Incidence
After skin cancer,prostate cancer is the most commonly diagnosed cancer in men. About a quarter of a million men will be diagnosed with prostate cancer each year. Unlike most cancers which have a peak age of incidence,the incidence of prostate cancer increases with age so that between 60 and 79 years of age it is about 1 in 8. However, when a family member has the disease,the relative risk is further increased. Because of the aging of the American male and the decrease in cardiovascular deaths from improved treatment,it is likely that a rise will be seen in prostate cancer. However,because of the broad spectrum of biological activity of prostate cancer,disease management may be difficult to individualize.

Prevention and Etiology
Testosterone profoundly affects the development of prostate cancer. Prostate cancer does not occur in eunuchs. There is an increased incidence of prostate cancer amongst relatives of patients with prostate cancer and in Afro-American men. A high-fat diet may also predispose towards prostate cancer. Along with a high fat diet,inflammatory cells within the prostate may lead to cells which may be precursors of prostatic intraepithelial neoplasia(PIN) and prostatic carcinoma.

a) risk factors
Risk factors include obesity,family history,African heritage,elevated PSA or velocity, or abnormal digital rectal examination(DRE). Certain viruses such as the retrovirus XMRV may also be a risk factor for developing prostate cancer.

b) prevention
Altering life style, periodic evaluation, and or possibly taking an alpha-reductase inhibitor medication such as proscar/avodart on a daily basis may be helpful.
Recent studies have suggested a small benefit in reducing the number of detectable prostate cancers when men take this medication daily.
Drugs that lower cholesterol (Statins) may also lower the risk of developing prostate cancer. Statins may also lower the risk of lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) and erectile dysfunction (ED).
Over the counter supplements have not shown any clear benefit in preventing BPH or preventing prostate cancer.
Men who are at risk as outlined above,men over 55,men who have difficulty with urination,men with an enlarged prostate or men with an elevated prostatic specific antigen(PSA) blood test but have a negative prostate biopsy may benefit from daily proscar/avodart. These drugs are 5 alpha reductase inhibitors and block the conversion of testosterone to dihydrotestosterone and these agents may also improve the diagnostic accuracy of PSA testing by enhancing its sensitivity.
Daily proscar/avodart can result in a reduction in the size of the prostate,decreased volume of ejaculate and a decrease in the PSA (but this reduction does not necessarily mean less of a chance of having prostate cancer). These medications have a low incidence of side effects that may include low libido or desire for intercourse,erectile dysfunction or breast enlargement. Statins may produce similar side effects without lowering the serum testosterone.

Symptoms
Most men with early prostate cancer have no symptoms. Minor voiding symptoms may be related to associated benign enlargement of the prostate than the early prostate cancer. More locally advanced prostate cancer may cause significant voiding symptoms or urinary retention and or obstruction of the ureters and renal failure. Prostate cancer that has spread to the bones may cause pain or fracture of the vertebrae with spinal cord compression and paralysis.

Signs
For early prostate cancer there are usually no signs. However,induration or a prostate nodule may be detected on a digital rectal examination(DRE)

Laboratory Findings
For early prostate cancer,usually the only abnormal finding will be an abnormal %free PSA (prostatic specific antigen) and or total PSA blood test. More advanced cases may show elevations of BUN and Cr,alk phos. and acid phos. blood levels.
Spurious laboratory results are also not uncommon and an abnormal blood result is worth repeating to verify the level before embarking upon a prostate biopsy.

PSA
Prostatic Specific Antigen( PSA) is a serine protease produced by the prostatic epithelium and periurethral glands in the male. This substance is secreted in the seminal fluid and is partly responsible for the liquefaction of the coagulated semen.

PSA Forms
a) % free PSA
Of the various forms in which the PSA can be measured,the % free PSA appears more sensitive in picking up early prostate cancer. PSA exists in both bound (to protein) and unbound states. Men with prostate cancer have a greater proportion of serum PSA that is bound resulting in a lower % free PSA. A % free PSA of 25 or above suggests a low likelihood of prostate cancer. However, we have found the % free PSA to be valuable in detecting early prostate cancer,especially when the total PSA (the most common form of PSA measurement) is between 1.6 and 4.0 and the % free is less than 20. The lower the % free PSA the greater the probability of having prostate cancer. Therefore you should ask your physician to measure your % free PSA.

b) total PSA
The normal total PSA is 4.0 ng/ml or less but does not hold a lot of accuracy. It can be deceptively normal and miss an early prostate cancer. Also, the total PSA can be elevated in men with a large prostate,if there is chronic prostatitis (often asymptomatic), after a urinary infection, ejaculation,prostate massage,prostatic infarct and after a prostate biopsy.

