**3. Methods of biopsy**

108 Prostate Cancer – Diagnostic and Therapeutic Advances

with risk calculators availability. Using single PSA cutoff value would be the same as claiming for a man, who runs marathon, has normal blood pressure, normal BMI, is a non-smoker, his parents lived till age 100 and has cholesterol of 5.3 mmol/L – to be at high risk for cardiac event because his cholesterol is elevated (above 5.2). Using single PSA value for biopsy decision would be the same as claiming for an overweight (BMI 30), sedentary man, heavy smoker, on three anti-hypertensive medications whose parents both died of cardiac event, because his cholesterol is 5.1 mmol/L (just normal) – not to be at risk for cardiac event. Everyone can clearly see ridiculosity, absurdity of such approach in cardiology – but we in urology use PSA as single dichotomous variable in our prostate biopsy decisions?! Risk calculators allow us to tell men with any PSA value their individual chances for biopsy outcome. Calculators report risk for high grade (Gleason 7 or more) and overall cancer probability. For example if calculator predicts 6% chance of significant prostate cancer (Gleason 7 or more) and 26% of overall cancer risk, we should tell patient his chance of being without cancer at present is approximately 74% (100-26), he has 6% chance of finding important high risk cancer and he has approximately 20% (26-6) chance biopsy would find cancer which may not be clinically important at present (but maybe in the future) and we would have to deal with this. If we explain this way, most men can and do take their own decision, whatever it is (to proceed with biopsy or

Using risk calculators often surprises us with values one would not expect. For example use Sunnybroke Prostate risk calculator (see below) and take 75 years old healthy Caucasian male with PSA of 3.9, %free PSA 22%, IPSS 9, in a good health (for example upper 25% of his generation), no family history for prostate cancer and negative DRE. He has more than 15 years of life expectancy, 39% risk of prostate cancer and 20% risk of having at present high grade prostate cancer (Gleason 7 or more). 20% risk of high grade cancer and more than 15

At present (june 2011), one of the most modern (can take into account PCA3, p2PSA...) prebiopsy nomograms is available from UT Health Science Center, San Antonio, head Ian Thompson (http://deb.uthscsa.edu/URORiskCalc/Pages/calcs.jsp). Opponents of his calculator state it has good estimation of overall cancer risk, but underestimates high risk cancers. Large urology collection of nomograms, also many pre-biopsy nomograms including estimation of biopsy risks, are available from Pierre Karakiewicz, Cancer Prognostics and Health Outcomes Unit from University of Montreal Health Centre, Canada (www.nomograms.org). Calculators derived from European Randomized study of Screening for Prostate Cancer (Fritz Schroeder) are available at SWOP Prostate Cancer Research Fundation: http://www.prostatecancer-riskcalculator.com/via.html. Useful, simple and modern (more accurate high risk cancers estimation) pre-biopsy nomogram is available from SunnyBrook Health Sciences Centre, Toronto: http://sunnybrook.ca/

Different nonograms, for example taking into account 3D biopsy approach (Sakura et al., 2011) are being developed and published constantly. Also, comparisons (Oliveira et al., 2011) and evaluations (Ngo et al., 2011) are permanently performed and published. When

NCCN guidelines on prostate cancer early detection not require nomogram use, follow in part risk adapted approach, cover most "before biopsy" issues, are regularly updated and

using nomograms, one should be aware of their limitations (Vickers & Cronin, 2010).

modern. They are available freely after registration from www.nccn.org.

continue PSA follow up).

content/?page=OCC\_prostateCalc.

years of life expectancy - would you suggest a biopsy?

Prostate cancer was in the past diagnosed most often using histology from transurethral resection, which was performed for local complications of prostate cancer or merely BPH. As it became clear such diagnosis is most often too late, makes subsequent radical surgical treatment more difficult and as PSA become available, biopsy had become diagnostic method of choice. At first, it was finger guided, blind. With development of transrectal ultrasound (trus – transrectal ultrasound guided prostate biopsy) and coupling it to 18G needle, Pandora box of prostate cancer was opened.

