The method used at the Prostate Institute of America to help determine how aggressive the interventional approach should be is the comparison of actual PSA (serum PSA found in the blood) with the predictable PSA (based on the volume of the prostate gland). Through skillful use of transrectal ultrasound, an accurate measurement of the prostate gland volume allows us to calculate the predicted PSA. If the serum PSA level is lower than the predicted level, the patient is in a lower-risk group or may have low-grade/latent carcinoma.
Diving Deep into Staging
We may not rush to biopsy to make a diagnosis at this time. Watchful waiting, with periodic PSA testing, may be adequate. However, if the serum PSA level is higher than the predicted level, the patient may be at a high-risk of having a significant tumor. In these cases, a biopsy would be performed unless other reasons for a high PSA are determined.
Careful ultrasound evaluations, including black and white and color Doppler imaging, are important to identify the size and the location of a tumor. Strategic (non-random) biopsies of the abnormal tissue and of the tissues immediately outside the prostate should be obtained to assess the exact extent of the cancer.
Diagnostic accuracy is highly dependent on the skill and experience of the physician as well as the quality of equipment. Under-staging (underestimation) the disease is the single-most common cause of selecting the wrong treatment options and as a result, leads to treatment failures.
In previous studies, we reviewed 140 men with known cancer diagnosis based on biopsies performed at other institutions that stated the cancer was confined within the prostate. All of the subjects had staging biopsies repeated by our staff. The result showed 30% of these men had cancer that was already outside of the prostate confinement. In these cases, it was necessary to reconsider the treatment options and overall cancer management.
Information provided by Dr. Duke Bahn, M.D., Medical Director of the Prostate Institute of America.
Color-Doppler Ultrasound and Targeted Biopsy
Since the advent of PSA screening the rate of prostate cancer being diagnosed has more than doubled, mainly due to the indiscriminate random biopsies. Ironically though, this presents a dilemma for the patients and the clinicians. Although lives are saved by early diagnosis, many men are being diagnosed with “latent” or “insignificant” tumors that do not need treatment. Random biopsy in every man with slightly elevated PSA causes a high incidence of over-diagnosis and over-treatment. (1-3). As a result, the prevailing practice of PSA screening and subsequent biopsy has been called into question by the United States Preventive Task Force (4) which recommends that PSA testing only be offered after a careful discussion of the risks and benefits.
More precise ultrasound evaluation with color-Doppler, Tissue harmonic, and Elastography combined with targeted biopsy can provide a possible solution to the ongoing controversy about PSA screening. However, this type of enhanced imaging followed by targeted biopsy is only available in limited centers around the United States. This paper will expound the many advantages of using high-resolution color- Doppler ultrasound for the diagnosis and staging of prostate cancer.
Absolute cut-off levels for PSA are too arbitrary to apply to all men. The prostate gland volume (and therefore the PSA) changes as men age. – I use a serum PSA threshold of >2.5 ng/mL as a trigger for a concern. However, in men at high-risk (family history of prostate cancer or African American) the cut-point would be PSA > 2.0. I also use a PSA increase of 0.75 ng/mL in a year as an indication for further investigation. Once the prostate size calculated the patient’s serum PSA takes on even greater meaning. If the patient’s serum PSA (blood test PSA) is greater than the “predicted” PSA (gland volume x 0.12), he is at high-risk for cancer.
Prostate cancer tissue is histologically different from normal prostate tissue. The cancer tissue shows loss of glandular architecture, more compact in tissue density, and increased the microvascular density (hypervascularity). This difference can be visualized by ultrasound as a various degree of hypoechoic lesion (dark spot on gray scale ultrasound). Hypervascularity (increased blood flow) can only be appreciated with “Color” Doppler or contrast-enhanced Doppler evaluation. About 15% of cancers are not seen on gray scale ultrasound and only are visible on color-Doppler ultrasound.
High resolution color-Doppler ultrasound can identify tumors greater than 5mm in size. The lesions visible on ultrasound are mostly clinically significant cancers. Clinically significant cancers are often hypervascular on the color-Doppler and typically have high Gleason scores (5). Targeted biopsy of such lesions can diagnose clinically significant cancer taking fewer biopsy cores while reducing the chance of detecting clinically insignificant tumors.
