161

July 2013, Vol. 20, No. 3 Cancer Control 161

Novel imaging techniques

for prostate cancer should

improve staging and better

evaluate treatment results.

IntroductionImaging for prostate carcinoma can serve several clini-

cal goals. First, it can assist in assessing the primary

or recurrent tumor within the prostate gland, as well

as tumor size, multifocality, extracapsular extension,

seminal vesicle extension, neurovascular bundle in-

volvement, and bladder involvement. Second, imag-

ing can be used to assess metastatic disease such as

spread to lymph nodes and bones. Third, imaging is

used to guide interventions such as prostate biopsies

or computed tomography (CT)-guided biopsy of sus-

picious lymph nodes. Fourth, functional or metabolic

imaging could potentially assess tumor aggressiveness

From the Department of Diagnostic Imaging at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.

Submitted January 24, 2012; accepted September 17, 2012.

Address correspondence to Eric K. Outwater, MD, Department of Diagnostic Imaging, Moffitt Cancer Center, 12902 Magnolia Drive, WCB-RAD MD/OPI, Tampa, FL 33612. E-mail: [email protected]

No significant relationship exists between the authors and the companies/organizations whose products or services may be ref-erenced in this article.

The authors have disclosed that this article discusses unlabeled/unapproved use of ferumoxytol, a contrast agent indicated for iron deficiency anemia, for lymph node imaging in prostate cancer.

Imaging of Prostate Carcinoma

Eric K. Outwater, MD, and Jaime L. Montilla-Soler, MD

Background: Imaging of prostate carcinoma is an important adjunct to clinical evaluation and prostate-

specific antigen measurement for detecting metastases and tumor recurrence. In the past, the ability to assess

intraprostatic tumor was limited.

Methods: Pertinent literature was reviewed to describe the capabilities and limitations of the currently available

imaging techniques for assessing prostate carcinoma. Evaluation of primary tumor and metastatic disease

by ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine

techniques is discussed.

Results: Ultrasonography and MRI have limited usefulness for local staging of prostate cancer because of

suboptimal sensitivity and specificity for identifying tumor extent and capsular penetration. Additional MRI

techniques such as magnetic resonance-based perfusion imaging, diffusion imaging, and spectroscopy may

provide incremental benefit. CT and bone scanning provide an assessment of metastatic disease but are also

limited by the poor sensitivity of lymph node size as a criterion for detecting metastases. Novel imaging techniques

such as hybrid imaging devices in the form of single-photon emission CT/CT gamma cameras, positron emission

tomography/CT cameras, and, in the near future, positron emission tomography/MRI combined with tumor-

specific imaging radiotracers may have a significant impact on tumor staging and treatment response.

Conclusions: Cross-sectional imaging and scintigraphy have an important role in assessing prostate carcinoma

metastases and treatment response. Increasingly, the incremental value of primary tumor imaging through

MRI is being realized.

Michele R. Sassi. Dhow, Musandam, Oman. Photograph.

162 Cancer Control July 2013, Vol. 20, No. 3

or other parameters that correlate with outcome, al-

though such techniques have not yet entered routine

clinical practice. It is hoped that these novel imag-

ing methods will be superior to the current standard

means in assessing mortality, tumor size, and thera-

peutic response to targeted therapies. This review

focuses on the main imaging methods and their use

for these purposes.

The National Comprehensive Cancer Network clini-

cal practice guidelines show a fairly limited role for

imaging in patients with prostate carcinoma (Table 1).1

According to these guidelines, imaging is largely used

to evaluate metastatic disease, with a limited role for

endorectal magnetic resonance imaging (MRI) in pa-

tients who have received radiation therapy but have

evidence of failure by prostate-specific antigen (PSA)

level. According to these recommendations, low-risk

prostate cancer requires no imaging; however, actual

adherence to these guidelines by urologists is highly

variable.2 Many more applications and types of imag-

ing have been explored, with a plethora of suggested

imaging applications for the management of prostate

carcinoma. Many of these, such as investigational

nuclear medicine agents, are exploratory, but others,

such as endorectal MRI for initial staging, have been

the focus of numerous studies.

Reports on the diagnostic performance of some of

these techniques vary widely in the literature, particu-

larly regarding MRI. In some respects, this resembles

the decline effect3 or other statistical biases,4 but meth-

odological aspects assess diagnostic performance in

the prostate that may give rise to these varying results.

To determine the accuracy of a diagnostic technique

such as MRI in locating a tumor within the prostate, it

is common to divide the prostate into multiple areas

or segments and determine the presence or absence

of the tumor in each segment. These results can be

correlated with the absence or presence of tumor on

MRI. If the prostate specimen is distorted during

processing or if discordance exists between the orien-

tation of the pathological specimen to MRI, then the

diagnostic accuracy will be poor, not related to the

actual performance of the technique.5,6 Different re-

sults can be obtained, for example, when exact corre-

spondence is required rather than when approximate

correspondence is required.6 These methodological

problems may lead to varying results and introduce

bias in reported results for the diagnostic performance

of MRI and for other diagnostic techniques. Turkbey

et al7 found a 61% sensitivity rate for the detection of

tumors larger than 3 mm in size on T2-weighted im-

ages using a stringent correlation and 94% sensitivity

rate for less stringent correlation. The magnitude of

this discrepancy indicates that correlating imaging

findings with histology is not as straightforward as

one might think.