#### **3.1 Transrectal or transperineal approach?**

Most prostate biopsies around the world are performed transrectally, as this naturally developed from transrectal finger guided approach, is cheaper, simpler, does not need any analgesia or anaesthesia (although it is highly recommended, see section 4.3). Transperineal approach does need at least local anaesthesia. On same occasions, like post surgical amputation of the rectum, if it is sutured, transperineal biopsy (or transgluteal) may be the only way. However, such biopsy is guided by US probe on the perineum or in the urethra or more often by CT or MRI, which is not the way transperineal biopsy is performed regularly. Regular transperineal biopsy is performed using probe in the rectum and needle is advanced through the skin above rectal opening. Transperineal approach has similarity with the way some treatments are performed (brachytherapy...). Treatment templates may be used for biopsy which may guide biopsy needle to a specific part of prostate, which is seen as potentially more effective and with better gain. Recently, stereotactic templates (even motorized and computer guided) have become available also for transrectal prostate sampling – mechanically assisted 3D TRUS guided biopsy system (Megwalu et al., 2008). Supporters of transperineal approach suggest transperineally apical and anterior parts of the prostate may be better accessed compared to transrectal approach. For those reasons, studies were designed to compare yields of transrectal versus transperineal biopsy approach in primary 12-core and saturation 20-core schemes (Hara et al., 2008; Abdollah et al., 2011). Those studies uniformly showed no difference in cancer yields. However, this has not convinced proponents of transperineal approach. In regions, where transperineal approach was used routinely and claimed to be better compared to transrectal (for example some parts of Italy), they are only lately discovering prostate biopsy with end-fire probe (Galosi et al., 2010). Due to technical development of ultrasound equipment, some manufacturers (also very respectful one), were using side-fire probe with needle "through-the-probe" technology. This was proved to be inferior (Chin et al., 2009) in comparison to end-fire biopsy approach (see below). Therefore comparison of perineal to side-fire transrectal approach is not appropriate. Combination of transrectal and transperineal approach has also been used and described, aiming at gaining best from both approaches and maximizing cancer detection rate (Kawakami et al., 2007).

Transrectal approach is recommended for routine primary and also saturation prostate biopsy. On rare occasions, where stereotactic guidance may be needed, decision on approach depends on availability of equipment. At present, equipment for transperineal stereotactic approach is more often available and more widespread, due to its use for brachytherapy (and different other new experimental approaches, such as cryotherapy or photodynamic therapy), compared to new and only limited availability of transrectal

Future of Prostate Biopsy: Who Will Get It and How? 111

differently formed prostate. For example, TargetScan (Envisoneering) declares needle movement of 2.2 cm (standard for most biopsy guns, but not all) and possibility of needle protruding 2 cm from tip of biopsy guide before firing – together 42 mm of needle penetration. This is a description of a dedicated "robotic" system. In every day life, where ultrasound system and needle guide are one thing, hospital's supply for needles another and hospital's selection of biopsy-guns third issue, this should be considered, measured and perhaps some longer needles acquired for bigger prostates. Many other variants of needle characteristics were evaluated. Regarding stroke length, 33 mm end-cut was proposed (Dogan et al., 2005) by some, others proposed 29 mm side-notch instead of 22 mm (Fink et al., 2005). It is obvious longer is better and at least 22 mm should be used instead of old 15 mm, which was used at introduction of now obsolete sextant biopsy scheme (Hodge et al., 1989). Also thickness of needle was questioned – 18G (1.27 mm) was compared to thinner needles (0.9 mm (20G), 0.8 mm and 0.7 mm(22G)) – this old study found 0.9 mm may be acceptable (Norberg et al., 1994) – however it is not used in practice today. More recent studies evaluated thickness of needles again – non-ferromagnetic titanium needles were evaluated for quality of yield in comparison to standard needles – 16G (1.65 mm) titanium needle was found to provide samples of good quality and better compared to 18G regular (Franiel et al., 2006). However, also for MRI guided puncture, commercially available product is 18G needle (TSK, Japan) with

Until recently, only straight needles were in wide use. This creates problem with accessibility (see section 3.2). Recent machine for stereotactic trus biopsy Targetscan aims to overcome this problem with new pliable needle, which bends and allows good approach to

In the beginning of transrectal prostate ultrasound era, large efforts were made attempting to recognize cancerous areas of prostate on gray ultrasound picture. Although hypoechoic lesions were identified as important (Terris et al., 1991) and we still lean toward specifically sampling hypoechoic areas as suspect in our every-day prostate biopsy work, we can not rely on them. After color doppler ultrasound was introduced, suspect areas were proposed to be the ones, which have higher or disorganized blood flow. Many studies have confirmed better sampling with the help of doppler or color flow imaging. However, presentation of subtly disorganized prostate vasculature and blood flow in potential cancer foci is very delicate and very dependent on sonographist, so only highly specialized individuals were and are able to put theory into practice. They are still trying to improve visualization of vasculature, either with ultrasound contrast or with other pharmacological agents, but other three presently available imaging techniques seem more promising as they may be more standardized and therefore easier for every urologist or radiologist, who, in a hurry and overwhelmed with other everyday work, perform mass of prostate biopsy burden:

Magnetic resonance imaging with different modalities has established its role in prostate cancer imaging. Apart from T1 and T2 weighted images (Jager et al., 1996), which are not enough, multi-modal approach, like diffusion weighted imaging and dynamic contrast enhanced imaging was found necessary to identify tumor suspicious regions. Role of endorectal coil, although sometimes debated (for example for 3T may not be so important as

characteristics comparable to regular needles.

**3.4 Image guidance** 

**3.4.1 Role of MRI** 

most sites in the prostate in side-fire configuration.

elastography, ANNA C-TRUS and HistoScanning.

computer and motor guided tools for prostate biopsy. Therefore, transperineal biopsy may be method of choice in selected cases.

