Transrectal Ultrasonography and Ultrasound-Guided Biopsies of the Prostate Gland: How, When, and Where

Athanasios Papatheodorou, MD,a Panagiotis Ellinas, MD,a Savvas Tandeles, MD,a Fotios Takis, MD,a Hercules Poulias, MD,b Irene Nikolaou, MD,c and Nikolaos Batakis, MD, PhDa

Transrectal ultrasound (TRUS) has revolutionized prostate biopsy technique and plays a central part in diagnosis of prostate cancer. Nevertheless TRUS is an inherently operator-dependent modality and its performance varies significantly due to equipment quality. Thus it is of great importance to the detailed knowledge of the complex 3D prostate anatomy, the integrated scanning procedure, the evaluation of every zone for chronic or suspicious change, and the performance of ultrasound-guided biopsies.1

Anatomy
The prostate is an exocrine gland lying just below the bladder neck and surrounding the urethra. Superolaterally to it lay the seminal vesicles and the vas deferens. The lateral venous plexus intermixed with arteries and nerves comprise the neurovascular bundles that pass from above to below along the posterolateral aspects of the prostate, piercing the capsule. Vessels, connective tissue, and fat surround the prostate. Histologically the prostate is composed of four zones: anterior fibromuscular stroma, periurethral transition zone (TZ), posterior peripheral zone (PZ), and posterosuperior central zone (CZ).
From the aRadiology Department, Hellenic Red Cross Hospital, Athens, Greece; bUrology Department, Hellenic Red Cross Hospital, Athens, Greece; and cHistopathology Department, Hellenic Red Cross Hospital, Athens, Greece. Reprint requests: Athanasios Papatheodorou, MD, Radiology Department, Hellenic Red Cross Hospital, 19 Sigrou Street, GR-151 26 Marousi, Greece. E-mail: athpapatheodorou@yahoo.gr. Curr Probl Diagn Radiol 2005;34:76-83. © 2005 Elsevier Inc. All rights reserved. 0363-0188/2005/$30.00 0 doi:10.1067/j.cpradiol.2004.12.003

Since the majority of patients referred for TRUS examination are middle aged or older, almost all of them have a hyperplastic transition zone. Peripheral and central zones are usually thin and compressed in a posterolateral position. This process is described as benign prostatic hyperplasia (BPH).2 The previously described middle lobe consists of part of the transition zone that protrudes in the urinary bladder base. Anteriorly lying fibromuscular stroma is nonglandular tissue. Virtually all BPH arise in the transitional zone. Seventy percent of adenocarcinomas arise in the peripheral zone, 20% arise in the transitional zone, and 10% arise within the central zone.2

TRUS Technique
The main workload of TRUS evaluation comprises patients with abnormal digital rectal examination (DRE) and/or elevated prostatic-specific antigen (PSA) levels that are candidates for ultrasound-guided biopsy. Infertility, clinical suspicion of acute or chronic prostatitis, and prostate abscess drainage are also indications for TRUS. When the patient arrives in the ultrasound department, every effort should be made to reassure him and explain to him the various steps of the procedure. An informed consent form is obtained. Urinary bladder should not be empty, to create a clear interface with prostate superior margin. The patient is placed in a right lateral decubitus position and a DRE is performed. If biopsy is considered, a needle guide should be secured on the transducer in advance. Then the patient is turned to a left lateral decubitus position and

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a broad bandwidth transducer of 5 to 7 MHz is inserted in the rectum (Fig 1). The patient is instructed to take a deep breath and relax to facilitate transducer’s insertion into the rectum. Some patients with hemorrhoids complain of anal discomfort. The entire gland is examined and every abnormality should be imaged in both axial and sagittal planes.3 The gland volume is measured using the formula: 0.52 W L H. The width is easily defined on axial scanning. The length is measured in the midline sagittal plane and is the distance between bladder neck and the apex of the gland. The height is measured perpendicularly to the length measurement (Fig 2). Consequently grayscale axial scanning is performed from apex to base including the seminal vesicles. Care should be taken that all parts of the prostate and periprostatic tissues are sufficiently scanned (especially fat planes in apical region, and middle lobe in large glands). Grayscale sagittal scanning is then performed from left to right. Color Doppler interrogation is performed in the axial plane from apex to base. The mode could be either color or Power Doppler and the color window must cover the entire gland. Every suspicious hypoechoic or hypervascular area is examined both in comparison to the opposite side and independently in the center of the image. Some authors warn that a lateral decubitus position of the patient could increase the color Doppler flow detected in the dependent part of the gland.4 Finally, biopsies are performed. After the procedure, the patient is given detailed written instructions. TRUS as well as TRUSguided biopsy are performed in an outpatient setting.