Certain medicines like proscar and avodart as well as non steroidal anti inflammatory drugs (NSAIDS) may reduce the serum levels of PSA.

Ultrasensitive PSA
This is a highly sensitive third generation PSA assay that can be used to detect very early disease progression after treatment especially for intermediate and high risk patients.

PSA velocity
Measures the rate at which a PSA rises. A PSA rising more than 0.75ng/ml per year may be significant.

PSA density
This is calculated by determining the figure of total PSA over prostatic volume.

PCA3
The PCA3 is a gene that exists in the nuclear material of epithelial cells from the prostate and that maybe shed into the urine. The gene is a noncoding segment of mRNA located on chromosome 9 and is over expressed by prostate cancer cells.The PSA,however, is a glycoprotein that can enter the bloodstream and is measured through a blood test.
The PCA3 urinary test begins with careful examination /massage of the prostate. The first voided urine after this examination is then collected and submitted to the laboratory for analysis. The result is expressed as a score,a ratio of PCA3 to PSAmRNA. A normal score is considered to be 35x10 to the minus 3 or less. This test maybe useful in men who have elevations of PSA and a negative biopsy or in those that have had a microfocus of prostate cancer on one biopsy and then a follow up negative biopsy.

Prostate Screening
Since the % free PSA is more sensitive in picking up early prostate cancer,screening for prostate cancer should be undertaken using this blood test rather than the inaccurate total PSA. Early detection is important since not all prostate cancers are slow growing,even in the elderly.
For prostate screening,the blood test is combined with the digital rectal examination of the prostate. The digital exam may have some usefulness in determining the approximate size of the prostate,it's texture ( a hard nodule may suggest cancer) and whether there is tenderness to touch. Although prostate cancer has variable biological potential,currently about 75% of all prostate cancers currently diagnosed are limited to the early T1-T2 stages. 

Prostate Biopsy (TRUS/BX)
This is done through a transrectal ultrasound guided needle biopsy of the prostate. In our practice we have patients stop anti coagulants for at least 5 days and start the antibiotics cipro and flagyl at least one day before, the day of and for three days after the biopsy. He also takes an enema 2 hours before the procedure. The patient is placed on his side and the ultrasound probe introduced into the rectum. Local anesthetic is injected about the prostate as a periprostatic block,the prostate volume determined (gland height,width, and length x0.52) and then a number of sextant needle biopsies taken. Most prostate biopsies performed in the office under a periprostatic nerve block normally sample six regions (sextant) areas of the prostate,base middle and apex of the prostate,right and left sides to give you 6 areas of tissue sampling.
Trying to infer cancerous areas on the basis of the ultrasound gray scale images is inaccurate and the only value of these images is to determine the size of the prostate,whether there are calcifications and or cysts and to know that the biopsy needle is in the area of the prostate that requires sampling.
There is no evidence for any prostatic cancer seeding from the needle biopsy as the tissue is extracted through the hollow core of the spring loaded biopsy needle.

Staging Saturation Biopsies. We will have men undergo a saturation biopsy under outpatient sedation where we will sample greater than 20 cores of prostate tissue,especially when a man has had a previous pathology report indicating a microfocus (5% or less of Gleason 6 prostate cancer in one needle core biopsy only), of prostate cancer or unilateral prostatic involvement with cancer and we wish to verify the presence of prostate cancer or be sure that it is indeed only in one side of the prostate.

Patient selection for focal therapy necessitates verification that the cancer is localized or organ confined to the prostate. In the low to intermediate risk groups (see Risk Assessment and D'Amico risk stratification for prostate cancer progression and recurrence below) the most accurate way of determining whether the prostate cancer is localized is to have the patient undergo a staging saturation (greater than 20 needle core samples) biopsy by biopsying the prostate as well as the margins of the prostate. This means biopsying the base of the prostate and seminal vesicles as well as the apex of the prostate adjacent to the external sphincter/membranous urethra. If the pathology report after the staging saturation biopsy indicates the presence of cancer at one or both margins of the prostate it is a safe bet that the prostate cancer is no longer organ confined and probably not suitable for focal therapy. However,if only the margins at the base are involved,Hifu may still be reasonable as the seminal vesicles can be included in the treatment zone.

