27 Contrast-Enhanced Ultrasound of the Prostate
J. Robert Ramey
J. R. Ramey, MD
Department of Urology, Suite 1100, Jefferson Prostate Diag- nostic Center, Thomas Jefferson University, 1015 Walnut Street, Philadelphia, PA 19107, USA
27.2
Conventional Gray-Scale Transrectal US and Sextant Biopsy
The classical description of prostate cancer is that of a hypoechoic lesion in the peripheral zone on conven- tional gray-scale transrectal US (Fig. 27.1). Hypoechoic lesions represent 60–70% of tumors (Purohit et al.
2003), even though only 17–57% of hypoechoic foci actually harbor a malignancy (Bartsch et al. 1982;
Lee et al. 1987; Rifkin et al. 1991; Spencer et al.
1994; Rifkin 1997, 1998; Weaver et al. 1991). Prostate cancer may also appear isoechoic (40% of tumors), occasionally rarely hyperechoic lesions have been reported. As such, <40% of nonpalpable tumors are identifiable sonographically with gray-scale imaging (Shinohara et al. 1989).
CONTENTS
27.1 Introduction 359
27.2 Conventional Gray-Scale Transrectal US and Sextant Biopsy 359
27.3 Prostatic Blood Supply 360
27.4 Prostate Cancer and Angiogenesis 360 27.5 Unenhanced Doppler Imaging 360
27.6 Contrast-Enhanced Transrectal US and Prostate Cancer Detection 360
27.7 Other Imaging Modalities 361 27.8 Conclusion 363
References 363
27.1
Introduction
Adenocarcinoma of the prostate is the most common solid organ malignancy in men. The American Cancer Society estimates 230,110 men will be diag- nosed with prostate cancer in 2004 and that approxi- mately 29,900 deaths will occur due to disease over the same time period (Jemal et al. 2004).
Prior to the widespread use of prostate-specific antigen (PSA) screening programs and transrec- tal ultrasound (US)-guided prostate biopsies, the diagnosis of prostate cancer was made on digital rectal examination and prostatic acid phosphatase.
Confirmation was obtained with manually guided, transperineal biopsy. Unfortunately, despite the advances in prostate cancer detection afforded by PSA and transrectal US-guided biopsy, a significant number of cancers still go undetected.
Fig. 27.1 Transverse image of the prostate demonstrates classi- cal hypoechoic lesion in the left mid-gland (arrows). Biopsies targeted to this lesion revealed a Gleason-7 adenocarcinoma
Due to the inability of gray-scale transrectal US
to accurately identify prostate cancer random sys-
tematic biopsy techniques have become routinely
employed in the diagnosis of prostate cancer. Intro-
duced by Hodge et al. (1989), transrectal US-guided
sextant biopsy has dramatically improved cancer
27.3
Prostatic Blood Supply
The paired prostatic arteries arise from the inferior vesical arteries and subsequently divide into two main divisions: (a) the urethral artery; and (b) the capsular artery (Brooks 2002). The capsular arteries course along the posterolateral aspect of the pros- tate, giving off perforator branches that supply the parenchyma of the gland (Halpern 2002a). These perforators are radially oriented in the transverse plane, producing a symmetric spoke-wheel pattern on Doppler imaging (Lavoipierre et al. 1998).
27.4
Prostate Cancer and Angiogenesis
The increased growth rate of malignant tissue requires increased blood flow to meet the higher metabolic demands. Angioneogenesis has been demonstrated in a variety of malignancies and often corresponds to local aggressiveness and metastatic proclivity (Chodak et al. 1980; Sillman et al. 1981;
Weidner et al. 1991). Overexpression of pro-angio- genic growth factors has been implicated in this process and vascular endothelial growth factor, epi- dermal growth factor, and basic fibroblast growth factor have all been demonstrated to be elevated in prostate tumors (Trojan et al. 2004). Pathologic examinations of prostate tumors from radical pros- tatectomy specimens have confirmed the presence of angioneogenesis within prostate cancer by dem- onstrating increased microvessel density compared with surrounding normal parenchyma (Bigler et al. 1993); thus, imaging techniques that provide
biopsies aimed at areas of abnormal flow have also been developed.