Evaluation of the Primary TumorTransrectal Ultrasonography

Ultrasonography is the most common method used for

direct visualization of the prostate, primarily because

it is indispensable to imaging-guided prostate biop-

sies. Ultrasonography has the advantages of real-time

imaging, portability, ease of use, and low cost. It can

visualize intraprostatic zonal anatomy, with the pe-

ripheral zone showing slightly increased echogenicity

compared with the central gland. Prostate carcinoma

typically presents as a hypoechoic area within the

peripheral zone (Fig 1). However, transrectal ultra-

sonography is not highly sensitive or specific for the

detection of prostate carcinoma.8 Color Doppler and

power Doppler imaging do not substantially add ac-

curacy to the technique.9 However, vessel density as

shown on color Doppler and power Doppler imaging

may have prognostic importance, with high vessel

densities predicting a slower rate of decline of PSA

with radiation treatment.10 Similarly, transrectal ultra-

sonography has limited accuracy for the detection of

extraprostatic extent of tumor.11 In general, ultraso-

Table 1. — Selected NCCN Clinical Practice Guidelines for Prostate Cancer

Clinical Group Indicated Imaging

New diagnosis: > 5-yr life expectancy

Bone scan if:

T1 and PSA > 20

T2 and PSA > 10

Gleason score 8

T3, T4, or symptomatic

Pelvic CT or MRI if:T3, T4, or T1–T2 and nomogram indicate probability of lymph node involvement > 10%a

Rise in PSA following prostatectomy

± CT

± MRI

± Bone scan

Rise in PSA following radiation

± Abdomen/pelvis CT or MRI± Endorectal MRI± MR spectroscopyBone scan

a Staging studies may not be cost effective until the likelihood of lymph node positivity reaches 45%.

CT = computed tomography; MR = magnetic resonance; MRI = magnetic resonance imaging; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen; T = tumor.

Reproduced/adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer. V.2.2013. © 2013 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and com-plete version of the NCCN Guidelines, go online to www.NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.


nography has no role in the evaluation of metastatic

disease. However, ultrasonographic-guided needle

biopsy of suspicious nodes found on CT or MRI is

useful for confirming metastatic disease.

Ultrasonographic contrast agents can show hy-

pervascularity, such as that caused by tumor angio-

genesis, and can be used in transrectal ultrasonogra-

phy of the prostate. However, the interpretation of

the literature on contrast-enhanced ultrasonography

for carcinoma detection is difficult for several rea-

sons.12 Multiple contrast agents have been studied,

and results may not be comparable across all contrast

agents. The contrast effect on the ultrasonographic

images is fleeting, and expertise is required. Further-

more, studies generally compare positivity rates of

directed biopsies with random biopsies rather than

whole mount sections after prostatectomy. However,

it seems clear that contrast-enhanced ultrasonography

can improve the positivity of directed biopsies vs

random biopsies. Furthermore, the additional benefit

of contrast-enhanced ultrasonography is fairly mod-

est.13,14 Because contrast-enhanced ultrasonography

detects hypervascularity, the detected tumors tend to

have higher Gleason grades and therefore are more

likely to be clinically significant.15,16 The vast majority

of targeted biopsies are negative, and many tumors

detected by blind biopsies are not targeted using

contrast-enhanced ultrasonography.13

Elastography is a relatively new technique that

measures tissue stiffness using ultrasonographic

waves. Cancer tissue is generally stiffer than non-

cancerous tissue and therefore is more resistant to

mechanically induced vibration. Initial results have

not shown high sensitivity and specificity.17,18

Magnetic Resonance Imaging

Although generally more involved and expensive than

ultrasonography, MRI has the potential to provide

significantly more information. Tissue properties such

as diffusion, enhancement, and specific metabolites

can be imaged with high resolution. In addition, a

high-resolution study of the prostate can be easily

combined with an examination of the abdominal and

pelvic lymph node chains for comprehensive evalua-

tion. A glossary of selected MRI terms are provided

in Table 2.

Performing the Examination

Clinical interest in staging prostate carcinoma with

MRI arose largely after the invention of the endorectal

Fig 1A-B. — Transrectal ultrasonographic imaging of prostate carcinoma (prostate-specific antigen level = 1.8 ng/mL). Biopsy showed a Gleason score of 3 + 3. (A) Transverse image reveals a slightly more echogenic peripheral zone (pz) and the carcinoma nodule (n) as a more hypoechoic focus. cg = central gland. (B) Sagittal image reveals a hypoechoic nodule (arrow). sv = seminal vesicle.

A

B

Table 2. — Glossary of Selected Terms Used in Magnetic Resonance Imaging

Term Definition

Diffusion-weighted imaging

Images or a series of images that show rela-tive loss of signal intensity in tissues or fluid that has unrestricted diffusion. Frequently, an image map of the apparent diffusion coef-ficient is calculated from a set of diffusion-weighted images with increasing strengths of the diffusion encoding gradients, or b value.

Dynamic contrast-enhanced imaging

A set of fast images obtained during the injection of a contrast agent, showing uptake of the contrast agent in the prostate and tumor. Rapid arterial enhancement of tumors is typical because of angiogenesis.

Superparamagnetic Having magnet-like properties, usually due to complexes of iron, which causes dephasing (loss of coherence) and, thus, loss of signal intensity on the images. Superparamagnetic iron oxide agents reveal loss of signal on the images due to this effect.

Endorectal coil A receiver coil covered with a latex inflat-able balloon and placed in the rectum to lie adjacent to the prostate to optimize the signal from the prostate, allowing higher-resolution images of the prostate.

Phased-array coils (multicoils)

A set of receiver coils that detects the magnetic resonance signal. These are placed in a rigid or flexible platform set directly on the patient anterior and posterior to the pelvis used in combination with the endorectal coil (or as a substitute for it).


coil, which permitted high-resolution images of the

prostate.19 Higher signal-to-noise images, high resolu-

tion images, or both can be obtained with the use of

the endorectal coil, phased-array coils, or high-field

imaging with 3 Tesla magnets, or any combination

of these (Fig 2). Imaging without the endorectal coil

will not provide the best possible examination for

staging purposes, but it may be suitable for certain

clinical situations.

To perform a standard examination, the patient

is placed on his side on the MRI table, and the en-

dorectal coil is slid into place in the rectum. The

coil is anteriorly oriented to receive a signal from the

prostate. The patient is turned on his back, and an

antiperistaltic agent such as glucagon is often intra-

venously administered. Phased-array coils are placed

against the skin anterior and posterior to the patient,

and the table is slid into the MRI magnet.

Multiple images of different types, or series, are

obtained on multiple planes. These typically include

T1-weighted images of the abdomen and pelvis for

lymph node disease. Smaller field-of-view (higher res-

olution) T1-weighted images, and T2-weighted images

on multiple planes (coronal, axial, and sagittal) are also

obtained. Additional sequences can include diffusion-

weighted imaging, dynamic contrast-enhanced (DCE)

imaging, and magnetic resonance spectroscopy.