Ensuring that the cancer is only involving one side of the prostate is important for those men considering treatment only to the involved area (focal) or involved half (unilateral) or subtotal portion of the prostate so that treatment can be focused on the involved areas and nerve sparing of the neurovascular bundles undertaken to preserve erections. The neurovascular bundles branch from the pelvic plexus and run along the postero-lateral borders (underside) of the prostate on each side towards the apex of the prostate before piercing the urogenital diaphragm and coursing towards the corpora cavernosa of the penis. At times,however,the cavernosal nerves may not be part of the neurovascular bundle. Also,in addition to preserving the neurovascular bundle,keeping the treatment away from the external sphincter will prevent damage to the sphincter and strictures or incontinence from occurring.

3D mapping using a brachytherapy grid when doing an extended saturation biopsy can be done using a TargetScan or Artemis biopsy system. These templated mapping biopsy systems may provide additional accuracy and confidence for those men seeking focal treatment and preserving erections. This accuracy is important especially when sextant biopsies can have a significant false negative rate. The sextant 12 core needle biopsy has about a 70% accuracy while the saturation biopsy may have about an 80 - 90% accuracy. However, close follow up and testing should allow early pick up of these initially false negative men and without compromise.

Pathology
Most prostate cancers (over 95%) are adenocarcinomas. The remainder are transitional,small cell (or neuro endocrine and may possibly occur in response to prolonged androgen deprivation) or sarcomas.Basically, the non-adenocarcinomas may be grouped into either epithelial or non-epithelial. PIN and atypical small acinar proliferation(ASAP) are believed to be precursor lesions to prostate cancer.

The prostate is divided into four distinct glandular zones,peripheral,central,preprostatic and transitional. About a third of the bulk of the prostate,however, is made up of the anterior fibromuscular stroma which is devoid of glands and not one of the zones. About 70% of prostate cancers originate in the peripheral zone of the prostate and about 20% in the transitional zone and 10% in the central zone of the prostate.

Gleason Grade
This is a grading of the histological patterns of the prostate cancer seen under the microscope and then given a score. The score is used to determine the aggressiveness of the adenocarcinoma (the most common type of prostate cancer).
As there are usually more than one histological pattern seen under the microscope,the two most prevelant are graded,primary and secondary,and the Gleason score is a combination of the two grades or patterns. Each pattern is given a grade between 1 to 5 with 1 being the least aggressive and 5 the most. The grades of the two most common patterns are combined for a Gleason score. A Gleason score of 7 or above indicates a more aggressive cancer and a poorer prognosis.

However,not all Gleason scores are the same. Remembering that the first number in the score is given to the most prevalent pattern of cancer seen under the microscope it will be evident that if we say look at a Gleason score of 7 for example,a 4 plus 3 is worse than a 3 plus 4 simply because the first number is given to the prevailing pattern of prostate cancer and if 4 is more prevalent,you have a predominantly more aggressive pattern than if the pattern was mainly a 3 with only some 4. Therefore,the first number in the Gleason score is the more important for prognosis. Also,this Gleason score does not seem to change in an individual over time.
In addition,since there is some subjectivity amongst pathologists in grading the prostate cancer and arriving at a Gleason score,it is reasonable to get a second or third opinion on your slides. Particularly with the low to moderate Gleason scores where there appears to be about a 25% either under grading or over grading of the score which may then alter ones prognosis.