Findings
While 8 to 10% of men have histologic evidence of BPH by their 40s, almost 90% demonstrate it by the age of 90. In men with BPH, the transition zone is enlarged sometimes asymmetrically. Middle lobe may protrude in the urinary bladder. TZ appears hypoechoic with a heterogeneous nodular pattern, while PZ and CZ are compressed and distorted. TZ nodules may be hypo-, iso-, or hyperechoic compared with the surrounding PZ. Hyperechoic foci without acoustic shadowing usually coexist. Some patients do not exhibit discrete nodular pattern. There is also increased incidence of small cysts in TZ (Fig 3). Color Doppler findings are unremarkable.3,5 Chronic prostatitis is demonstrated as TZ inhomogeneity with dystrophic calcifications. Color Doppler

interrogation is usually normal. Frequently chronic prostatitis is a histological finding and TRUS does not provide important information.5 Chronic granulomatous prostatitis is generally presented as a very hypoechoic nodular area with clear margins. Periprostatic fat planes are intact and color Doppler interrogation is normal3 (Fig 4). Prostate abscess and hematoma are rare pathologic entities. Predisposing factors are diabetes, previous TRUS with biopsy, and hemorrhagic disorders. Abscess appears as a hypoechoic area within the gland with indistinct margins. The gland is sometimes enlarged and color Doppler shows hypervascularity in adjacent parts of prostate. Hematoma shows ill-defined borders and color Doppler flow is not increased (Fig 5). Prostate cancer is the most common noncutaneous cancer diagnosed in American men. In 2003 approximately 220,900 men were diagnosed with this cancer and 28,900 have died from it in the United States alone.6,7 Acinar prostatic adenocarcinoma constitutes 95% of all malignant prostatic neoplasms. Eighty percent of cancers occur in the peripheral and central zone. TRUS imaging has no role in early detection of confined prostate cancer, beyond biopsy guidance and tumor staging. Small cancers appear as hypoechoic areas in the peripheral zone.8 Differential diagnosis for hypoechoic areas in the peripheral zone is prostatic atrophy, prostatitis, granulomatous prostatitis, lymphoma, and ductal ectasia. Cancer may appear as focal nodule (30%), nodule with infiltrative component (50%), and predominantly infiltrative pattern (20%)5 (Fig 6A). Prostate cancer may also be multifocal. As neoplasms enlarge, they tend to become isoechoic. Rarely tumors may appear hyperechoic. Any focal area in the peripheral zone should be evaluated by Doppler interrogation. Normal blood flow is normally detected in periurethral and pericapsular areas.8 Typically an area of cancer demonstrates hypervascularity (Fig 6B). Hypervascular areas may exist independently of the grayscale hypoechoic areas. Also not all tumors demonstrate increased vascularity. Current imaging technology is unable to detect very slow flow and demonstrate neovascularity associated with tumors.3,8 The prostatic contour is a very important landmark in the evaluation of extracapsular extension (ECE) of prostate cancer, especially near the superior and inferior neurovascular bundles. An irregular capsular

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son tumor grading system is the most widespread one. Gleason score is the sum of a primary and a secondary grade (each one ranging from 1 to 5), thus ranging from 2 to 10. The pathologist assigns the first grade to the most commonly observed cancer pattern in biopsy specimens and the second grade to the second pattern.9

Ultrasound Microbubble Contrast Agents (USCA)
The potential role of USCA in the detection of prostate cancer is currently being investigated. There are reports that after the IV administration of either first- or better second-generation USCA, the sensitivity of TRUS for cancer detection may be improved, because tumors show enhancement.5,14,15 Such application of USCA requires that the ultrasound equipment have harmonic capabilities and USCA application software. Nonetheless areas of BPH can also demonstrate enhancement and small, low Gleason score tumors may demonstrate no enhancement.16 A simple application that requires no special equipment is the IV bolus injection of a USCA that results in a substantial increase of color Doppler signal intensity of prostatic vasculature.