#### **3.2 Transrectal ultrasound probe**

After analogue ultrasound probes have settled to history, electronic probes prevailed. Rotating mechanical sector probes have not gained popularity in the past. Present standard is electronic multi-element transducer - array. They come in two configurations. Side-fire probes have longitudinal transducer and take biopsies in longitudinal sections – sagittal plane, while endfire probes have curved array detector and allow biopsies to be taken also in transverse plane. In the past, Bruel and Kjaer and Kretz offered for prostate biopsy primarily side-fire probes and this was subjectively seen as better approach compared to end-fire probes (vaginal probes), used "secondarily" also for prostate biopsies. However, end-fire proponents build hypothesis better detection rate to be expected with end-fire sampling in transverse plane due to ability to direct needle more towards lateral part of the peripheral zone, where most tumors arise. This hypothesis was at first tested and confirmed for sextant biopsy in PSA range 4-10 (Paul et al., 2004). This issue was challenged again in 2009, hypothesising end-fire probe has more oblique angled trajectory allowing better peripheral sampling (Ching et al., 2009). To reach anterior gland and apex in longitudinal plane, side-fire probe should be turned a lot and moved in a way which often causes pain as moves point of entry of the needle below dentate line of the rectum. End-fire probe allows better manipulation and targeting desired areas of prostate. Hypothesis was confirmed in their study, finding significantly better detection rate overall in the end-fire group compared to side-fire group and better detection in side-fire group for biopsies with more than 8 cores (8-12, 13-19 and 20 and more) and all PSA ranges (below 2.5, 2.5-4, 4-10 and more than 10) (Ching et al., 2009)

Later, side-fire probes were often bi-planar, therefore allowing better orientation in the prostate, if one views it in two planes and offering choice between end-fire or side-fire biopsy guide. At present, interest has moved from purely end-fire or side-fire biopsy towards combined biopsy opinions and probe designs are now aiming further at 3-plane, 3D imaging and computer guidance... Biplanar probes have become standard equipment also because linear longitudinal array on the probe is necessary for transperineal prostate procedures guidance, while end-fire part is used for standard transrectal biopsy. Ideally, one should have the ability to use biplanar probe, but probably prefer end-fire setting for taking most biopsy cores.

As history is repeating and revealing again in many aspects of human life, new TargetScan device (Envisioneering Medical Technologies, St. Louis, MO, USA) uses mechanical sector probe with single rotating element, applying it in "side-fire" configuration, but with needle, which bends, thus overcoming drawbacks from side-fire systems (Taneja, 2006).

#### **3.3 Biopsy needle**

Form, length, thickness, shape of biopsy needle, as everything regarding prostate biopsy, is being constantly challenged. It seems at present thickness of the needle is settled to 18G, needles are side-notch, true-cut, straight with stroke length of 22 mm.

But it was not always so – aspiration biopsy (cytological biopsy) was around and well not so many years ago (Gustafsson et al., 1990). Length of the needle may not seem important at first sight, but for systematic sampling of all areas of big prostates, standard needle length may become limiting factor, as it may simply not be possible to advance needle from biopsy guide into the prostate enough to get sampling of all desired areas in a big or a bit

computer and motor guided tools for prostate biopsy. Therefore, transperineal biopsy may

After analogue ultrasound probes have settled to history, electronic probes prevailed. Rotating mechanical sector probes have not gained popularity in the past. Present standard is electronic multi-element transducer - array. They come in two configurations. Side-fire probes have longitudinal transducer and take biopsies in longitudinal sections – sagittal plane, while endfire probes have curved array detector and allow biopsies to be taken also in transverse plane. In the past, Bruel and Kjaer and Kretz offered for prostate biopsy primarily side-fire probes and this was subjectively seen as better approach compared to end-fire probes (vaginal probes), used "secondarily" also for prostate biopsies. However, end-fire proponents build hypothesis better detection rate to be expected with end-fire sampling in transverse plane due to ability to direct needle more towards lateral part of the peripheral zone, where most tumors arise. This hypothesis was at first tested and confirmed for sextant biopsy in PSA range 4-10 (Paul et al., 2004). This issue was challenged again in 2009, hypothesising end-fire probe has more oblique angled trajectory allowing better peripheral sampling (Ching et al., 2009). To reach anterior gland and apex in longitudinal plane, side-fire probe should be turned a lot and moved in a way which often causes pain as moves point of entry of the needle below dentate line of the rectum. End-fire probe allows better manipulation and targeting desired areas of prostate. Hypothesis was confirmed in their study, finding significantly better detection rate overall in the end-fire group compared to side-fire group and better detection in side-fire group for biopsies with more than 8 cores (8-12, 13-19 and 20 and more) and all PSA ranges