Diffusion-weighted imaging is typically performed

using echoplanar fast imaging with diffusion-encoding

gradients in three directions. These gradients degrade

the signal intensity of water moving in the direction of

the gradient, and using gradients in three directions

diminishes the signal in any direction. Therefore, the

tissue has a lower signal from water motion due to

perfusion and diffusion. Acquiring two or more sets

of images with increasing gradient strength allows a

calculated apparent diffusion coefficient (ADC) map;

by necessity, these images are low resolution.

DCE images are fast, fat-saturated, T1-weighted

images obtained during and after the administration

of an intravenous contrast agent (eg, gadopentetate).

These rapid images reveal the arrival of the contrast

to the vessels and tissues as increased signal inten-

sity, which will sequentially reflect the arterial arrival

of the contrast, venous perfusion, uptake in the tis-

sue interstitium, and the subsequent washout from

these compartments. Such images may be acquired

at several time points for qualitative assessment and

at many time points for quantitative analysis. Addi-

tional acquisitions may also include magnetic reso-

nance spectroscopy. A complete examination usually

takes 45 minutes.

Anatomy of the Prostate

The most important anatomical features of the pros-

tate are shown in T2-weighted images (Fig 3). The

central gland of the prostate includes the periurethral

and transitional zones, generally with lower signal

intensity than the peripheral zone.20 The signal in-

tensity of the peripheral zone is generally high on

T2-weighted images largely due to glandular fluid;

by contrast, the signal intensity of the central gland

is variable and highly dependent on the amount and

characteristics of any present benign prostatic hyper-

trophy.20 The anterior central gland appears as low

signal intensity, the anterior fibromuscular stroma. A

low signal intensity line, the prostatic capsule, limits

the peripheral zone. Neurovascular bundles can be

identified as a group of vessels posterolateral to the

prostatic capsule on either side.

Seminal vesicles appear as high-signal-intensity,

grape-like clusters of tubules that reveal low-signal

intensity smooth muscle walls (Fig 3).20 This appear-

ance is due to the high-signal-intensity folded mucosa

filling the lumen with pockets of fluid. The ampullae

of the vas deferens can be identified as well as the

Fig 2A-B. — Imaging of the prostate with and without endorectal coil. (A) Transverse image of the prostate performed with phased-array coils with-out an endorectal coil reveals adequate differentiation of the central gland (cg), peripheral zone (pz), and the tumor nodule (n). However, visualization of the prostatic capsule near the tumor is poor (arrow). (B) Transverse image of the prostate with the endorectal coil shows the central gland (cg), peripheral zone (pz), and tumor nodule (n), with better visualization of the prostatic capsule near the tumor (arrow).

A

B


ejaculatory ducts.20,21 The low-signal intensity bladder

wall can also be seen. Periprostatic structures such as

veins, puborectalis and pubococcygeal muscles, and

lymph nodes will also be visible.21

Prostate Cancer Imaging

Prostate carcinoma appears on MRI as intermediate-

signal intensity (gray) on T2-weighted images (Fig 2).

Because the peripheral zone normally has high-signal

intensity (bright), carcinomas are generally clearly

visible in the peripheral zone. Conversely, because

the signal intensity of the central gland is variable and

generally low or intermediate, tumors are not well

visualized in this area. On diffusion-weighted images,

prostate carcinoma has low-signal intensity, which

reflects restricted diffusion (Fig 4) that often correlates

with the degree of cellularity, macromolecular density,

or fibrous tissue. Diffusion imaging may also assist

Fig 3A-D. — Prostate anatomy on endorectal coil magnetic resonance imaging. (A) Transverse image at the midprostate reveals high-signal intensity (brighter) in the peripheral zone (pz), low-signal intensity (darker) in the central gland (cg) with several scattered benign prostatic hyperplasia (BPH)nodules, and prostatic capsule (arrowhead), the neurovascular bundles (thick black arrows), urethra (thin black arrow) and the rectal wall (white arrow). (B) Coronal image of the prostate shows a high-signal intensity peripheral zone and a low-signal intensity central gland with the prostatic capsule (thick white arrows). The irregular ampulla of the vas deferens are visible (thin white arrows), as well as the prostatic urethra and verumontanum (black arrow). (C) Sagittal view of the prostate reveals the central gland (cg) with BPH producing a prominent subtrigonal nodule (stn) that protrudes into the bladder, a variant appearance of BPH. The peripheral zone (pz) has a higher signal intensity. The seminal vesicles and vas deferens lie superiorly (black arrow). White arrows denote the membranous urethra. (D) Transverse image of the seminal vesicles (black arrows) shows high-signal intensity lumens surrounded by the low-signal intensity walls. The ampullae of the vas deferens (white arrowheads) are visible as well as the low-signal intensity bladder wall (black arrowhead). The central subtrigonal nodule of the prostate is noted (stn).

A B

C D


in differentiating between hemorrhage and tumor in

the peripheral zone.22 The enhancement of prostatic

tumors is somewhat variable; however, tumors typi-

cally enhance more rapidly and to a greater degree

than the peripheral zone normal tissue. Therefore,

they may be best displayed on an early arterial phase

image (Fig 5). Increased or more rapid contrast en-

hancement correlates with microvascular density in

the prostate tumor.23

Extracapsular extension, when gross, is mani-

fested by protrusion of the intermediate-signal in-

tensity tumors through the prostate capsule. More

subtle capsular penetration may be manifested by a

tumor that abuts the capsule over a wide area, capsu-

lar thickening, nodularity or bulging of the capsule,

or irregularity (Fig 6).24 Seminal vesicle invasion is

manifested by a low-signal intensity tumor, replacing

the high-signal intensity seminal vesicle lumens, the

mucosa, or both.25 Similarly, bladder wall invasion

will be manifested by intermediate-signal intensity on

T2-weighted images or enhancing tissue interrupting

the low-signal intensity bladder wall.

