Color Doppler and Tissue Harmonic Ultrasound in the Early Detection and Staging of Prostate Cancer
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Duke K. Bahn, M.D., Prostate Institute of America
Reprinted from PCRI Insights November 2002 v5.2

 

Transrectal ultrasound (TRUS) imaging has long been an essential tool for prostate cancer (PC) diagnosis. In fact, the combination of prostate specific antigen (PSA) testing with TRUS and digital rectal examination (DRE) has been responsible for diagnosing most prostate cancers in the U.S. each year. Actually, early detection and early intervention of progressive PC may help to reduce the 30,000 prostate cancer-related deaths each year.

Over the years, increases in the reported incidence of PC have been disproportionate to the changes in population demographics. The main reason for this rapid rise may be the easy access to PSA and subsequent ultrasound guided biopsies (random biopsy). Ironically though, this presents a dilemma for the patients and the clinicians. Although saving the lives of many men, some men may have so-called “latent” or “insignificant” tumors that may not need any treatment. Precise ultrasound evaluation with proper biopsy will provide us with valuable information to make a decision between watchful waiting and appropriate early intervention.

Gland Volume and Diagnosis

There is much debate about how to use the diagnostic tools that we have – DRE, diagnostic PSA levels, PSA in relation to age, and gland volume – for early detection of PC. In our practice, a serum PSA > 3ng/ml, a PSA increase of 1ng/ml in a year, or abnormal DRE are the indications for TRUS. If a man’s serum PSA is greater than the predicted PSA (gland volume x 0.12), he is in a “high-risk” group for cancer. This group is subjected to careful ultrasound evaluation.

Making the Decision to Biopsy

• Determine the gland volume with TRUS measurements: Gland Volume =
[width (w) x height (h) x length (l) x 0.5]

• Predicted PSA = gland volume x 0.12

• Excess PSA = serum PSA – predicted PSA

• Expected tumor volume = excess PSA/2 (1 cm3 of cancer produces near 2 ng/ml of PSA)

• To determine average tumor dimension (w + h + l)/3, use the cube root of expected tumor volume.

• Then search for a hypoechoic lesion of this size.

Sonographic Evaluation

Because clinically relevant (>0.5 cm3) PC is nearly always hypoechoic (black on ultrasound) compared with normal prostate tissue, we only biopsy lesions that are visible by ultrasound.

Depending on tumor architecture, the degree of hypoechogenicity (darkness on ultrasound) ranges from obvious (nodular) to subtle (infiltrative) changes. Thus, it is incumbent on the physician performing the examination to be familiar with the zonal anatomy and morphologic presentation of prostate cancer.

Cancers in the outer gland (peripheral zone and central zone) and inner gland (transition zone) have different sonographic appearances and biologic behavior, and our threshold that defines whether to biopsy varies depending on lesion size, location, and amount of excess PSA.

Sites of Anatomic Weakness - Inner and Outer Gland

Outer Gland Cancers

Outer gland cancers have a greater propensity than inner gland cancers for extracapsular spread because they can escape easily through the area of anatomic weakness (entry of neurovascular bundle branches, seminal vesicles, and apex). Fortunately, these tumors are easy to visualize because the background tissue is more homogeneous than that of the inner gland. Most outer gland cancers originate laterally at the entrance of the neurovascular bundles. To visualize and sample this area, we have found it best to perform the scanning and biopsy in the transverse plane. When targeting outer gland lesions, we first biopsy the lesion and then sample the accompanying neurovascular branches tangentially along a plane just external to the prostatic capsule. A finding of a tumor intermixed with fat definitively diagnoses histologic stage T3 cancer.

When outer gland tumors extend to the midline, we perform a biopsy of the confluence of the seminal vesicle and trapezoid space of the apex. The base and apex of the gland in this area are always biopsied to aid in the evaluation of the internal spread of cancer.

Hypoechoic lesions of the outer gland should be pursued vigorously because they can escape when they are relatively small. For this reason, we generally perform a biopsy of the lesions we see on the ultrasound when excess PSA suggests that a 1cm3 lesion may be present (excess PSA greater 2 ng/ml).

If we do not find lesions in the outer gland by ultrasound, we generally do not perform random biopsies. At this point, we shift our attention to the inner gland (transition zone).

Inner Gland Cancers

TRUS can detect cancers in the inner gland, though its sensitivity is less than that for the outer gland. If the excess PSA is 4 to 6 ng/ml and no lesion is found in the outer gland, one must carefully scan the inner gland for a homogeneous, poorly defined hypoechoic lesion. We focus on the sites of anatomic weakness of the inner gland, the anterior apex and the bladder neck. Color-flow Doppler and (lately) Tissue Harmonic aid in the diagnosis of these more difficult-to-see inner gland cancers because most tumors larger than 1 cm3 have neovascularity (abundant vessel inside of tumor) that is easily identifiable with these new technologies. Given the confusing heterogeneous nature of the transition zone, color-flow may be the only clue for the presence of cancer in a subtle hypoechoic lesion.

Subtle Lesion Viewed In Gray Scale and Color Doppler

For the inner gland, we take a watchful waiting approach when (1) gland volume is greater than 50 cm3, (2) no suspicious lesion of the anterior apex or bladder neck area is seen, (3) excess PSA is less than 4 to 6 ng/ml, and (4) there is no outer gland lesion. In general, inner gland cancers have less aggressive prognostic factors (Gleason score and DNA ploidy) than outer gland cancers and tend to be confined until they attain very large volumes. Therefore, we feel that these cancers do not need to be pursued as aggressively as outer gland cancers. To ensure that we have not overlooked a significant tumor, we repeat serum PSA testing at 4- to 6-month intervals. Should an upward trend continue, we re-ultrasound.