Later, side-fire probes were often bi-planar, therefore allowing better orientation in the prostate, if one views it in two planes and offering choice between end-fire or side-fire biopsy guide. At present, interest has moved from purely end-fire or side-fire biopsy towards combined biopsy opinions and probe designs are now aiming further at 3-plane, 3D imaging and computer guidance... Biplanar probes have become standard equipment also because linear longitudinal array on the probe is necessary for transperineal prostate procedures guidance, while end-fire part is used for standard transrectal biopsy. Ideally, one should have the ability to use biplanar probe, but probably prefer end-fire setting for

As history is repeating and revealing again in many aspects of human life, new TargetScan device (Envisioneering Medical Technologies, St. Louis, MO, USA) uses mechanical sector probe with single rotating element, applying it in "side-fire" configuration, but with needle,

Form, length, thickness, shape of biopsy needle, as everything regarding prostate biopsy, is being constantly challenged. It seems at present thickness of the needle is settled to 18G,

But it was not always so – aspiration biopsy (cytological biopsy) was around and well not so many years ago (Gustafsson et al., 1990). Length of the needle may not seem important at first sight, but for systematic sampling of all areas of big prostates, standard needle length may become limiting factor, as it may simply not be possible to advance needle from biopsy guide into the prostate enough to get sampling of all desired areas in a big or a bit

which bends, thus overcoming drawbacks from side-fire systems (Taneja, 2006).

needles are side-notch, true-cut, straight with stroke length of 22 mm.

be method of choice in selected cases.

**3.2 Transrectal ultrasound probe** 

taking most biopsy cores.

**3.3 Biopsy needle** 

(below 2.5, 2.5-4, 4-10 and more than 10) (Ching et al., 2009)

differently formed prostate. For example, TargetScan (Envisoneering) declares needle movement of 2.2 cm (standard for most biopsy guns, but not all) and possibility of needle protruding 2 cm from tip of biopsy guide before firing – together 42 mm of needle penetration. This is a description of a dedicated "robotic" system. In every day life, where ultrasound system and needle guide are one thing, hospital's supply for needles another and hospital's selection of biopsy-guns third issue, this should be considered, measured and perhaps some longer needles acquired for bigger prostates. Many other variants of needle characteristics were evaluated. Regarding stroke length, 33 mm end-cut was proposed (Dogan et al., 2005) by some, others proposed 29 mm side-notch instead of 22 mm (Fink et al., 2005). It is obvious longer is better and at least 22 mm should be used instead of old 15 mm, which was used at introduction of now obsolete sextant biopsy scheme (Hodge et al., 1989). Also thickness of needle was questioned – 18G (1.27 mm) was compared to thinner needles (0.9 mm (20G), 0.8 mm and 0.7 mm(22G)) – this old study found 0.9 mm may be acceptable (Norberg et al., 1994) – however it is not used in practice today. More recent studies evaluated thickness of needles again – non-ferromagnetic titanium needles were evaluated for quality of yield in comparison to standard needles – 16G (1.65 mm) titanium needle was found to provide samples of good quality and better compared to 18G regular (Franiel et al., 2006). However, also for MRI guided puncture, commercially available product is 18G needle (TSK, Japan) with characteristics comparable to regular needles.

Until recently, only straight needles were in wide use. This creates problem with accessibility (see section 3.2). Recent machine for stereotactic trus biopsy Targetscan aims to overcome this problem with new pliable needle, which bends and allows good approach to most sites in the prostate in side-fire configuration.

#### **3.4 Image guidance**

In the beginning of transrectal prostate ultrasound era, large efforts were made attempting to recognize cancerous areas of prostate on gray ultrasound picture. Although hypoechoic lesions were identified as important (Terris et al., 1991) and we still lean toward specifically sampling hypoechoic areas as suspect in our every-day prostate biopsy work, we can not rely on them. After color doppler ultrasound was introduced, suspect areas were proposed to be the ones, which have higher or disorganized blood flow. Many studies have confirmed better sampling with the help of doppler or color flow imaging. However, presentation of subtly disorganized prostate vasculature and blood flow in potential cancer foci is very delicate and very dependent on sonographist, so only highly specialized individuals were and are able to put theory into practice. They are still trying to improve visualization of vasculature, either with ultrasound contrast or with other pharmacological agents, but other three presently available imaging techniques seem more promising as they may be more standardized and therefore easier for every urologist or radiologist, who, in a hurry and overwhelmed with other everyday work, perform mass of prostate biopsy burden: elastography, ANNA C-TRUS and HistoScanning.