Magnetic Resonance Spectroscopy

Spectroscopy is a magnetic resonance technique to

assess the presence of metabolites in tissue. Proton

spectroscopy can detect certain hydrogen-containing

metabolites in the prostate such as choline, creatinine,

and citrate. The normal prostate gland produces high

levels of citrate and low levels of choline. Because of

phospholipid metabolism and higher cell membrane

turnover, prostate cancer has higher levels of choline.

Fig 4A-D. — Typical appearance of prostate carcinoma on magnetic resonance imaging. Subsequent biopsy revealed a Gleason score of 4 + 4. (A) T1-weighted image shows homogeneous low signal of the prostate (p), with no discrimination of the central and peripheral gland. The tumor nodule is not seen because no tissue contrast is present between the tumor and peripheral zone. The neurovascular bundles (black arrows) are seen laterally. (B) T2-weighted image shows the lower-signal intensity tumor (n) compared to the curve from zone on either side. (C) Coronal image shows the tumor nodule (n) with the adjoining apical prostatic capsule shown (arrow). (D) Early-phase gadolinium chelate-enhanced sections from a fast 3-dimensional gradient echo sequence show rapid intense enhancement of the tumor nodule (n), manifested by brighter signal intensity in the rest of the prostate, with tumor extending laterally to greater extent than is apparent on the T2-weighted image.

A B

C D


Fig 5A-C. — Prostatic carcinoma on magnetic resonance imaging with dif-fusion-weighted imaging of a patient with a prostate-specific antigen level of 3.1 ng/mL. Subsequent biopsy revealed a Gleason score of 3 + 4 with extracapsular extension. (A) T2-weighted and rectal coil image reveals a tumor nodule (n) contrasted with a higher-signal intensity peripheral zone. The central gland (cg) is expanded by benign prostatis hyperplasia, which has a lower signal intensity. (B) Apparent diffusion coefficient (ADC) map of the prostate reveals that the tumor nodule (n) has a lower signal intensity than the peripheral zone or the central gland (cg). Low signal intensity indi-cates that the ADC is lower than that of water and the water diffusion within the tumor is restricted. The ADC map is calculated from a set of three images at the same level (not shown) and performed with three different magnitudes of strength of diffusion-encoding gradients. (C) Early-phase gadolinium chelate-enhanced slice from a fast 3-dimensional gradient-echo sequence reveals rapid, intense enhancement of the tumor nodule (n). Portions of the central gland (cg) also reveal rapid enhancement. Note: Multiparametric imaging refers to the characteristics of abnormalities on all three sets of images.

A

B

C

Fig 6A-C. — Typical enhancement characteristics of a tumor on dynamic contrast-enhanced images in a patient with a prostate-specific antigen level of 15 ng/mL. Biopsy showed a Gleason score of 4 + 4. (A) Transverse T2-weighted image reveals a tumor nodule (n) involving both the central gland and the peripheral zone on the right side of the prostate. The arrow points to the capsular involvement on the right. (B) Early-phase gadolinium chelate-enhanced slice from a fast 3-dimensional gradient-echo sequence reveals a rapid, intense enhancement of the tumor nodule (n) on the right side of the prostate. (C) Late-phase enhanced T1-weighted image reveals the tumor nodule (n) with a lower signal intensity, indicating washout of the contrast compared with the rest of the prostate. Typically, a tumor dem-onstrates early enhancement and early washout (as shown in this case).

A

B

C


The ratio of choline to citrate is increased in patients

with cancer. At 1.5 Tesla, the spectroscopic peaks of

choline overlap with creatinine; however, these can

be resolved at 3 Tesla.

Magnetic resonance spectroscopy of the prostate

can be performed with a 3-dimensional (3D) water

and lipid suppressed, double-spin-echo point-resolved

spectroscopy sequence; however, 3D magnetic reso-

nance spectroscopy is time consuming and technically

challenging. Adequate water and lipids suppression

is necessary to exclude contamination from tissue

outside the prostate. Data sets are typically acquired

with 16 × 8 × 8 phase-encoded spectral arrays. The

magnetic resonance spectra can be displayed as an

rectangular array from the individual voxels.

Multiple studies have suggested improved detec-

tion, localization, and staging with magnetic resonance

spectroscopy.6,26-28 However, a multisite prospective

trial showed no benefit of magnetic resonance spec-

troscopy compared with MRI alone for tumor identifi-

cation and compared with sextant localization on the

prostatectomy specimens.29 It is not clear whether

the results of this study represent inherent limitations

of magnetic resonance spectroscopy for the localiza-

tion of prostate cancer or difficulties in a technically

demanding technique with a multicenter trial design.

Accuracy of Staging

The reported sensitivity and specificity for prostate

carcinoma staging vary from high to low, and it is

difficult to determine the most appropriate figures to

use.30-32 Studies commonly vary in patient population,

particularly regarding the Gleason grading spectrum

of patients or PSA levels, as well as in techniques or

pulse sequences used (eg, diffusion imaging, dynamic-

enhanced imaging), without standardization for coils

(eg, endorectal or body coils), or field strength. Fur-

thermore, the vast majority are single institutional and

retrospective studies, which are prone to bias and can

be insufficiently powered. Finally, methodological

problems exist with mapping tumors or sites of cap-

sular penetration to precise sites on any prostatectomy

specimens to determine imaging accuracy.5

Results from a multicenter prospective trial dem-

onstrated limited accuracy of MRI in locating the pros-

tate tumor.29 One would expect that the accuracy for

staging would be even lower. Several generalities

can be stated regarding the accuracy of MR staging.

First, the accuracy for extracapsular extension is prob-

ably between 70% and 80%, while the identification

of seminal vesicle invasion is more accurate.24,30,33-36

Second, MRI at 3 Tesla is probably superior to MRI

at 1.5 Tesla.33,37 Third, diffusion-weighted and DCE

imaging may provide small incremental increases in

accuracy.6,7,33 Fourth, MRI probably provides a small

incremental increase in accuracy over clinical nomo-

grams based on PSA, digital rectal examination, and

Gleason grade, among others.38 Fifth, MRI is more

accurate in patients at intermediate or high risk, but

it is less accurate in patients with low-volume tumors

and low Gleason grades.39 The detection rate of tu-

mors is also dependent on size, with tumors smaller

than 2 cm unlikely to be detected.40

Multiparametric imaging, or the integration of

various sequences such as diffusion, DCE, and T2-

weighted imaging, may provide higher accuracy.6,33

However, how these varying data are combined for

optimal accuracy is not clear.