Depending on tumor architecture, the degree of hypoechogenecity (darkness on gray scale ultrasound) ranges from obvious (nodular) to subtle (infiltrative) changes. It is incumbent upon 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 the lesion size, location and amount of excess PSA.
Outer gland (Peripheral Zone) cancers have a greater propensity than inner gland cancers for extracapsular spread because they can escape easily through the sites of anatomic weakness (entry of neurovascular bundle branches (NVB), seminal vesicles (SV), and apex). Fortunately, these tumors are easy to visualize because the background tissue is more homogeneous than that of inner gland tissue.
Most outer gland cancers develop in the lateral section of the prostate near the entrance of the neurovascular bundles. When targeting outer gland lesions, taking a sample from the lesion in the prostate and one from the adjacent neurovascular bundle enable us to assess the tumor extension outside the prostate (Extra Capsular Extension).
When outer gland tumors extend toward the midline, we take tissue samples from the confluence of seminal vesicle and/or trapezoid space of the apex. Hypoechoic lesions of the outer gland should be pursued vigorously because they can escape when they are relatively small.
Inner gland (Transition Zone) cancer detection is more difficult than outer gland tumors. They are usually poorly defined hypoechoic lesions. Cancers that are in the center portion of the prostate, the anterior apex and the bladder neck need to be watched carefully for possible extra-prostatic spread. Vascular evaluation with Color-Doppler is essential because most tumors larger than 1.0 cc have relatively abundant vascularity. Often, the increased blood flow may be the only clue for the presence of cancer. Recently developed Elastography can help to identify the inner gland tumor by measuring the tissue stiffness.
The biopsy protocol should include taking one sample from the center of the lesion and additional samples from the routes of possible tumor escape based on the tumor location. Random biopsy only harvests samples from the prostate. Therefore, it cannot provide the staging information of the cancer whether it is contained in the prostate or not. When a biopsy core is obtained, the rectal end of the tissue core is stained with blue ink before sending it to the laboratory. This helps the pathologist orientates the biopsy core in relation to the front and back of the prostate gland and evaluates the closeness of the cancer to the prostate capsule and the rectum.
- Where is the exact location of the tumor? Is it an inner gland or outer gland tumor? Is it in the base, mid or apical portion of the prostate?
- What is the tumor diameter in millimeters? Does the size of the lesion detected by imaging coincide with the length of cancer reported in the biopsy report by the pathologist?
- What is the Gleason grade? (If it is 7, is it 3+4 or 4+3, and the percentage of 4?)
- Is the tumor close to the neurovascular bundle (NVB) or seminal vesicle (SV), or areas of easy spread of the tumor outside of the gland, such as the apex tumor with external sphincter (ES) invasion?
- Is the tumor contained in the prostate or not (Stage T1 -2 or T3-4)?
- Is the tumor size or vascularity on sequential scanning increasing over time for men who are on active surveillance?
This information will help the physician and patients choose appropriate further staging study needed and decide on the best treatment options.
It is necessary to use a state-of-the-art ultrasound equipment for an early detection and accurate staging biopsy. Power color-Doppler ultrasound demonstrates the blood flow patterns inside of the prostate. Usually, cancer tissue shows a higher blood flow (tumor neo-vascularity) than normal tissue. Color Doppler improves the detection of the cancer and the estimation of the cancer size.
Tissue Harmonic technology improves spatial resolution to permit visualization of smaller objects and improve contrast resolution to discern very subtle differences in grayscale. This is different from conventional ultrasound imaging, which sends out a burst of ultrasound and listens for that burst to back off structures in the body (an echo that is usually weak and distorted). In Tissue Harmonic technology, instead of listening of the same sound burst to return in the echo, it listens only for a sound burst at twice the transmitted frequency.
Another new technology is Elastography. Ultrasound Elastography quantifies the stiffness of tissue during the manual or mechanical compression of the gland by the transducer (tumors have increased stiffness than background normal tissue). Target biopsy of an area of abnormal stiffness has been shown to improve cancer detection compared to the systemic biopsy with fewer tissue cores taken (6).
Contrast-Enhanced Ultrasound is another exciting technology that is in use extensively in Europe and Asia. The contrast agents are composed of tiny bubbles of injectable gas contained within a supporting shell. The gas is a strong echogenic material and the Doppler signal is greatly enhanced, particularly within areas of cancer. Contrast enhanced color-Doppler imaging will definitely improve the sensitivity of cancer detection and cancer extent. Unfortunately, it still waits for FDA approval here in the United States.