Reviewing your prostate needle biopsy report
After your systematic sextant transrectal needle biopsy of the prostate a number of needle core samples are taken and evaluated histologically under the microscope by the pathologist. Usually between 12 and 20 representative sextant core samples are taken from the prostate.
a) the sextant location is given ie right or left,base, mid zone or apex ( a minimum of 2 needle biopsies from each sextant should be taken)
b) the length of the needle core sample is given and a standard length biopsy core is about 15mm
c) the needle gauge used for the biopsy is usually about 18g. An 18g prostate needle biopsy specimen represents only about 0.03% of the prostate gland tissue.
d) each needle core is analyzed for tumor and the length of tumor involvement measured and recorded as length and as a percentage of that needle biopsy.
A core tumor length of 3mm or more in one or two needle biopsy specimens can predict a prostate cancer of clinically significant volume (0.5cc or greater). Also, a small amount of tumor is not equivalent to a low grade tumor or a small amount of prostate cancer necessarily.
e) microscopy, stains and ploidy
in order to examine the needle biopsy samples of the prostate each of the preserved specimens undergoes a 2 micron cut and placed on a slide and stained with H+E (hematoxylin and eosin) and examined with the microscope using low and high power. Most labs also utilize a triple immunohistochemistry stain to improve cancer detection.
The immunohistochemistry stain consists of 3 antibodies:
a. racemase (P504s) Staining of this protein is seen in prostate cancer and high grade PIN but not benign prostatic tissue.
b. high molecular weight cytokeratin (34b-E12). Stains the cytoplasm of basal cells of the prostate. Cancer cells fail to react with this antibody.
c. p63 antibody. Stains the nucleus of basal cells.
f) the Gleason grade (discussed above) for each needle biopsy specimen is recorded. A Gleason score of 7 or greater indicates a more aggressive lesion.
g) associated findings
i) prostatic intraepithelial neoplasia (PIN)
ii) atypical small cell acinar proliferation (ASAP)
These are both thought to be precursor lesions for prostate cancer and men found to have these on their biopsy report may warrant repeat biopsies at some future time.
iii) atypia. Here there may be some abnormal cellular morphology but not consistent with malignancy.
iv) perineural invasion. The prognostic significance of perineural invasion by prostate cancer is debatable.

Ploidy analysis,micro vessel density and neuroendocrine differentiation are other pathologic variables of which the most important is the aggressive small cell variant of neuroendocrine differentiation.

If your biopsy report indicates a MICROFOCUS (defined as 5% or less prostate cancer in one needle biopsy core only) of prostate cancer (assuming enough biopsies of appropriate core length were taken) then we would not act on such a biopsy but have you undergo a saturation biopsy,possibly under sedation to verify whether the existence of prostate cancer can be confirmed. It has been our experience that we cannot always confirm the existence of prostate cancer after previously finding one microfocus amount amongst all the specimens taken . Therefore, we will not direct a man to undergo prostate cancer treatment based on the presence one microfocus of prostate cancer in the report. A PCa3 test may be useful corroborating data also.Close follow up with PCa3's and further biopsies are of course warranted.

Imaging
a) Sonogram
Sonography of the prostate alone without a needle biopsy cannot determine the presence or absence of cancer. The use of ultrasound to image the prostate via a transrectal approach can come in various forms.
i) conventional
ii) color doppler sonography
iii) contrast enhanced sonography
iv) ultrasound based realtime elastography
v) microbubble ultrasound
Here ultrasound involves the use of color doppler imaging with microbubble contrast. The microbubbles are tiny bubbles of gas and since blood flow is more prevalent in cancerous tissue,the microbubbles tend to concentrate here and then identify the cancerous lesion.
vi) HistoScanning
With this technique, computer assisted ultrasonography is used which is capable of acquiring and transferring volumetric radiofrequency data.
Further imaging is undertaken to ensure that the prostate cancer is indeed localized to the prostate so that the treatment selected will be appropriate for optimizing cure. Imaging is usually not necessary when the PSA is 10 or less. However, aggressive prostate cancers (those with a Gleason score of 7 or greater) may produce less PSA than expected and imaging may still be appropriate here although the PSA may be 10 or less.
b) CT/MRI Scans
CT and MRI scans are also used to localize cancerous lesions within the prostate and also to determine possible localized spread. MRI but especially functional multimodality MR imaging includes high resolution MR imaging,dynamic contrast enhanced MR imaging,MR spectroscopy (MRS) and diffusion weighted MR imaging. With this functional multimodality MR imaging it is possible to detect and localize the prostatic cancer lesion with a high degree of accuracy. In this way it is feasible to perform image guided focal therapy.
c)Bone scan
Patients with a PSA of 15 or greater are at risk for bone spread and should be considered for a bone scan to determine whether there has been spread from the prostate.
d) Endo rectal magnetic resonance imaging
This involves the use of a specialized coil inserted into the rectum and may improve imaging of the prostate and prostate cancer and determine whether the cancer has spread beyond the confines of the prostate.
Use of magnetic resonance spectroscopy in conjunction with the MRI may improve the imaging accuracy of prostate cancer even further.
e) Prostascint scan
An antibody to a prostate specific antigen is conjugated to inidium but the scans usefulness has been limited by too many false positives and negatives.
f) PET scan
Positron emission tomography (PET) when combined with a computer tomography (CT) scan and the use of the imaging agent choline,is able to detect recurrent prostate cancer earlier than conventional methods can.