FIG 1. The patient assumes left lateral decubitus position and the transrectal transducer is inserted in the rectum. (Simulated examination.) (Color version of figure is available online.)

bulge and/or tumor extension into the periprostatic fat demonstrated as hypoechoic strands are signs of ECE (Fig 7). Seminal vesicle (SV) invasion is suggested by soft-tissue echogenicity and loss of normal SV “beak” at prostatic base in sagittal image.9 Five percent (5%) of all prostatic malignancies are rare variants such as comedocarcinoma, mucinous adenocarcinoma, squamous cell and signet-ring carcinomas, neuroendocrine neoplasms, sarcomas, and metastatic neoplasms.10,11 Comedocarcinoma appears as multiple hyperechoic lesions within a larger hypoechoic area.5 Sarcomas are usually large infiltrating tumors. Lymphomas tend to appear as large hypoechoic areas within the prostate and sometimes beyond its confines.8 There is limited literature concerning the imaging characteristics of TZ cancers.12,13 No specific sonographic characteristics have been reported and further investigation is needed in this area. Currently TZ cancers are found only by systematic biopsies (Fig 8). Two general rules apply: a normal-appearing gland does not exclude the presence of cancer and every hypoechoic hypervascular peripheral zone lesion is not necessarily cancer. Tumor grade describes the metastatic and invasive potential in prostate cancer. Glea-

Ultrasound-Guided Biopsies
The main contribution of TRUS in prostate cancer diagnosis is to guide systematic biopsies of the gland. The superiority of TRUS versus digitally guided prostate biopsies has been well demonstrated.17

Indications for First Biopsies
TRUS-guided biopsies are performed on patients over age 50, when DRE is abnormal (presence of induration, palpable nodule, asymmetry) and/or serum PSA is more than 4 ng/mL.18 The presence of suspicious TRUS findings is also an indication for biopsy (hypoechoic or hypervascular peripheral zone nodule). For younger patients (age 40 to 49) the PSA decision level is 2.5 ng/mL.3 There are several risk factors for prostate cancer that have to be taken into consideration when biopsy is considered,3,5,18 as follows: ● A positive family history (father, grandfather, brother, uncle with prostate cancer) ● Black race ● PSA refinements such as PSA velocity and free PSA/total PSA ratio.

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FIG 3. Grayscale axial image, middle. BPH. TZ is enlarged with nodular heterogeneous pattern. Middle lobe protrudes in the bladder. There are also small cystic formations.

FIG 2. (A) Grayscale axial image, middle. Width measurement. Enlarged prostate due to BPH. (B) Same patient. Grayscale sagittal image, midline. Length and height measurement.

FIG 4. Grayscale axial image, middle. There is a hypoechoic area in the left lateral PZ. Power Doppler showed no increased vascularity. Biopsy demonstrated chronic granulomatous prostatitis.

An increase of PSA more than 0.75 to 1 ng/mL/year (PSA velocity) is a risk parameter. At least three PSA measurements over a 2-year period are required. A lower fraction of unbound or free PSA is seen more frequently in cancer patients than in BPH patients. The decision level is when the free PSA/total PSA ratio is less than 25%. Other PSA refinements such as PSA density, complexed PSA,19 and ultrasensitive PSA are under clinical trials and further assessment. Therefore, younger patients (age 40 to 49) with some risk factors (increased PSA velocity or low free/total PSA ratio, etc.) may be considered as candidates for early first biopsy. Older patients with intermediate PSA (4 to 10 ng/mL) with low risk profile

(normal free/total PSA ratio, normal PSA velocity, no family history, advanced age) may decide on a more conservative follow-up with PSA measurements or to repeat TRUS rather than immediate biopsy.3

Preparation
A written information and consent form is given to all patients scheduled for prostate biopsy. A detailed clinical history is a must. Any medication that alters bleeding time and blood clotting should be discontinued 10 days before the biopsy. Aspirin in small doses is not considered a contraindication. A recent international normalized ratio (INR) count is asked as well as all previous PSA counts. A secondgeneration quinolone antibiotic is prescribed twice

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FIG 5. Grayscale axial image, middle. Large hypoechoic avascular area with the prostate. Prostatic hematoma.

daily for 3 days, the first oral dose given the morning before the biopsy day. The evening before the biopsy, patients are asked to administer a low bowel enema and to have bowel movement. Bisacodyl rectal preparation is an alternative.20 Usually TRUS-guided biopsies are well tolerated with minimal pain reported by the patients,21 with spring-driven biopsy devices contributing to this. Younger patients tend to report more often mild-to-severe discomfort or pain. If an extended biopsy protocol is considered, the infiltration of 2 mL of 2% lidocaine around neurovascular bundles using a 20-cm-long needle under TRUS guidance eliminates pain.22 An 18-gauge 20-cm-long biopsy needle (22- to 25-cm-long in large glands) is used. The right lobe is biopsied first; then the transducer is turned upside down and the left lobe is also biopsied. Biopsies are performed in the axial plane. All specimens are individually labeled, placed in a 10% formalin solution, and sent to the histopathology department.