Good ultrasound evaluation with staging (targeted and strategic) biopsy may eliminate an uncomfortable and costly MRI study (that is still an imaging study without tissue confirmation). However, an MRI study can be a good complement to TRUS in selective cases.
Recently, multiparametric magnetic resonance imaging and ultrasound fusion biopsy technique has been developed. The MR images obtained before the biopsy procedure are superimposed to the ultrasound images obtained at a different setting. This fusion allows targeting suspicious lesions seen on MRI for biopsy under real-time ultrasound. As an alternative, the ultrasound experts can cognitively fuse the MRI reported areas of abnormality on the real time ultrasound image for a target biopsy (cognitive fusion biopsy). Studies have shown that clinically significant tumors can be diagnosed this way in patients who had prior negative ultrasound biopsies (7).
The Role of Ultrasound-Guided targeted and staging biopsy.
- Identification of the lesions enables proper targeted biopsy rather than blind, random systemic biopsy (Take less number of tissue core and decreased chance of complications)
- Increase the yield in cancer detection and minimize the diagnosis of “latent carcinoma”.
- Provide an accurate cancer location, volume (size), neovascularity and stage.
- Based on our published data, 26% of the stage T1-T2 (tumor contained within the prostate) cancers defined by systemic systemic biopsy were upstaged to T3-T4 (non-confined) by our staging biopsy technique (8).
- The Gleason grade was higher in staging biopsy (8-9).
- The cancer invasion in the core (by %) was higher (8-9).
- The tumor size can be measured precisely and it can be monitored objectively along with the tumor vascularity changes. It is extremely important in active surveillance management setting.
- Diagnosing unsuspected extracapsular extension of the cancer objectifies the prognosis and the choice of definitive treatment.
Understanding The Disease
Recently diagnosed cancer patients are faced with the enormous task of understanding the disease and choosing the most appropriate treatment. The cancer characteristics and staging information based on blind systemic biopsy are often “guestimations”. Today’s patients seek answers through patient advocacy groups, internet, and through scientific literature. When a patient consults with the “specialist”, he quickly surmises their uncertainty and discovers to his consternation that the ball is in his court and he alone must make the elusive three-point shot.
Using of state-of-the-art ultrasound with color-Doppler, Tissue Harmonic and Elastography helps resolve the uncertainty of whether a cancer is organ-confined. Then, and only then, can a clinical decision be made that is based on accurate staging information.
- Schroder FH, Hugosson J, Roobol MJ. Screening and prostate cancer mortality in a randomized Europeal study. N Engl J Med 2990, 360. 1320-1328
- Andriole GL, Crawford ED, Grubb RL et al. Mortality results from a randomized prostate cancer screening trial. N Engl J med 2009; 360. 1310-1319
- Ilic D, Neuberger MM, Djulbegovic M, Dahm P. Screening for prostate cancer. Cochrane Database Sys Review 2-13
- Lin K, Lipsita R, Janakiraman S. Benefits and harms of prostate specific antigen screening for prostate cancer: an evidence update for the US Preventive Services Task Force. www.Ncbi.nim.nih.gov/books/NBK43401
- Mitterberger M, Pinggera GM, Horminger W. Comparison of contrast enhanced color Doppler targeted biopsy to conventional systemic biopsy: Impact on Gleason score. J Urol 2007: 178:464-468.
- Pallwein L. Mitterberger M, Struve R. Comparison of sonoelastography guided biopsy with systematic biopsy: Impact on prostate cancer detection. Eur Radiol 2007; 2278-2285
- Vourganti S, Rastinehad A, Yerran N, et al. Multiparametric magnatic resonance imaging and ultrasound fusion biopsy detect prostate cancer in patients with prior negative transtectal ultrasound biopsies. J Urol 2012: 188: 2152-2157
- Lee F. Bahn D. The role of TRUS-guided staging biopsies for the determination of internal and external spread of prostate cancer. Seminars in Urologic Oncology 1998:129-136
- Ukimura O, de Castro Abreu, Bahn D. et al. Image-visibility of cancer to enhance targeting precision and spatial mapping biopsy for focal therapy of prostate cancer. BJUI 2013; 111: E354-364
Information provided by Dr. Duke Bahn, M.D., Medical Director of the Prostate Institute of America.