Staging
This is an attempt to determine through the studies already mentioned as to whether the prostate cancer is localized, spread locally or spread to more distant sites. The staging system for prostate cancer used currently is the T(tumor)N(nodes)M(metastasis) system. This system uses the results of the imaging, DRE and the TRUS (trans rectal ultrasound) but not the results of the needle biopsy.

Tis carcinoma in situ (PIN)
T1 subclinical
  • T1a <5% in BPH resection has PCa,normal DRE
  • T1b >5% in BPH resection has PCA,normal DRE
  • T1c detected by elevated PSA,normal DRE
T2 palpable
  • T2a tumor palpable by DRE,visible on TRUS one side
  • T2b tumor palpable by DRE visible by TRUS both sides
The T1c and T2a and T2b lesions are the ones that are typically picked up on prostate screening
T3 outside prostate capsule or into seminal vesicle
  • T3a extracapsular extension on one or both sides
  • T3b seminal vesicle involvement
T4 locally advanced beyond the prostate
Tumor extends into bladder neck,sphincter or rectum

N0 no regional node involvement
N1 regional node involvement

M0 no metastatic spread
M1 metastatic spread
  • M1a metastasis in non regional lymph nodes
  • M1b metastasis to bone
  • M1c distant metastasis to other sites

Reviewing your Risk Assessment (D'Amico risk stratification for prostate cancer)
The following criteria may be used to formulate your risk group when considering treatment options with curative intent.
1. Low Risk
PSA <10ng/ml
Gleason< or equal to 6. If 50% of the biopsies contain cancer,your risk increases.
T1,T2a
Because this group may have a recurrence rate of less than 20%,these men may be suitable candidates for minimally invasive treatment options for their prostate cancer.

2. Intermediate Risk
PSA 10-20ng/ml
Gleason 7. If 50% of your biopsies contain cancer,your risk increase
T2b, T3a
Some men in this group may also be candidates for minimally invasive treatment options.

3. High Risk
PSA>20ng/ml
Gleason 8-10
T3b

The challenge of categorizing your prostate cancer risk level of low,intermediate or high can be difficult when the number of positive biopsies or volume of disease is factored in. For example, a man with a PSA of 10ng/ml or less and a Gleason score of 6 or less and a T1-T2a stage cancer behaves more like an intermediate risk level than a low risk level prostate cancer if more than 50% of the needle core biopsies are positive.

DO YOU HAVE LOCALIZED PROSTATE CANCER?

Although prostate cancer has great variable biological potential,each year many men still die from the disease and the dilemma is in trying to identify those men at risk for progression of their localized prostate cancer so that they may benefit from one of the four definitive curative treatment options such as HIFU. Some of these options such as HIFU can deliver focal treatment if a man elects to have just the area of cancer involvement in his prostate treated.

If your %free PSA is still abnormal on a repeat study (to exclude spurious laboratory results) you should consider a transrectal ultrasound and biopsy. The transrectal ultrasound on it's own,without a biopsy, is worthless.
The purpose of the prostate biopsy is to determine,with a reasonable degree of accuracy,whether or not you have prostate cancer.
Most commonly,the biopsy is performed under local anesthetic in the urologist's office. This is usually a 12 needle core,random biopsy covering the sextant areas (base,middle and apex,right and left) of the prostate. Saturation biopsies,greater than 20 needle cores, may be done under sedation as an outpatient in those men where more data is required for accurate staging of the prostate cancer.