#### **3.4.1 Role of MRI**

Magnetic resonance imaging with different modalities has established its role in prostate cancer imaging. Apart from T1 and T2 weighted images (Jager et al., 1996), which are not enough, multi-modal approach, like diffusion weighted imaging and dynamic contrast enhanced imaging was found necessary to identify tumor suspicious regions. Role of endorectal coil, although sometimes debated (for example for 3T may not be so important as

Future of Prostate Biopsy: Who Will Get It and How? 113

ANNA technique detected 66 cancers, taking up to 6 cores in a series of 132 patients with previous negative prostate biopsy. Series included 62 patients with previous 1 negative biopsy, 41 with previous 2 negative biopsies, 18 with 3 negative biopsies, 6 with 4 negative biopsies and 5 with previous more negative biopsies (5-6) (Loch, 2010). This indicates 50% positive biopsy in a setting where lower numbers would be obviously expected, but data are not clear which part of the C-TRUS ANNA positive biopsies belongs to group of only one previous negative biopsy, some of them with only 6 cores, and which was percentage in a subgroup of patients with more negative biopsies. Method is commercially available from Fresenius Kabi Deutschland, Bad Homburg and costs in 2010 without tax (VAT)

Prostatic HistoScanning was developed proprietary by company AMD, Waterloo, Belgium in cooperation with B/K ultrasound manufacturer. According to company's web site (accessed in April 2011), it is commercially available in EU and Canada and awaits FDA approval for US. First it was aimed as "triage test for men deemed to be at risk for prostate cancer and who wish to avoid prostate biopsy" (Braeckman et al., 2008). Later it seems they realized getting rid of biopsy is at present not attainable goal and they focused on improving sampling of the prostate at biopsy (Braeckman et al., 2008). It seems method was developed by comparing raw ultrasound data from prostates before biopsy to histological results of patients, positive for cancer, who underwent radical prostatectomy. In this way it seems development was similar to ANNA C-TRUS, each using own mathematical modeling for differentiation between benign and malign areas of prostate. However, AMD's HistoScann uses in a way "more straightforward" data, in a technical sense – but it needs specific B/K ultrasound machine and specific probe and is limited regarding other US manufacturer's data. In the community, availability of proper US machines for addition of HistoScann technology is limited. Advantage, compared to C-TRUS ANNA is in data analysis and processing in a "black box", which is for AMD's HistoScanning on site, while with C-TRUS ANNA one has to send data (over internet) to central facility and wait for analysis, therefore ultrasound prostate examination and biopsy can not be performed the same day, while HistoScann allows this. How often algorithms are changed and which are better, has not been evaluated yet although both systems are already commercially available

Some specific claims about HistoScanning were challenged in the letter to the editor of BJU (Aigner & Frauscher, 2009), objecting name of the method and questioning resolution and ability of ultrasound to detect small tumor foci. In response, authors admit some limitations of their method, specifically lower quality of signal and therefore potentially less reliable analysis in case of dense calcifications in the prostate or for analyzing anterior component of a very large prostate. They compare it with MRI claiming there is wider availability or US compared to MRI. It is at present not true – MRI is available in a lot of hospitals, endorectal coils are single use, however, specific B/K ultrasound machine with particular probe and motorized machine for rectal probe guiding and AMD's "black box" are not available and seem at present more costly compared to MRI examination. Advantage of all ultrasound approaches compared to MRI approaches lies in assumption of ultrasound picture to be easier for use in subsequent sample acquisition. With the expected development of programs for US – MRI picture fusion, this advantage of pure-ultrasound approach may disappear. Question which is better or are all those methods (MRI (T-2, DW and spectroscopy), elastography, C-TRUS ANNA and HistoScanning) comparable or perhaps

approximately 378 eur per use (one set of pictures analysis – one patient).

in Europe and are, as such, competitors.

for 1.5T), seems also well established (Comet-Batlle et al., 2003). Tumor suspicious regions are found in different proportions, depending on criteria and number of different imaging modalities applied and can reach up to 98% even in post-trus-negative biopsy setting. After tumor suspicious regions are identified, sampling is needed.

The easiest approach would be image fusion to trus picture, which is moving from development phase (Hu et al., 2010) and in some centers already represents routine practice (for example Heidelberg, Germany). Two systems are in development: transrectal Artemis - Eigen, Grass Valley, CA, USA (Natarajan et al., 2011) and transperineal BiopSee - MedCom, Darmstadt, Germany (Hadaschik et al., 2011). Incidental reports show identification and confirmation of cancer in patients with previously negative ANNA C-TURS biopsy, however, at present there are no studies which would compare any of the mentioned techniques and show individual strengths and indications.

Some researchers perform MRI examination with plastic simulator of endorectal probe insitu to simulate deformation expected during trus biopsy setting (Ukimura et al., 2010). Others perform 3D ultrasound imaging and use electromagnetic positioning device to perform biopsies (Turkbey et al., 2011).

Straightforward use of MRI would be MRI guided biopsy of MRI identified suspicious regions of prostate. Although at present available only in few institutions, this may very soon become more widespread as technology, procedure and equipment seem more and more ready for prime time (Roethke et al., 2011). Two independent retrospective series, performed with 1.5T or 3T magnets, from Netherlands (Hambrock et al., 2010) and from Germany (Roethke et al., 2011), report 52% and 58% (of patients with tumour suspicious regions identified) of positive MRI-guided biopsies after previous negative trus guided prostate biopsies.

