
in imaging the urinary tract [47,48,53,54].
The study by Ramdave et al. included eight
patients with suspected local recurrence or metastatic disease. FDG PET was true positive in seven
patients and true negative in one, yielding a diagnostic accuracy of 100% (CT: 88%). Of eight patients in
whom CT suggested potentially resectable metastatic
disease, FDG PET revealed widespread metastases in
four. In one patient, PET accurately distinguished
between post radiation changes and local recurrence.
The findings lead to a change in treatment in four of
eight patients (50%) by avoiding or altering planned
surgical procedures [47].
Safaei and coworkers studied FDG PET in 36
patients with advanced renal cell cancer who were
referred for restaging. 85% of confirmed lesions were
assessed accurately (sensitivity 88%, specificity
75%). They concluded that FDG PET could be useful
in characterizing anatomic lesions of unknown
significance [53].
Majhail and coworkers studied 24 patients with
RCC and suspected recurrence at distant sites. Of the
33 sites of histologically proven metastatic sites, 21
(64%) were identified by FDG PET. Sensitivity and
specificity were 64% and 100%. These findings were
independent of initial Fuhrman grade, prior
immuno- or chemotherapy, or the site of distant
metastases. However, the average size of metastatic
lesions correctly identified by FDG PET was larger
than that for false-negative findings (2.2 cm versus
1.0 cm; P < 0.01). In no case did FDG-PET identify
distant metastases that had not been visualized by
CT or MRI [54].
In the larger study by Kang and coworkers a total
of 172 soft tissue and bone lesions were confirmed
as metastatic RCC either by subsequent imaging
studies or histopathology, and 115 of these (67%)
were identified by PET. Specifically FDG PET
detected 89 of 139 soft tissue metastases (64%)
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eau-ebu update series 5 (2007) 93–104
Fig. 3 – 18F-FDG PET in a patient with recurrent renal cell carcinoma. FDG PET identified multiple metastases in intra thoracic
lymph nodes and in the upper lobe of the left lung.
and 26 of 33 bone metastases (78%). Lung metastases
were detected with a sensitivity of 75% and
specificity of 97%. As expected, CT was more
sensitive than FDG PET in detecting lung metastases
(91%) (Figs. 3 and 4). In addition, the combination of
CT and bone scan showed higher sensitivity for
detecting osseous metastases (94%).
For retroperitoneal nodal metastases, FDG PET was
75% sensitive and 100% specific (CT: 93% and 98%).
Multiple lesions within a single patient often exhibited differing levels of FDG uptake and some were
undetectable: In 44% of studies FDG PET detected all
metastatic lesions, in another 44% only some lesions,
and in 12% PET failed to detect any metastasis.
Overall, the specificity of FDG PET was generally
higher than that of any other test or a combination of
CT and bone scan (for bone lesions) [48].
2.4.
PET and testicular cancer
2.4.1.
Initial diagnosis and staging
FDG-PET was studied by Albers et al. for initial
staging of lymph nodes in 37 patients with stage I
and II germ cell tumors (CGT) [55]. PET was
compared with CT and final histology after retroperitoneal lymph node dissection. FDG-PET was 70%
sensitive and 100% specific in the detection of nodal
metastases, compared with 40 and 78% for CT,
respectively. Three false-negative PET results were
seen in 2 small (<0.5 cm) nodal metastases and a
mature teratoma. PET did not improve staging
in comparison with CT in clinical stage 2 GCT.
Cremerius et al studied FDP PET in 50 patients with
GCT [56]. CT, tumor markers and histology (in 12/50
patients) were used as reference. FDG-PET was
87% sensitive and 94 % specific in the detection of
nodal metastases, compared with 73% and 94% for
CT, respectively. Quantification of uptake of FDG
resulted in a wide rang from 1.8 to 17.3. Metastases
below the size of 10 mm were not identified with PET.
Again teratoma failed to show uptake of FDG. Hain
and workers studied FDG PET in the initial staging of
both seminoma and nonseminoma in a retrospective
study in 31 cases. CT scan, clinical follow up and
histology were used as reference. In this study FDG
PET showed a sensitivity of 67%. Lack of histology
Fig. 4 – 18F-FDG PET/CT fusion images in patient with recurrent renal cell carcinoma. High uptake of FDG in sub
diaphragmatic pathological node and in the intra thoracic lesions.
eau-ebu update series 5 (2007) 93–104
interfered with proper judgment in 5 cases with
retroperitoneal mass on CT [57]. In a subset of 12
patients with stage I and II nonseminoma by
Spermon et al. equivalent results for PET and CT in
initial staging were reported [58].
FDG PET was also studied for staging after
orchiectomy in stage 1 NSTCGT in a study by Lassen
and coworkers. In a cohort of 46 patients FDG PET
was superior to CT in the prediction of tumor
recurrence in retro peritoneal lymph nodes with a
PPV and NPV of 92% and 100% [59].
In general, the majority of the studies suggested
that PET is slightly superior to CT. However, clinical
decision making is not influenced in all cases by FDG
PET.
2.4.2.
Restaging of residual and recurrent disease
A majority of patients with bulky nodal disease have
residual mass on CT scan after chemotherapy.
Differentiation between viable tumor cells inside
the mass versus fibrosis and/or necrosis is essential
for further treatment versus a watchful follow-up.
Unnecessary additional radiotherapy or chemotherapy can potentially increase toxicities. Considering
the fact that these individuals are young and most of
them will live more than 15 to 20 years when cured,
both short term and long-term toxicities are likely to
occur. Although the serum tumor markers are very
useful in this regard, occasionally they may be
misleading and not helpful to locate the site of
recurrence/residual. Therefore imaging has a central role in locating the residual/recurrent disease.