Evaluation of Prostate Cancer Metastases Patients with prostate carcinoma are evaluated for

possible metastatic disease if they fall into a high-

risk group with a new diagnosis or after biochemical

failure following prostatectomy, radiation treatment,

or local therapy.

Computed Tomography

CT is an important part of the management of prostate

carcinoma. CT scanning provides a quick evalua-

tion for metastases in the chest, abdomen, or pelvis.

It is efficient at identifying enlarged lymph nodes,

although lymph node enlargement is not highly sen-

sitive and not entirely specific for lymph node me-

tastases.41,42 Since CT provides poor tissue contrast

within the prostate itself, evaluation of the intrapros-

tatic tumor is limited.

CT scanning can detect bone metastases, particu-

larly those that are osteoblastic; therefore, it is useful

in patients at high risk of metastatic spread on initial

evaluation or with suspected progression after pros-

tatectomy or radiation treatment. It is also useful in

patients with identified metastases to monitor the

effectiveness of therapy.

Because lymph node size is not sensitive or spe-

cific for metastasis in patients with prostate carci-

noma, there is no one size criterion that is highly ac-

curate. A commonly used criterion is a pelvic lymph

node smaller than 10 mm but 8 mm or larger in size (if

round in shape) or 10 mm or larger in size (if oval in

shape). Using this criterion with contemporary scan-

ners, one study found a sensitivity rate of 34% and a

specificity rate of 97% for the detection of lymph node

metastases.43 If CT is used to evaluate for lymph node

metastases, suspicious nodes are generally subjected

to fine-needle aspiration for confirmation, which can

produce false-negative results. For these reasons, CT

is recommended with a very high pretest probability

of metastatic disease (Table 1).1


MRI can survey for metastatic disease similar to CT of

the lymph nodes and skeletal structures. MRI of the


abdomen and pelvis is used to evaluate for lymphade-

nopathy, bone metastases, and metastases elsewhere,

but it is generally more time consuming and more

expensive than CT scanning while providing similar

diagnostic information.

Recent developments exist to provide a more spe-

cific evaluation of lymph node metastases than an

assessment based solely on size. Diffusion-weighted

imaging of lymph nodes may be a more specific as-

sessment than size criteria.44 Metastatic lymph nodes

demonstrate a lower apparent ADC than benign lymph

nodes,14,15 presumably reflecting greater cell density in

lymph nodes with metastatic tumor. DCE properties

of lymph nodes differ between normal and metastatic

lymph nodes in that lymph nodes with metastases

show stronger and more rapid enhancement.45

Another innovation in lymph node imaging us-

ing MRI has been the development of superparamag-

netic contrast agents with preferential lymph node

uptake. These agents accumulate in normal lymph

nodes, causing losses of signal intensity within these

lymph nodes on imaging. Conversely, lymph nodes

with metastases within them do not accumulate the

agents in the metastatic portion and do not lose signal

intensity, or, conversely, they will lose signal intensity

in the normal part of the lymph node. A large trial of

men with intermediate or high risk of having nodal

metastases compared this MR contrast agent with CT

showed 82% sensitivity for lymph node metastases vs

34% for CT.38 This could obviate the need for lymph

node dissection in patients with a negative MRI.43

Because an MRI examination using a lympho-

tropic agent reveals all the lymph nodes in the pelvis,

it can reveal metastatic lymph nodes outside the nor-

mal range of the pelvic lymph node dissection chains.

For example, in a study of 296 men with prostate

cancer, MRI with a superparamagnetic agent revealed

lymph nodes outside of the pelvic lymph node dis-

section in 18 of the 44 patients (44%) with positive

lymph node metastases.46 Currently, no approved

superparamagnetic contrast agent exists in the United

States for lymph node imaging. An off-label use of

ferumoxytol, an agent indicated for iron deficiency

anemia, is being investigated for lymph node imaging

in prostate cancer, as it has similar properties to pre-

viously investigated contrast agents (NCT01296139).

MRI is sensitive for bone metastases (Fig 7). An

MRI technique for skeletal imaging, as well as other

organs to some extent, is termed whole-body MRI

and most of the skeleton is revealed, comparable

with bone scintigraphy or positron emission tomog-

raphy (PET)/CT. Methods of evaluating for bone

metastases by MRI include T1-weighted sequences,

short TI inversion recovery imaging, and diffusion-

weighted imaging. Large field-of-view coronal images

can quickly image the chest, abdomen, and pelvis for

bone metastases and lymph node metastases with

short TI inversion recovery imaging or diffusion-

weighted images. These survey examinations may

be more sensitive than PET/CT or scintigraphy in

identifying metastases.47,48 Diffusion-weighted im-

ages using weak diffusion gradient strength are simi-

lar in performance.49

Nuclear Medicine

The use of scintigraphic (nuclear medicine) exami-

nations for the evaluation of prostate cancer is usu-

ally reserved for patients with suspected osteoblastic

skeletal metastatic disease or those with a rising

PSA assay level without demonstrable bulky distant

metastatic disease or skeletal metastatic disease fol-

lowing prostatectomy.

Fig 7A-E. — Nuclear medicine evaluation of prostate carcinoma metastases. (A) Technetium 99m hydroxymethylene diphosphonate bone scan shows skeletal uptake of the tracer but no evidence of metastases. (B) 18F-sodium fluoride positron emission tomography scan performed 18 months later reveals uptake in numerous sites, including the L4 and L5 vertebral bodies. (C) Sagittal reformatted image from the 18F-sodium fluoride PET scan reveals uptake in the vertebral bodies (arrows). (D) 111In-capromab pendetide scan (sagittal reformatted image) shows no discernible uptake in the metastases. (E) T1-weighted sagittal magnetic resonance imaging reveals bone marrow metastases in L4 and L5 (arrows).