#### **3.4.2 ANNA C-TRUS and HistoScanning**

Idea about reflected ultrasound wave analysis, which should reveal more data than can be seen just with naked eye, is old. There were and are still experiments taking place in developing algorithms of data analysis. Most often prostate is evaluated with transrectal ultrasound before radical prostatectomy and pictures are saved. After radical prostatectomy, histological sections of prostate with known areas of cancer and benign tissue are correlated with saved ultrasound data. Aim is to allow identification of cancer regions on ultrasound before biopsy or surgery. There may be many usages – HistoScanning is evaluated for prediction of Gleason score, volume of cancer, number and localization of cancer foci, prediction of location of cancer focus in relation to neurovascular bundle and in relation to prostate borders – all those data may be useful not only for decision to proceed or postpone biopsy and to guide biopsy, but also for preand peri-operative or other treatment planning.

ANNA C-TRUS is a method, which analyzes typical transrectal ultrasound pictures of prostate in transversal plane (for example 5, on sections, where one normally takes biopsy cores). Pictures can be taken with any digital US scanner. Pictures are then sent, uncompressed (using either .tif, .bmp or .png format), using internet, to the provider. After analysis, suspect areas are marked on pictures and urologist repeats examination, this time taking samples from areas marked. All data available about this method seem at present still from the inventor and copyright holder of the technique, prof. Loch from Flensburg, they seem at present not independently evaluated. From author's report in 2010, it seems C-TRUS

for 1.5T), seems also well established (Comet-Batlle et al., 2003). Tumor suspicious regions are found in different proportions, depending on criteria and number of different imaging modalities applied and can reach up to 98% even in post-trus-negative biopsy setting. After

The easiest approach would be image fusion to trus picture, which is moving from development phase (Hu et al., 2010) and in some centers already represents routine practice (for example Heidelberg, Germany). Two systems are in development: transrectal Artemis - Eigen, Grass Valley, CA, USA (Natarajan et al., 2011) and transperineal BiopSee - MedCom, Darmstadt, Germany (Hadaschik et al., 2011). Incidental reports show identification and confirmation of cancer in patients with previously negative ANNA C-TURS biopsy, however, at present there are no studies which would compare any of the mentioned

Some researchers perform MRI examination with plastic simulator of endorectal probe insitu to simulate deformation expected during trus biopsy setting (Ukimura et al., 2010). Others perform 3D ultrasound imaging and use electromagnetic positioning device to

Straightforward use of MRI would be MRI guided biopsy of MRI identified suspicious regions of prostate. Although at present available only in few institutions, this may very soon become more widespread as technology, procedure and equipment seem more and more ready for prime time (Roethke et al., 2011). Two independent retrospective series, performed with 1.5T or 3T magnets, from Netherlands (Hambrock et al., 2010) and from Germany (Roethke et al., 2011), report 52% and 58% (of patients with tumour suspicious regions identified) of positive MRI-guided biopsies after previous negative trus guided

Idea about reflected ultrasound wave analysis, which should reveal more data than can be seen just with naked eye, is old. There were and are still experiments taking place in developing algorithms of data analysis. Most often prostate is evaluated with transrectal ultrasound before radical prostatectomy and pictures are saved. After radical prostatectomy, histological sections of prostate with known areas of cancer and benign tissue are correlated with saved ultrasound data. Aim is to allow identification of cancer regions on ultrasound before biopsy or surgery. There may be many usages – HistoScanning is evaluated for prediction of Gleason score, volume of cancer, number and localization of cancer foci, prediction of location of cancer focus in relation to neurovascular bundle and in relation to prostate borders – all those data may be useful not only for decision to proceed or postpone biopsy and to guide biopsy, but also for pre-

ANNA C-TRUS is a method, which analyzes typical transrectal ultrasound pictures of prostate in transversal plane (for example 5, on sections, where one normally takes biopsy cores). Pictures can be taken with any digital US scanner. Pictures are then sent, uncompressed (using either .tif, .bmp or .png format), using internet, to the provider. After analysis, suspect areas are marked on pictures and urologist repeats examination, this time taking samples from areas marked. All data available about this method seem at present still from the inventor and copyright holder of the technique, prof. Loch from Flensburg, they seem at present not independently evaluated. From author's report in 2010, it seems C-TRUS

tumor suspicious regions are identified, sampling is needed.

techniques and show individual strengths and indications.

perform biopsies (Turkbey et al., 2011).

**3.4.2 ANNA C-TRUS and HistoScanning** 

and peri-operative or other treatment planning.

prostate biopsies.