Conventional imaging modalities including CT
cannot confirm the presence of viable tumor cells
in a residual mass. FDG PET was first studied by
Stephens et al. as a feasibility study in 30 nonseminomatous GCT patients before surgical resection of residual masses. PET was able to differentiate
viable tumor from residual necrosis/fibrosis or
teratoma. Unfortunately PET did not differentiate
necrosis/fibrosis from teratoma [60]. In a series of 70
patients by Hain et al. the sensitivity, specificity,
PPV, and NPV of 88, 95, 96, and 90%, were calculated
respectively for FDG PET in differentiating viable
tumor from fibrosis or necrosis or mature teratoma
[61].
FDG PET is also used for the evaluation of response
to chemotherapy. Bokemeyer et al. studied PET in
comparison with CT, serum tumor markers and
prognostic groups. FDG-PET accurately predicted the
successful outcome of high-dose chemotherapy in
91%; in comparison CT and serum markers predicted
successful outcome in 59% and 48% of the cases. PET
identified all failures of chemotherapy in the lowintermediate and high risk groups. A negative FDP
101
PET correctly predicted favorable outcome in the low
and intermediate prognostic groups [62].
In a study of 54 patients with post chemotherapy
seminoma residual by Becherer and De Santis et al.
FDG PET was superior to CT in the detection of viable
residual tumor. The PPV and NPV for FDG PET was
100% and 96% versus CT 37% and 92% respectively.
FDG PET is recommended for treatment evaluation
in advanced seminoma after chemotherapy with
residual mass >3 cm [63].
2.5.
Penile cancer
The use of PET for the staging of penile cancer is very
limited. So far there is one feasibility study by Scher
et al. in 13 patients with suspected (recurrent) penile
cancer using a PET/CT system in combination with
FGD [64]. PET/CT data were compared with histopathological reference at biopsy or during surgery.
The primary tumor and regional lymph node
metastases exhibited a increased uptake of FDG.
Sensitivity in the detection of primary lesions was
75% and specificity was 75%. The sensitivity and
specificity in the detection of nodal metastases on a
per-patient basis were 80% and 100% respectively.
On a nodal-group basis, PET/CT showed a
sensitivity of 89% in the detection of metastases
in the superficial inguinal lymph node basins and a
sensitivity of 100% in the deep inguinal and
obturator lymph node basins. The use of PET/CT
provided additional information, useful for planning
surgery. The clinical value of FDG PET cannot be
determined before additional studies with increased
number of patients have been performed.
3.
PET in non-oncological urology
The only non oncological area in which PET is
currently studied is the central control of bladder
function, detrusor overactivity and the female pelvic
floor. Cerebral blood flow, measured by H215O is
used for functional imaging of the brain and
brainstem. From the initial studies by Blok et al.
the specific areas in brain stem and higher brain
who were involved in micturition control in healthy
human volunteers were identified [65,66]. Kitta et al
reported on detrusor overactivity in 9 patients with
Parkinson’s disease. In this study an alteration of
brain activation sites in response to bladder filling
was noticed compared to the know areas in healthy
men [67]. The pelvic floor musculature plays an
important role in behaviors such as defecation,
micturition, mating behavior, and vomiting. Blok
et al. studied brain structures involved in the
102
eau-ebu update series 5 (2007) 93–104
voluntary motor control of the pelvic floor with PET.
The results revealed the major areas involved on the
motor cortex. No activations were found in subcortical structures belonging to the emotional motor
system [68].
So the feasibility for monitoring the central
nervous system and micturition reflexes with PET
has been demonstrated.
4.
Conclusion
The developments in both imaging systems with
PET/CT as current standard and in the development
of specific (targeted) radiopharmaceuticals will
improve molecular imaging using PET in the coming
years. Based on the current literature no additional
value for PET compared to conventional imaging has
been shown in tumor detection and initial staging of
prostate, bladder and renal cancer. In metastatic
disease the studies are ongoing. In restaging of
prostate cancer PET or PET/CT using choline or
acetate are able to identify the site of recurrence.
However the value in clinical decision making
seems limited at low PSA values. At present there
are two accepted clinical indications for FDG PET, i.e.
restaging of renal cell cancer and treatment evaluation after chemotherapy in seminomatous germ cell
tumors.
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CME questions
Please visit www.eu-acme.org/europeanurology
to answer these CME questions on-line. The CME
credits will then be attributed automatically.
1. The main difference between Positron Emission
Tomography and conventional nuclear imaging
is for:
A. The use of molecular processes to obtain
images
B. The type of radiation the camera system
detects
C. The isotopes used to obtain images
D. The spectrum of clinical applications
2. Which of the statements is correct on immunoPET?
A. The technique is widely used for patient
stratification
B. The use of monoclonal antibodies in combination with the radioisotope 18 fluoride
C. The use of monoclonal antibodies in combination with radioisotopes with a long half life
D. The technique offers an universal imaging
technique in different specific cancers
3. Clinical indication of PET in oncological urology is
currently relevant in:
A. Recurrent prostate cancer
B. Recurrent renal cancer
C. Primary prostate cancer
D. Primary testicular cancer
4. Which of the statements on radiopharmaceuticals for PET in urology is not correct?
A. Universal radiopharmaceuticals are not available
B. The background of uptake of choline and
acetate in cancer cells are not well known
C. Targeted immuno-radiopharmaceuticals can
offer patient tailored treatment
D. FDG-PET/CT has overcome the limitations of
FDG-PET