A B C D E


In patients with suspected osteoblastic skeletal

metastatic disease, nuclear medicine currently offers

the option of gamma emitters, such as technetium-

99m (99mTc) linked to a radioligand — in this case, a

“bone-seeking” agent, such as methylene diphospho-

nate or hydroxymethylene diphosphonate. Imaging of

such radiotracers is performed using gamma cameras

in the single detector (head), dual-head, or triple-head

configuration. In the last 10 years, hybrid nuclear

medicine–CT camera systems have become available

that combine a diagnostic quality CT gantry with a

dual-headed gamma camera system. These systems

provide the option of obtaining a nuclear medicine

tomographic examination (single-photon emission

computed tomography [SPECT]) registered to a co-

acquired low (nondiagnostic) or high radiographic

dose (diagnostic) CT for localization purposes.

The major drawback of the radiotracers used for

skeletal scintigraphy (bone scan) is low specificity.

Inflammatory processes such as degenerative joint

disease and osteoarthritis can demonstrate signifi-

cant uptake. Certainly other active inflammatory pro-

cesses, such as autoimmune processes, can also have

increased uptake. Infectious or reparative processes

involving the bone can also have increased uptake.

The above-discussed radiotracer primarily depos-

its within the cortical bone through chemoabsorption.

This radiotracer deposits in areas of bone deposition;

therefore, these examinations demonstrate areas of

osteoblastic response to tumoral deposits in bone,

not deposition within the tumor tissue. Sensitivity for

detection of osteoblastic activity related to metastatic

prostate cancer can reach a rate of 95% in patients

with PSA levels above 20 ng/mL.50-52 In cases where

a rising PSA level is present following prostatectomy

and negative skeletal scintigraphic findings, the likeli-

hood of soft-tissue metastatic disease increases.

Skeletal scintigraphy is mainly reserved for pa-

tients with high-risk cancer, elevated serum alkaline

phosphatase levels, bone pain, or equivocal osseous

lesions on other imaging modalities.53,54

Prior studies have demonstrated the relationship

of increased incidence of skeletal metastatic disease

with elevated PSA levels.50-52 The flare phenomenon,

which refers to evidence of increasing osteoblastic

metastatic disease (worsening of bone scan appear-

ance) following therapy, with decreasing symptom-

atology has been previously described.54-58 It is vis-

ible in patients with prostate carcinoma metastatic

to the skeleton, observable in 20% to 25% of scans if

obtained soon after therapy has been instituted.56-58

Because of this paradoxical worsening of scintigraph-

ic appearance in patients with favorably responding

metastatic disease, skeletal scintigraphy is not the

only test for the evaluation of such patients. Bone

scans are useful for the evaluation of patients with

diagnosed prostate cancer with a rising or elevated

PSA level, patients with normal PSA levels following

hormonal therapy, or patients who have a normal PSA

level but are symptomatic.

Bone scans using planar and tomographic tech-

niques have adequate sensitivity and specificity rates

and have been the main tool utilized for many years.

However, tumor detection using novel radiotracers and

newer imaging techniques may prove advantageous in

the future. Novel radiotracers such as positron emit-

ters (eg, 18F-fluoride [NaF]), as well as PET or PET/CT

and PET/MRI techniques, may prove indispensable in

the evaluation of metastatic skeletal disease. In malig-

nant bone lesions, NaF reflects the increase in regional

blood flow and skeletal turnover associated with meta-

static osteoblastic deposits (Fig 7). NaF PET/CT has

been shown to be more sensitive for the detection of

metastases than 99mTc methylene diphosphonate bone

scans. The use of hybrid imaging techniques such

as PET/CT reduces the risk of false-positive findings

and improves specificity of abnormalities detected by

virtue of the imaging capabilities for lesion-by-lesion

characterization using CT (Fig 7).59

In a recent study that reviewed the use of 99mTc

methylene diphosphonate and NaF, a direct compari-

son was made using whole-body planar images and

tomographic (SPECT) bone scans as well as PET alone

and PET/CT NaF for the detection and characterization

of skeletal metastases in 44 patients with high-risk

prostate cancer.59 In this study, whole-body planar

imaging had sensitivity and specificity rates of 57%.

Conversely, whole-body planar plus SPECT was 78%

sensitive and 67% specific. 18F PET was 100% sensi-

tive and 62% specific, whereas 18F PET/CT was 100%

sensitive and 100% specific. Conversely, fludeoxyglu-

cose 18F PET for the detection of prostate carcinoma

skeletal metastases had a low yield with a sensitivity

of less than 20% compared with skeletal scintigraphy.60

Soft-Tissue/Lymph Node Metastatic Disease Evaluation

Molecular imaging techniques, such as the use of 111In capromab pendetide, allow for the evaluation

of suspected metastatic prostatic carcinoma outside

of the prostate bed, particularly the pelvic sidewall

and retroperitoneal lymph nodes. 111In capromab

pendetide consists of a murine monoclonal antibody

(7D11-C5.3) covalently jointed to a liner-chelator mol-

ecule. It is directed against the intracellular domain of

prostate-specific membrane antigen (PSMA) expressed

on the surface of prostate cancer metastases as well

as the normal prostatic tissue. It is also expressed in

other tissue types, such as the kidney, liver, bowel,

and brain. PSMA is upregulated in hormone-resistant

states and in metastatic disease, which is why it is

used for the detection of extraprostatic, bone-scan-

negative metastatic disease.


These molecular imaging techniques involve mul-

tiday examinations, and time is allowed for the ra-

diopharmaceutical to circulate in the blood pool and

migrate to the targeted metastatic foci. Usual imaging

protocols call for dosing on day 0, with imaging per-

formed on day 4, day 5, or both (96 and/or 120 hours

after injection). Imaging techniques available include

the use of planar gamma camera images, evaluating the

whole body from an anterior and posterior projection,

as well as tomographic images obtained using SPECT

or SPECT/CT camera systems. However, with all the

advanced imaging systems used, the sensitivity rate

ranges from 62% to 75% (Fig 7).61-63 This technique

is also limited by nonspecific uptake in bowel, vas-

culature, bone marrow, and normal prostatic tissues,

and it has a low sensitivity rate for low-tumor-burden

prostate fossa disease as well as small metastases.