Halpern and Strup (2000) investigated the ability of color and power Doppler imaging to sonographically diagnose carcinoma of the pros- tate. Using a sextant biopsy protocol, they detected cancer in 211 cores from 85 patients. Doppler imag- ing prospectively identified 35 of the 211 foci as malignant.
Another recent study compared cancer detection rates between color- and power Doppler-targeted biopsy and sextant biopsy. Confirming previously reported results (Kelly et al. 1993; Rifkin et al. 1993;
Newman et al. 1995; Sakarya et al. 1998; Okihara et al. 2000; Shigeno et al. 2000) the positive biopsy rate was improved with targeted cores (13 vs 9.7%).
Unfortunately, 33% of patients (6 of 18) diagnosed with cancer had tumors that were undetected by tar- geted biopsy alone (Halpern et al. 2002a).
27.6
Contrast-Enhanced Transrectal US and Prostate Cancer Detection
The inability of unenhanced transrectal US imag-
ing techniques to accurately identify malignant
foci and to reliably detect all tumors with only
targeted biopsies has led several groups to study
contrast-enhanced transrectal US as a means to
improve prostate cancer detection. Microvessels of
prostate tumors have been shown to range in diam-
eter from 10–50 µm (Bigler et al. 1993), which is
well below the 1-mm-resolution limit of conven-
tional Doppler imaging (Halpern 2002a). This
explains the promising yet limited improvements
in prostate cancer detection seen with unenhanced
Doppler imaging.
Fig. 27.2a,b. Unenhanced transverse (a) color and (b) power Doppler imaging of a Gleason-7 prostate adenocarcinoma in the left mid to apex of the gland (arrow)
a b
Contrast-enhanced transrectal US has been shown to increase the sensitivity of color and power Doppler imaging from 37 to 53% without significantly alter- ing specificity (Frauscher et al. 2002a). The small size of microbubble contrast agents make them ideal for imaging blood flow within the vascular beds of prostate tumors. Microbubbles readily traverse these low-flow, small-diameter vessels amplifying Doppler signals and allowing selective visualization of blood flow within malignant foci (Fig. 27.3).
Initial work by Halpern et al. (2000) in a phase-II study of the microbubble-based contrast agent Ima- gent (AFO-150, Imcor Pharmaceutical, San Diego, Calif.) demonstrated the ability to prospectively identify focal areas of enhancement with power Doppler imaging during contrast infusion. These areas of enhancement were all noted to be isoechoic on baseline imaging, but corresponded to foci of cancer on pathologic review of biopsy specimens.
Another early study showed similar success using Levovist (SHU 508 A, Schering, Berlin, Germany) and a color Doppler-based targeted-biopsy protocol. Posi- tive biopsy rates were significantly improved with tar- geted cores vs sextant cores (13 vs 4.9%, respectively).
Furthermore, targeted biopsies detected cancer in 7 patients with negative systematic biopsies while fail- ing to diagnose a cancer detected on sextant biopsy in only one patient (Frauscher et al. 2001).
A recent study of 230 patients utilized contrast- enhanced color Doppler imaging to target biopsies and compared cancer detection rates to sextant biop- sies performed in the same subjects. Targeted biop- sies were again found to be significantly superior to systematic biopsy with 10.4 vs 5.3% positive cores, respectively (Frauscher et al. 2002b). Several addi-
tional studies have further confirmed that contrast- enhanced US improves cancer detection, although none have demonstrated superiority for either color or power Doppler imaging (Fig. 27.4; Halpern et al.
2001; Halpern 2002b; Roy et al. 2003).
27.7
Other Imaging Modalities
Newer techniques, such as contrast-enhanced har- monic imaging, have also been evaluated in prostate cancer imaging studies (Halpern et al. 2000, 2001, 2002b). Using phase-inversion technology, harmonic imaging exploits the nonlinear behavior of the micro- bubbles to differentiate between vascular echoes and surrounding tissue (Frauscher et al. 2002b).
In a prospective study of the contrast agent Defin- ity (MRX 115, Bristol-Myers Squibb Medical Imag- ing, North Billerica, Mass.), 60 patients were imaged at baseline and during continuous contrast infusion.