FIG 6. (A) Grayscale axial image, apex. There is a hypoechoic area in the left PZ. (B) Color Doppler, axial image, apex. There is increased vascularity in left PZ. Biopsy: adenocarcinoma with Gleason score 7 (4 3) infiltrating left PZ and TZ. (Color version of figure is available online.)

Sites/Protocols
Sextant biopsies (specimens from each prostatic sextant from right and left lobes at the level of apex, middle, and base) have been shown to be inadequate for prostate cancer detection.8,23 Targeted-only biopsies also miss a substantial number of cancers.24,25 A modified sextant protocol, consisting of the classic sextant biopsies with additional biopsies obtained from the lateral aspect of the peripheral zone at the base and mid gland (10 biopsies),

reported increased cancer detection rate.26,27 Currently, various extended field biopsy protocols are suggested. They combine laterally directed biopsies, which sample the lateral aspects of the PZ with posteromedial biopsies of the PZ. Midline biopsies of the PZ are not widely accepted yet.28 All these biopsies are performed in three levels (apex, mid level, base) or four levels in large glands (a total number of 15 to 20 biopsies). Additional biopsies may be performed at seminal vesicles. Some protocols recommend as many as 30 biopsies per patient. TZ biopsies are not recommended for the initial biopsy work-up due to their low yield of cancers. However, they are useful in patients with persis-

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FIG 8. Grayscale, axial image, middle. Markedly enlarged and inhomogeneous TZ. Biopsy: there is an adenocarcinoma with Gleason score 4 (2 2) well differentiated in the left TZ. PZ and right TZ have no indication of cancer.

We regularly perform TZ biopsies, although primary TZ cancers are rare because we often find TZ infiltration in middle to high Gleason score PZ cancers.

Complications and Treatment
TRUS-guided biopsies are considered safe and can be performed in the outpatient setting. Minor complications such as perineal pain, transient mild hematuria, hematospermia, and rectal bleeding are relatively frequent and self-limiting. Severe complications such as urinary retention and infection, severe rectal bleeding or hematuria, prostate infection, or abscess with fever/sepsis are very rare (less than 1%) if patients comply with the given instructions. Massive rectal hemorrhage may occur for up to 4 days after the biopsy. Although direct digital compression is useful for immediate postprocedure bleeding control, endoscopy with Foley balloon tamponade, coaptive coagulation, and epinephrine injection are very successful in attaining hemostasis.30 Urinary retention requires Foley catheterization. Infection is managed with IV antibiotic administration and hospitalization. A written information form with the possible complications is given to the patients after the procedure. They are advised to stay at home at least for 1 day, to increase fluid intake, and to abstain from alcohol and sexual activity for 2 weeks.

FIG 7. (A) Grayscale, axial image, middle. There is a hypoechoic area in the left PZ. (B) Grayscale sagittal image, middle. There is a hypoechoic area occupying the left PZ from base to apex. Fat around apex is hypoechoic, indicating ECE. Biopsy: adenocarcinoma with Gleason score 8 (4 4) with ECE.

tently elevated PSA and negative initial biopsy work-up.28,29 The authors perform a version of extended field protocol consisting of: Laterally directed PZ biopsies. Medially directed peripheral and transition zone biopsies in three levels (a total of 12 biopsies) (Fig 9). If the prostate gland is larger than 60 mL, an additional level with another four biopsies is added. Also, if there are suspicious focal findings in PZ or in seminal vesicles, additional targeted biopsies are performed.

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FIG 9. (A) 3D image of prostate gland with medium BPH. Three (3) axial biopsy levels at base, middle, and apex. (B) Axial image, base. Lateral and medial biopsies. PZ red, TZ purple, fibromuscular stroma yellow. (C) Axial image, middle. Lateral and medial biopsies. (D) Axial image, apex. Lateral and medial biopsies.

In the case of a severe complication, patients are instructed to seek professional medical help on an emergency basis.