Staging Biopsy Technique

The biopsy samples should include one sample from the middle of the lesion, and all routes of possible tumor escape based on known sites of anatomic weakness. The positive neurovascular bundle biopsy has to include fat cells in contact with tumor cells or the invaded nerve sheath; a seminal vesicle biopsy should include pigmented epithelium (specific cell layer of seminal vesicle). Because the prostate gland does not contain fat, the presence of this tissue in the specimen confirms an extraprostatic invasion. We stain the rectal end of the tissue core with blue ink before sending it to the laboratory. This will allow us to determine the exact location of the tumor – an inked end signifies an outer gland (peripheral zone) tumor and a non-inked end tumor indicates an inner gland tumor (transition zone).

USING TRUS in PC
Staging and Diagnosis

• Measure gland volume.

• Determine predicted PSA. This forms our high-risk group.

• Search for hypoechoic lesion in the outer gland that has a lateral location.

• Transverse imaging and biopsy of these lesions is most precise. Biopsy of the seminal vesicle and apex should be done when the lesion extends to the midline.

• Suspect inner gland transition zone lesions when the excess PSA is 4 to 6 ng/ml and the outer gland is normal.

• Color-flow Doppler is especially important for evaluation of the inner gland.

Information (Risk Factors) Needed
from TRUS and Staging Biopsy

    • What is the exact location of the tumor? Is it an inner gland or outer gland tumor?
    • What is the tumor size in the core by millimeters and the dimension of the lesion on TRUS?
    • What is the Gleason grade? (If it is 7, what percentage is 4?)
    • Is there a presence of perineural invasion (PC invading the nerve sheath within the prostate)?
    • Is the tumor contained in the prostate or not (T1-2 or T3-4)?
    • What is the ploidy of the tumor?

This information will provide the exact local staging of the cancer and will thereby help the physician and patient choose appropriate a further staging work-up and decide on eventual treatment options.

State-of-the-Art Ultrasound Equipment

It is important to use a high-end up-to-date ultrasound unit for an early detection and accurate staging biopsy. Power Color Doppler ultrasound demonstrates all the blood flow patterns inside the prostate. Usually, cancer tissue shows a higher blood flow (tumor neovascularity) than that of normal tissue. This capability will improve detection and actual tumor size measurement.

The newly developed Tissue Harmonic technology improves spatial resolution to permit visualization of smaller objects and improves contrast resolution to discern very subtle differences in grayscale. This is different from conventional ultrasound imaging, which sends out a burst of sound and listens for that burst to echo off structures in the body, (an echo that is usually weak and distorted). The time it takes for the echo to return is proportional to the distance the sound wave traveled. In Tissue Harmonic technology, instead of listening for the same sound burst to return in the echo, the ultrasound equipment listens only for a sound burst at twice the transmitted frequency. Good ultrasound evaluation with staging (strategic) biopsy may eliminate an unnecessary endorectal MRI study (that is still an imaging study without tissue confirmation). Moreover, it will eliminate the “guesstimation” from random biopsies. Currently, we use the Hitachi EUB-6500 Ultrasound model. Soon, there will be further developments in TRUS that will include contrast (IV form of micro-bubbles), enhanced Color Doppler, and three-dimensional imaging capability.

The Role of TRUS-Guided (Not Random) Biopsies in Determining the Internal and External Spread of PC

Dr. Fred Lee and I published our data comparing sextant (random) biopsy proven PC data with our staging biopsy data on 110 men. All men came to us for a second opinion with known cancer. We performed TRUS with repeat staging biopsies on all of those men. (Seminars in Urologic Oncology, Vol 16, 1998, p 129-136.)

The results were as follows:

    • 26% of the Stage T1-T2 (tumor confined within the prostate) cancers defined by sextant biopsy were upstaged to T3-T4 (non-confined) by our staging biopsy technique.
    • The Gleason sum was also higher in our staging biopsies.
    • Perineural invasion was demonstrated in 52% of staging biopsies compared to 21% in sextant biopsies.
    • Diagnosing unsuspected extracapsular extension and perineural invasion objectifies the choice of definitive treatment.

Conclusion

Current methods for determining confined PC for the individual patient are only guesstimations. The pathological outcomes for clinically confined PC have only a 50% probability of being correct. Today’s patients seek answers through patient advocacy groups, Internet surfing, and scientific literature. When one of our patients consults with the “specialists”, he quickly surmises their uncertainty. In our hands, the use of state-of-the-art TRUS with Color Doppler and Tissue Harmonic has helped us and others resolve the uncertainty of whether a cancer is or is not confined and what other risk factors they may have. Then, and only then, do we more reliably predict a prognosis and guide our patients to those treatments that are most appropriate for them.

References

McNeal J: Cancer volume and site of origin of adenocarcinoma in the prostate: Relationship to local and distant spread. Hum Pathol 23:258-266, 1992

Lee F: Prostate cancer: Transrectal ultrasound and pathology comparison. Cancer 67:1132-1142, 1991

Epstein J. Corellation of prostate cancer nuclear deoxyribonucleic acid, size, shape and gleason grade with pathological stage at radical prostatectomy. J Urol: 148:87-91, 1992

Bostwick D. Optimized microvessel density analysis improves prediction of cancer stage from prostate needle biopsies. Urology 48: 47-57, 1996

Lee F. Bahn D. The role of TRUS-guided biopsies for determination of internal and external spread of prostate cancer. Seminars in Uro Oncology 16: 129-136, 1998