Real-time and intermittent (scan delays of 0.5, 1.0,
2.0, and 5.0 s) harmonic imaging were performed in
addition to power Doppler imaging. The increasing
interscan delays during intermittent imaging allow
more contrast to enter the prostate between each
image producing dramatic enhancement within
malignant foci (Fig. 27.5). At baseline cancer was
identified at 14 foci in 11 subjects while contrast-
enhanced imaging identified cancer at 24 foci in
15 subjects. Sensitivity was significantly improved
with contrast-enhanced imaging (65 vs 38%), while
specificity was not significantly different (Halpern
et al. 2001).
Fig. 27.3 Transverse imaging of a Gleason-6 prostate cancer in the left mid-gland. Baseline unenhanced (a) color and (b) power Doppler images reveal minimal focus of increased fl ow (arrow), while contrast-enhanced (c) color and (d) power Doppler images clearly demonstrate diffuse hypervascularity in the site of neoplasia (arrows).
c d
Fig. 27.4 Contrast-enhanced imaging of a Gleason-7 prostate tumor (arrow) in the left prostatic base on (a) color and (b) power Doppler
a b
Fig. 27.5 a Color and b power Doppler images of a Gleason-7 adenocarcinoma of the left mid-gland (arrow). Intermittent harmonic imaging of the same tumor shows increasing enhancement (arrow) with increasing interscan delays (c 0.2-s delay and d 1.0-s delay).
a b
c d
27.8 Conclusion
The clear association between increased microvascu- larity and prostate cancer (Bigler et al. 1993) suggests that contrast-enhanced transrectal US should signifi- cantly improve our ability to detect prostate cancer.
Additionally, since increased microvessel density has been correlated with metastatic disease (Weidner et al. 1993) and disease-specific survival (Lissbrant et al. 1997; Borre et al. 1998), the cancers identi- fied with contrast-enhanced imaging techniques are likely to be more aggressive tumors and thus require treatment. To date, several studies have shown sig- nificant improvements in cancer detection using con- trast-enhanced imaging and targeted-biopsy proto- cols. These promising results indicate that further study is clearly warranted to define the clinical role for this imaging modality in our armamentarium of diagnostic tools for prostate cancer detection.
References
Babaian RJ, Toi A, Kamoi K et al (2000) A comparative analy- sis of sextant and an extended 11-core multisite directed biopsy strategy. J Urol 163:152–157
Bartsch G, Egender G, Hubscher H, Rohr H (1982) Sonometrics of the prostate. J Urol 127:1119–1121
Bigler SA, Deering RE, Brawer MK (1993) Comparison of microscopic vascularity in benign and malignant prostate tissue. Hum Pathol 24:220–226
Borre M, Offersen BV, Nerstrom B, Overgaard J (1998) Microves- sel density predicts survival in prostate cancer patients subjected to watchful waiting. Cancer 78:940–944 Brooks JD (2002) Anatomy of the lower urinary tract and male
genitalia. In: Walsh PC, Retik AB, Vaughn ED, Wein AJ (eds) Campbell’s urology, 8th edn. Saunders, Philadelphia Brossner C, Bayer G, Madersbacher S et al (2000) Twelve pros-
tate biopsies detect significant cancer volumes (>0.5 ml).