ANNA technique detected 66 cancers, taking up to 6 cores in a series of 132 patients with previous negative prostate biopsy. Series included 62 patients with previous 1 negative biopsy, 41 with previous 2 negative biopsies, 18 with 3 negative biopsies, 6 with 4 negative biopsies and 5 with previous more negative biopsies (5-6) (Loch, 2010). This indicates 50% positive biopsy in a setting where lower numbers would be obviously expected, but data are not clear which part of the C-TRUS ANNA positive biopsies belongs to group of only one previous negative biopsy, some of them with only 6 cores, and which was percentage in a subgroup of patients with more negative biopsies. Method is commercially available from Fresenius Kabi Deutschland, Bad Homburg and costs in 2010 without tax (VAT) approximately 378 eur per use (one set of pictures analysis – one patient).

Prostatic HistoScanning was developed proprietary by company AMD, Waterloo, Belgium in cooperation with B/K ultrasound manufacturer. According to company's web site (accessed in April 2011), it is commercially available in EU and Canada and awaits FDA approval for US. First it was aimed as "triage test for men deemed to be at risk for prostate cancer and who wish to avoid prostate biopsy" (Braeckman et al., 2008). Later it seems they realized getting rid of biopsy is at present not attainable goal and they focused on improving sampling of the prostate at biopsy (Braeckman et al., 2008). It seems method was developed by comparing raw ultrasound data from prostates before biopsy to histological results of patients, positive for cancer, who underwent radical prostatectomy. In this way it seems development was similar to ANNA C-TRUS, each using own mathematical modeling for differentiation between benign and malign areas of prostate. However, AMD's HistoScann uses in a way "more straightforward" data, in a technical sense – but it needs specific B/K ultrasound machine and specific probe and is limited regarding other US manufacturer's data. In the community, availability of proper US machines for addition of HistoScann technology is limited. Advantage, compared to C-TRUS ANNA is in data analysis and processing in a "black box", which is for AMD's HistoScanning on site, while with C-TRUS ANNA one has to send data (over internet) to central facility and wait for analysis, therefore ultrasound prostate examination and biopsy can not be performed the same day, while HistoScann allows this. How often algorithms are changed and which are better, has not been evaluated yet although both systems are already commercially available in Europe and are, as such, competitors.

Some specific claims about HistoScanning were challenged in the letter to the editor of BJU (Aigner & Frauscher, 2009), objecting name of the method and questioning resolution and ability of ultrasound to detect small tumor foci. In response, authors admit some limitations of their method, specifically lower quality of signal and therefore potentially less reliable analysis in case of dense calcifications in the prostate or for analyzing anterior component of a very large prostate. They compare it with MRI claiming there is wider availability or US compared to MRI. It is at present not true – MRI is available in a lot of hospitals, endorectal coils are single use, however, specific B/K ultrasound machine with particular probe and motorized machine for rectal probe guiding and AMD's "black box" are not available and seem at present more costly compared to MRI examination. Advantage of all ultrasound approaches compared to MRI approaches lies in assumption of ultrasound picture to be easier for use in subsequent sample acquisition. With the expected development of programs for US – MRI picture fusion, this advantage of pure-ultrasound approach may disappear. Question which is better or are all those methods (MRI (T-2, DW and spectroscopy), elastography, C-TRUS ANNA and HistoScanning) comparable or perhaps

Future of Prostate Biopsy: Who Will Get It and How? 115

increased above 80% and lead authors to propose, if their results are further confirmed, in case of negative elastography and doppler, biopsy in this group and in relatively stable PSA,

On recent demonstration of C-TRUS ANNA and elastography at the occasion of EAU Congress in Vienna (march 2011), where both techniques were exposed to a patient with 4 previous negative biopsies and rising PSA, both techniques failed to find cancer in those two patients. This shows, as one can deduce from literature cited above: in approximately 50% of patients with suspicious characteristics (PSA) and previous negative biopsy, we are unable to find cancer at present. For how long? Will they develop cancer in the future? What is the right strategy to follow them? How they end? All those questions are important and need

Angiogenesis is important in development of cancer and increased vascularity was detected in tumors in general and in radical prostatectomy specimens, therefore use of ultrasound to detect those changes was proposed. Color doppler imaging estimates mean frequency shift of doppler signal to determine velocity and direction of flow. Power doppler shows total energy of the signal by integrating it, therefore resulting in sig`nal with homogenous background and more precise detection of smaller and low flow vessels (Remzi et al., 2004). Study of usefulness of power and color doppler for evaluation of hypoechoic lesions showed 80% sensitivity and 82% specificity for detecting prostate cancer (Cho et al., 2000). Standardized criteria for scoring different degrees and distributions of prostatic vascularity were developed and also subjective scales seem to work well (Mitterberger et al., 2010), however this points to high subjectivity of the