Novel Radiotracer

Novel radiotracers in different stages of research eval-

uation include positron emitters such as 11C-acetate

and 11C-choline.

Malignant transformation within the prostate cells

leads to a change in intracellular metabolic processes,

which result in a change from citrate-producing nor-

mal cells to citrate-oxidizing neoplastic cells, thereby

leading to an increased acetate turnover with increased

expression of fatty acid synthase. Hence, increased

anabolic metabolism is associated with cytoplasmic

lipid synthesis. Imaging with acetate-linked radiotrac-

ers benefits from this process.

Early studies using dedicated PET imaging sys-

tems comparing the use of fludeoxyglucose 18F and 11C-acetate for the evaluation of recurrent prostate

carcinoma showed promise when used to detect

metastatic disease over the use of fludeoxyglucose 18F alone, which had limited sensitivity and specific-

ity rates (Fig 8). However, a study by Oyama et al64

showed a statistical difference in the detection of re-

current disease in patients with elevated PSA levels

above 3 ng/mL but limited results in patients with

PSA levels of 3 ng/mL or below. 11C-acetate PET was

shown to have a sensitivity rate of 59% compared with

a sensitivity rate of 17% for fludeoxyglucose 18F PET.

Fig 8A-B. — Comparison of fludeoxyglucose 18F and 18F-acetate positron emission tomography scans. (A) Normal scan. (B) 18F-acetate examination of the same patient reveals prostate carcinoma metastases within the pelvic nodal stations. From Yu EY, Muzi M, Hackenbracht JA, et al. C11-acetate and F-18 FDG PET for men with prostate cancer bone metastases: relative findings and response to therapy. Clin Nucl Med. 2011;36(3):192-198. Reprinted with permission by Wolters Kluwer Health.

A

Pre-RX

PSA 432

B

Post-RX

PSA < 1

FDG PET Acetate PETBone Scan


Of note, this study used stand-alone PET imaging

systems. In one report, Fricke et al65 noted a higher

rate of overall lesion detection with acetate (83%)

compared with fludeoxyglucose 18F (75%).

In a recent pilot study by Yu et al66 involving 8

participants, conventional skeletal scintigraphy was

compared with 99mTc methydiphosphonate, fludeoxy-

glucose 18F, and 11C-acetate in the detection of skel-

etal metastases and follow-up after therapy. Acetate

PET generally detected more metastases and had a

higher ratio of tumor-to-normal uptake. These results

indicate that acetate PET holds promise for response

assessment of prostate cancer skeletal metastases; it

was also complementary to fludeoxyglucose 18F in the

detection of bone metastasis.11C- and 18F-labeled choline derivatives have been

used to detect primary or relapsing prostate carci-

noma based on increased levels of phosphorylcholine,

upregulated enzymes of choline metabolism, choline

kinase with increased phosphatidylcholine turn-

over, and the metabolic flux of radiolabeled choline

through phospholipid biosynthesis and degradation

in prostate carcinoma.67 This uptake is unrelated to

proliferation (Ki67). Several authors68-70 have shown

that 11C-choline is taken up by prostate carcinoma and

its nodal and distant metastases (Fig 9).

In a recent study using hybrid imaging (PET/CT),

Reske et al71 investigated the ability of 11C-choline

contrast-enhanced PET/CT for the evaluation of pros-

tatic carcinoma and differentiation of prostatic cancer

tissue from normal prostate tissue, benign prostate

hyperplasia, and focal chronic prostatitis. The authors

concluded that 11C-choline PET/CT accurately located

and detected major areas of prostate carcinoma within

the prostate gland and differentiated segments with

prostate cancer from those with chronic prostatitis,

benign hyperplasia, or normal prostatic tissue (Fig 10).

A study that compared 11C-choline and 11C-acetate

PET in 10 patients with residual or recurrent prostate

cancer showed similar detection rates for local tumor,

lymph node, and skeletal metastases, but only in pa-

tients with high PSA levels.70 In those with low PSA

levels, studies performed thus far have shown low to

moderate sensitivity in detection of local residual or

Fig 9. — Anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid image of a patient with extensive prostate carcinoma (arrowheads) with involved bilater-al obturator (open arrows) and left iliac lymph nodes (solid straight arrows). Urinary activity is minimal and not present on the image (curved arrow at bladder location). From Schuster DM, Votaw JR, Nieh PT, et al. Initial experi-ence with the radiotracer anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid with PET/CT in prostate carcinoma. J Nucl Med. 2007;48(1):56-63. Re-printed by permission of the Society of Nuclear Medicine.

Fig 10A-B. — Focal (A) and multifocal (B) distribution of prostate carcinoma within the prostate gland (arrows). Scatter plots of the segmental 11C-choline maximal standardized uptake value reveal higher 11C-choline maximal standardized uptake values in most segments with prostate carcinoma compared with segments with benign histopathological lesions. From Reske SN, Blumstein NM, Neumaier B, et al. Imaging prostate cancer with 11C-choline PET/CT. J Nucl Med. 2006;47(8):1249-1254. Reprinted by permission of the Society of Nuclear Medicine.

7.5

5.0

0.0Benign

SU

Vm

ax

PCa

2.5

7.5

5.0

0.0Benign

SU

Vm

ax

PCa

2.5

A B


recurrent tumor. Similarly, these studies have shown

moderate sensitivity in the detection of distant meta-

static disease.72,73 In a recent study, Vees et al74 evalu-

ated 20 patients with early-stage prostate carcinoma

staging after prostatectomy with low PSA levels (< 1

ng/mL) for the presence of local or metastatic prostate

carcinoma with 18F-choline, 11C-acetate, or both. Two

of the 20 patients were evaluated with both radiotrac-

ers. Both radiopharmaceuticals detected the presence

of neoplastic disease in 50% of the participants.