Br J Urol Int 85:705–707
Chodak GW, Haudenschild C, Gittes RF, Folkman J (1980) Angiogenic activity as a marker of neoplastic and pre- neoplastic lesions of the human bladder. Ann Surg 192:762–771
Durkan GC, Sheikh N, Johnson P et al (2002) Improving pros-
of contrast enhanced color Doppler targeted biopsy with conventional systematic biopsy: impact on prostate cancer detection. J Urol 167:1648–1652
Halpern EJ (2002a) Color and power Doppler evaluation of prostate cancer. In: Halpern EJ, Cochlin DL, Goldberg BB (eds) Imaging of the prostate. Dunitz, London, pp 39–50 Halpern EJ (2002b) Advanced sonographic techniques for
detection of prostate cancer. In: Halpern EJ, Cochlin DL, Goldberg BB (eds) Imaging of the prostate. Dunitz, London, pp 65–75
Halpern EJ, Strup SE (2000) Using gray-scale and color and power Doppler sonography to detect prostatic cancer. Am J Roentgenol 174:623–627
Halpern EJ, Verkh L, Forsberg F et al (2000) Initial experience with contrast-enhanced sonography of the prostate. Am J Roentgenol 174:1575–1580
Halpern EJ, Rosenberg M, Gomella LG (2001) Prostate cancer:
contrast-enhanced US for detection. Radiology 219:219–
225
Halpern EJ, Frauscher F, Strup SE et al (2002a) Prostate: high- frequency Doppler US imaging for cancer detection. Radi- ology 225:71–77
Halpern EJ, Frauscher F, Rosenberg M, Gomella LG (2002b) Directed biopsy during contrast-enhanced sonography of the prostate. Am J Roentgenol 178:915–919
Hodge KK, McNeal JE, Terris MK, Stamey TA (1989) Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol 142:71–74
Jemal A, Tiwari RC, Murray T et al (2004) Cancer statistics, 2004. CA Cancer J Clinicians 54:8–29
Kelly IMG, Lees WR, Rickards D (1993) Prostate cancer and the role of color Doppler US. Radiology 189:153–156 Lavoipierre AM, Snow RM, Frydenberg M et al (1998) Prostatic
cancer: role of Doppler imaging in transrectal sonogra- phy. Am J Roentgenol 171:205–210
Lee F, Littrup PJ, McCleary RD et al (1987) Needle aspiration and core biopsy of prostate cancer: comparative evalu- ation with biplanar transrectal US guidance. Radiology 163:515–520
Levine MA, Ittman M, Melamed J, Lepor H (1998) Two consec- utive sets of transrectal ultrasound guided sextant biop- sies of the prostate for the detection of prostate cancer. J Urol 159:471–476
Lissbrant IF, Stattin P, Damber JE, Bergh A (1997) Vascular density is a predictor of cancer-specific survival in pros- tatic carcinoma. Prostate 33:38–45
Am 30:279–293
Rifkin MD (1997) Ultrasound of the prostate. Lippincott- Raven, New York
Rifkin MD (1998) Prostate cancer: the diagnostic dilemma and the place of imaging in detection and staging. World J Urol 16:76–80
Rifkin MD, Alexander AA, Pisarchick J, Matteucci T (1991) Palpable masses in the prostate: superior accuracy of US- guided biopsy compared with accuracy of digitally guided biopsy. Radiology 179:41–42
Rifkin MD, Sudakoff GS, Alexander AA (1993) Prostate: tech- niques, results, and potential applications of color Dop- pler US scanning. Radiology 186:509–513
Roy C, Buy X, Lang H, Saussine C, Jacqmin D (2003) Contrast enhanced color Doppler endorectal sonography of the prostate: efficiency for detecting peripheral zone tumors and role for biopsy procedure. J Urol 170:69–72
Sakarya ME, Arslan H, Unal O et al (1998) The role of power Doppler ultrasonography in the diagnosis of prostate cancer: a preliminary study. Br J Urol 82:386–388 Shigeno K, Igawa H, Shiina H et al (2000) The role of colour
Doppler ultrasonography in detecting prostate cancer. Br J Urol Int 86:229–233
Shinohara K, Wheeler TM, Scardino PT (1989) The appear- ance of prostate cancer on transrectal ultrasonography:
correlation of imaging and pathological examinations. J Urol 142:76–82
Sillman F, Boyce J, Fruchter R (1981) The significance of atypi- cal vessels and neovascularization in cervical neoplasia.
Am J Obstet Gynecol 139:154–159
Spencer JA, Alexander AA, Gomella L et al (1994) Ultrasound- guided four quadrant biopsy of the prostate: efficacy in the diagnosis of isoechoic cancer. Clin Radiol 49:711–714 Trojan L, Thomas D, Knoll T et al (2004) Expression of pro-
angiogenic growth factors VEGF, EGF, and bFGF and their topographical relation to neovascularisation in prostate cancer. Urol Res 32:97–103
Weaver RP, Noble MJ, Weigel JW (1991) Correlation of ultrasound guided and digitally guided directed transrectal biopsies of palpable prostatic abnormalities. J Urol 145:516–518 Weidner N, Semple JP, Welch WR, Folkman J (1991) Tumor
angiogenesis and metastasis: correlation in invasive breast carcinoma. N Engl J Med 324:1–8
Weidner N, Carroll PR, Flax J et al (1993) Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma.
Am J Pathol 142:401–409