Repeat Biopsies
In the case of a negative initial biopsy, a repeat biopsy should be performed: ● In patients with persistently elevated PSA 4 ng/mL. ● In patients with a high-grade PIN (prostate intraepithelial neoplasia) found in the first biopsies. PIN is a histopathologic entity at the precancerous cellular borderline. There are low-grade and high-grade PIN, with the high grade being an indication for patient follow-up with a repeat biopsy.31 ● In patients with increased prostate volume more than 60 mL.

● In patients with risk factors such as family history of prostate cancer, black race, free/total PSA ratio less than 25%, and PSA velocity more than 0.75 to 1 ng/mL/year. The interval between initial and repeat biopsy is between 6 and 12 months.32–34 Repeat biopsy technique should direct needles to a more apico-dorsal location and transition zone biopsies should always be performed. Although a second prostate biopsy is justified when indications apply and prostate cancer is found in 10% of biopsies, third repeat biopsy should be spared for selected patients since they tend to detect rare cancers (5%) with low grade and stage.

Summary
TRUS- and ultrasound-guided biopsies of the prostate gland have become a valuable tool in the detection and

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management of prostate cancer and other benign prostatic pathology. Detailed knowledge of prostatic anatomy, TRUS examination technique, the various imaging findings, as well as the biopsy technique contribute to improved treatment planning and therapeutic outcome.

REFERENCES
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17. Rifkin MD, Alexander AA, Pisarchick J, et al. Palpable masses in the prostate: superior accuracy of US-guided biopsy compared with accuracy of digitally guided biopsy. Radiology 1991;179:41-2. 18. Partin WA, Stutzman ER. Elevated prostate-specific antigen, abnormal prostate evaluation on digital rectal examination and transrectal ultrasound and prostate biopsy. Urol Clin North Am 1998;25:581-9. 19. Okihara K, Fritsche AH, Ayala A, et al. Can complexed prostate specific antigen and prostatic volume enhance prostate cancer detection in men with total PSA between 2.5 and 4.0 ng/ml. J Urol 2001;165:1930-6. 20. Jeon SS, Woo SH, Hyun JH, et al. Bisacodyl rectal preparation can decrease infectious complications of transrectal ultrasound guided prostate biopsy. Urology 2003;62:461-6. 21. Bastide C. Tolerance of pain during transrectal ultrasoundguided biopsy of the prostate: risk factors. Pr Cancer Prostatic Dis 2003;6:239-41. 22. Bulbul MA. Periprostatic infiltration with local anesthesia during TRUS guided prostate biopsy is safe, simple and effective: a pilot study. Clin Imaging 2002;26:129-32. 23. Basillote JB. Influence of prostate volume in the detection of prostate cancer. Urology 2003;61:167-71. 24. Kuligowska E, Barish MA, Fenlon HM, et al. Predictors of prostate carcinoma: accuracy of grayscale and Doppler US and serum markers. Radiology 2001;220:757-64. 25. Halpern JE, Frauscher F, Strup ES, et al. Prostate: highfrequency Doppler US imaging for cancer detection. Radiology 2002;225:71-7. 26. Presti CJ. Prostate cancer: assessment of risk using digital rectal examination, tumor grade, prostate-specific antigen and systematic biopsy. Radiol Clin North Am 2000;38:49-58. 27. Purohit SR, Shinohara K, Meng VM, et al. Imaging clinically localized prostate cancer. Urol Clin North Am 2003; 30:279-93. 28. Terris KM. Prostate biopsy strategies: past present and future. Urol Clin North Am 2002;29:205-12. 29. Djavan B, Remzi M, Marberger M. When to biopsy and when to stop biopsying. Urol Clin North Am 2003;30:253-62. 30. Kinney PT, Kozarek AR, Ylvisaker TJ, et al. Endoscopic evaluation and treatment of rectal hemorrhage after prostate biopsy. Gastrointest Endosc 2001;53:117-9. 31. Iczokowski AK, Bostwick GD. Prostate biopsy interpretation. Current concepts 1999. Urol Clin North Am 1999;26:435-52. 32. Leventis KA, Shahrokh FS, Kevin MS. Local recurrence after radical prostatectomy: correlation of US features with prostatic fossa biopsy findings. Radiology 2001;219:432-9. 33. Swindle WP, Kattan WM, Scardino TP. Markers and meaning of primary treatment failure. Urol Clin North Am 2003;30: 377-401. 34. Nudell MD, Wefer EA, Hricak H, et al. Imaging for recurrent prostate cancer. Radiol Clin North Am 2000;38:213-29.

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