Power doppler was used for evaluation of peripheral prostatic capsular vessels, parenchymal vessels and vessels anastomosing with extraprostatic vessels (Sauvain et al., 2003). Criteria for suspicion of cancer in this study were increase in number of intra-lesional vessels, disoriented vessels or verticalized vessels in peripheral gland, asymmetrical blood flow, mass effect on the intraprostatic perilesional vessels and vessels in peripheral margins. Analyzing all those criteria, they aimed at estimation of prostate cancer stage by dividing lesions into three groups: absent extracapsular involvement, undetermined extracapsular involvement and presumably present extracapsular involvement. In this series, 55.7% patients had cancer and sensitivity of power doppler ultrasound was claimed to be 92%, specificity 72% (compared to 88% and 58% for ultrasound only). Group with ultrasound estimated lack of extracapsular involvement had this found in final pathology in 11%, while group with ultrasound suspicious for extracapsular involvement had it confirmed in 87%. Authors (Sauvain et al., 2003) conclude power doppler ultrasound improves accuracy of ultrasound imaging in the diagnosis of cancer, can increase detection rate, optimize number of biopsy cores and also predict extracapsular invasion by identification of capsule

When using ultrasound for evaluation of minor differences in prostate blood flow between cancerous and benign areas, many factors can interfere with the results – for example position of the patient – it was shown left decubitus position caused flow asymmetry resulting in more biopsies directed toward left side without improving detection rate

may be avoided.

answers in future research.

**3.4.4 Color, power doppler** 

method, which is its drawback.

perforating vessels.

(Halpern et al., 2002).

they may supplement each other, will become important source of research endeavours in the future. HistoScanning manufacturer intends to use the technology also for other cancers, like ovary, thyroid and breast, which may be advantageous as prostate diagnosis may benefit from multidisciplinary team. On the other side, C-TRUS ANNA was developed by urologists for urologists, can be used in almost any setting (any digital ultrasound machine is good) and seems to have at present more peer reviewed data. HistoScanning is not aiming only towards prostate biopsy guidance, but also aims at other potentially useful predictions regarding prostate cancer and seems to have larger research base with groups from different countries (UK, Germany) who study its potential applications. Whether one or both techniques will stand the test of time and what role they will play remains open.

#### **3.4.3 Elastography**

Real time transrectal ultrasonoelastograpy of the prostate is aimed at discrimination between harder and softer areas of prostate tissue. MRI elastography technology was also developed (S. Li et al., 2011), but here only ultrasound is described. Back-scattered ultrasound waves are displaced with compression or decompression of tissue (approximately 2%), harder areas showing less displacement compared to softer (Salomon et al., 2008). Elastography is performed in real-time, at the time of biopsy – no previous transrectal ultrasound examination (as for C-TRUS ANNA) is necessary. By subjectively observing US elastography picture, operator aims at evaluating symmetry of stiffness, focal areas of hardness and persistence of stiffness with probe tilting, aiming at stiff nodule more than 5 mm in diameter and persistence of stiffness after probe tilting (Giurgiu et al., 2011). There are different scoring systems (Salomon et al., 2009), some focus on identifying smaller lesions and potentially showing increased sensitivity (Kamoi et al., 2008). Technique of elastography is still improving, better differentiation markers are being developed constantly (Zhang et al., 2011). Further, standardization of compression with idea of leaving this part to the machine is also in testing (Tsutsumi et al., 2010). Regarding companies which provide elastography equipment, most studies have been performed using Hitachi machine, which is commercially available for prostate applications and most tested, although other manufacturers also offer this technology. Among target-biopsy techniques elastograpy seems at present most widely spread as technology is also in use for breast cancer (primarily) and investment needed is only in US machine and probe, there are no perinvestigation charges as for C-TRUS ANNA. Elastography procedure is also much simpler compared to MRI-US fusion. Another advantage of elastography is in its compatibility with power/color doppler techniques for image guidance, which can be performed simultaneously, therefore gaining from two sources. There are quite a few published studies describing experience with prostate elastograpy from different parts of the world. Study results are positive and seem to support claims that elastography improves cancer detection rate. One of the very appealing studies, from USA, analyzed help of elastograpy in biopsy of men with PSA values between 1.25 and 4 and free/total PSA ratio less than 18% (Aigner et al., 2010). They were able to detect 24% of cancers using 5 cores with elastography guidance compared to 5.1% cancers using 10 systematic biopsies. Another study, from Romania, used and compared in the same set of patients gray scale, doppler and elastograpyh data (Giurgiu et al., 2011). They found, in a series of 65 patients and 43% of them with identified cancer on biopsy, sensitivity of elastograpy to be 68% and specificity 62%. Particularly promising was elastography in a subgroup of older than 70 years, where sensitivity increased above 80% and lead authors to propose, if their results are further confirmed, in case of negative elastography and doppler, biopsy in this group and in relatively stable PSA, may be avoided.

On recent demonstration of C-TRUS ANNA and elastography at the occasion of EAU Congress in Vienna (march 2011), where both techniques were exposed to a patient with 4 previous negative biopsies and rising PSA, both techniques failed to find cancer in those two patients. This shows, as one can deduce from literature cited above: in approximately 50% of patients with suspicious characteristics (PSA) and previous negative biopsy, we are unable to find cancer at present. For how long? Will they develop cancer in the future? What is the right strategy to follow them? How they end? All those questions are important and need answers in future research.