Other radiopharmaceuticals being evaluated in-

clude 11C-methionine, 18F-fluoro-5-dihydrotestosterone,

and anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic

acid (Fig 9).75

Evaluation of the Prostate or Surgical Site Following TherapyMRI and sonography are two methods used to evalu-

ate for local recurrence following local therapy or

prostatectomy. PET and CT scanning are not accurate

methods for identifying recurrent tumor.76,77

Ultrasonography

Following prostatectomy in the surgical bed, transrec-

tal ultrasonography may detect recurrence of pros-

tate carcinoma.78 Recurrences appear as ill-defined

hypoechoic lesions in the bladder neck or at the

anastomosis.79 Power Doppler imaging and contrast

enhancement may improve the sensitivity of ultraso-

Fig 11A-D. — Recurrent tumor following radical prostatectomy (prostate-specific antigen level = 4.8 ng/mL). (A) Sagittal T2-weighted image reveals low-signal intensity soft tissue (thick arrow) posterior to the urethrovesical anastomosis (thin arrow). b = bladder. (B) Transverse T2-weighted image of the bladder lumen reveals the low-signal intensity soft tissue (thick arrow) involving the rectum muscularis posterior kidney urethrovesical anastomosis (thin arrow). (C) Early-phase gadolinium chelate-enhanced image shows a rapidly enhancing tumor nodule (arrow) that appears as a higher signal intensity plaquelike lesion involving the rectum muscularis propria. The other structures, which are low in signal intensity, including the urethrovesical anastomosis, on the T2-weighted image are not rapidly enhancing. (D) Early-phase gadolinium chelate-enhanced image at a higher level through the retained seminal vesicles reveals the right-retained seminal vesicle with diffuse enhancement (arrow), which was subsequently proven to be a recurrent tumor. By contrast, the left seminal vesicle (sv) does not contain a recurrent tumor.

A B

C D


nography in identifying recurrent tumor.80 However,

biopsies of the surgical site are still more sensitive

than ultrasonographic imaging.81

Ultrasonography and Doppler imaging of the

prostate following local therapy (eg, cryosurgery,

Fig 12A-C. — Recurrent tumor with magnetic resonance imaging follow-ing brachytherapy with radiation seed implants (prostate-specific antigen level = 1.2 ng/mL). (A) T1-weighted image with a rectal coil through the prostate that has numerous low-signal intensity foci representing an artifact arising from the individual radiation seeds. (B) T2-weighted image reveals diffuse low-signal intensity throughout the prostate with poor discrimina-tion between the central gland and peripheral zone. No definite tumor can be identified, although the central gland is slightly higher in signal intensity. The radiation seeds identified are less apparent because fewer artifacts are visible on the image. (C) An early dynamic contrast-enhanced study reveals focal enhancement within the central gland (between arrows) that was sub-sequently demonstrated to represent recurrent tumor.

A

B

C

brachytherapy) may have little role in identifying re-

sidual tumor. Contrast-enhanced ultrasonography

may have increased sensitivity and specificity and

may help in evaluating the degree of ablation in local

therapies by distinguishing between vascularized and

nonvascularized (ie, ablated) tissue.82


Following total prostatectomy, MRI can detect recur-

rence in the prostatic bed. The usual appearance

after radical prostatectomy includes a descended

bladder neck in the prostatectomy space with a small

amount of fibrotic tissue around the urethrovesical

anastomosis. Linear scarring may be present at the

expected former site of the seminal vesicles.83 T2-

weighted images can detect recurrence as a higher

signal intensity nodule compared with the surround-

ing fibrosis and smooth muscle of the bladder neck,

urethra, and urethrovesical anastomosis.84 Sensitivity

rates of 95% and specificity rates of 100% have been

reported for MRI.84 DCE images may increase sen-

sitivity and identify enhancing nodules of recurrent

tumor (Fig 11).85,86

Following hormonal deprivation therapy, the

prostate becomes smaller in size with diminished

signal intensity of the peripheral zone, so tumors are

more difficult to localize on T2-weighted images.87 As

a result of apoptosis, androgen-deprivation therapies

may cause atrophy of the prostatic epithelium.26

The histologic changes in the prostate caused by

external beam irradiation include glandular atrophy,

inflammation, prostate shrinkage, and fibrosis.88 After

external beam radiation therapy, the peripheral zone

generally loses signal intensity on T2-weighted imag-

ing,89 which can effectively render most carcinomas

difficult or impossible to identify on standard MRI

following radiation therapy. Similar effects are vis-

ible using brachytherapy with radiation seeds. Diffu-

sion-weighted imaging or DCE imaging may increase

sensitivity in the irradiated prostate for the presence

of cancer.90 On diffusion-weighted or ADC imaging,

carcinoma generally appears as a more restricted dif-

fusion than the remainder of the prostate gland. MRI

may detect residual or recurrent tumor in patients

treated with high-intensity focused ultrasonography.91

DCE images are more sensitive than T2-weighted im-

ages to tumor recurrence (Fig 12).91,92

Similar to the effects on T2-weighted images

with external beam therapy, spectroscopic results

also change with radiation. The citrate levels tend

to decrease after radiation in nontumorous prostate

and choline levels increase, causing confusion with a

tumor. Nonetheless, spectroscopy can identify some

patients with residual tumor after radiation, although

reported accuracies are not as high as those seen in

patients with untreated prostate cancer.27,93


ConclusionsLocal staging of the prostate tumor is limited in ultra-

sonography and magnetic resonance imaging; both

techniques provide suboptimal sensitivity and speci-

ficity for tumor identification and capsular penetra-

tion. Additional magnetic resonance imaging tech-

niques such as dynamic contrast-enhanced imaging,

diffusion imaging, and spectroscopy may provide in-

cremental benefit; however, none of these are highly

sensitive. Computed tomography and bone scans are

used to assess metastatic disease, but both techniques

are limited by the poor sensitivity of lymph node size

as a criterion for detecting metastases.

Accepted methodologies for evaluating metastatic

prostate carcinoma to the skeletal system and soft

tissues include skeletal scintigraphy (bone scan) and

monoclonal antibody imaging that targets prostate-

specific membrane antigen. However, novel imaging

techniques such as hybrid imaging devices in the

form of single-photon emission computed tomogra-

phy/computed tomographic gamma cameras, posi-

tron emission/computed tomographic cameras, and,

in the near future, positron emission tomography/

magnetic resonance imaging combined with tumor-

specific imaging radiotracers may significantly and

favorably affect tumor staging, the accuracy of therapy

response, and patient care.

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