As the majority of prostate needle biopsies are read and interpreted by general pathologists and because of the great amount of subjectivity involved in the reading of these prostate specimens,you should demand to have your prostate biopsy slides validated by an independent reference laboratory that specializes in diagnosing prostatic diseases.

If your PSA continues to rise and or your PCA3 is abnormal despite a previous negative validated biopsy,you should consider a further biopsy at some time to ensure that a low volume prostate cancer has not been missed on the previous biopsy.

If your biopsy shows High Grade PIN or atypical small acinar proliferation (maybe prostate cancer precusor lesions),you should undertake active surveillance with periodic PSA's and PCA3's as well as a repeat biopsy of your prostate at some later date.

If your prostate biopsy shows a microfocus of prostate cancer (5% or less of a Gleason 6 in one needle core), active surveillance is in order as the microscopic area of prostate cancer may not be confirmed on a subsequent prostate biopsy.

If your validated prostate biopsy indicates more cancer than just a microscopic focus,one needs to consider the following when evaluating either a definitive total treatment or a focal treatment of your prostate cancer.
a) tumor volume on validated biopsy report
b) Gleason score on validated biopsy report
c) risk stratification (see above D'Amico risk stratification based on PSA,tumor volume,Gleason score and stage)
d) life expectancy ie age at presentation
e) co morbidities ie heart disease,diabetes etc
f ) areas of tumor involvement within your prostate
This last issue is VERY IMPORTANT as the very best survival results for the four definitive treatment options are for LOCALIZED prostate disease and knowledge of the exact areas of cancer involvement within the prostate is crucial in attempting to determine the correct stage of your prostate cancer.

If your prostate cancer exists only within the MID zones of your prostate,you can be fairly comfortable that your cancer is localized to the prostate and one of the four definitive treatment options such as HIFU would be ideal.

If your prostate tumor exists at the BASE or APEX of your prostate (according to your validated prostate biopsy report) you should check to see what tumor volume and what Gleason score has been noted in these areas.

If only a small volume of prostate cancer exists in the base and or apex of your prostate and the Gleason score is 6 or less,your prostate cancer is likely still localized to the prostate and a definitive treatment option such as HIFU would be ideal.

h) MARGIN STATUS
If the validated prostate biopsy report indicates that there is more substantial prostate cancer at the base or apex of your prostate and or you have a Gleason score 7-10, you should undergo a staging biopsy of your prostate (may be performed under sedation as an outpatient) and have the margins of your prostate and seminal vesicles biopsied to determine your prostate margin status. This information,once validated, can decide if your prostate cancer is still localized or has infiltrated beyond the margins of your prostate.

If the apical margins are positive and indicate infiltration of your prostate cancer towards the sphincter,your cancer is no longer localized to the prostate and you should consider radiation as the other definitive treatment options may potentially cause more harm to your urinary sphincter which is adjacent to the apex of your prostate to cause a urethral stricture and or urinary incontinence.

If the margins at the base of your prostate are positive and or your seminal vesicle biopsies indicate infiltration of your prostate cancer you should again check the amount of tumor infiltration and the Gleason score that is reported on in the needle biopsy cores of these areas. If a substantial amount of prostate cancer exists,and or you have a Gleason score 7-10 in these areas,you should consider radiation to the whole prostate and the pelvic lymph nodes as in the face of significant cancer infiltration,the other three definitive treatment options for prostate cancer likely would not be curative.
If there is a small amount of prostatic cancer infiltration at the base of the prostate and or the seminal vesicles, and with a Gleason score of 6 or less,one of the four definitive treatment options such as HIFU may be considered as it also can be taken outside the prostate and used to treat the bladder neck and seminal vesicles.

Watchful Waiting and Active Surveillance
Although prostate cancer exhibits variable biological potential, surveillance maybe reasonable in some elderly men where low volume and low grade prostate cancer has been documented on biopsy. The risk of disease progression and spread of the cancer is related to cancer grade. Therefore,men who elect to follow their prostate cancer with active surveillance should be followed carefully with serial PSA's,examinations and prostate biopsies so that intervention can be undertaken at the first sign of disease progression.

It will be apparent that in men electing to undergo Active Surveillance (AS), documenting increasing progression of disease must be as unbiased as possible to prevent both under estimating and over estimating an individual's prostate cancer progression.
Progression of T1a or a microfocus of prostate cancer (5% or less of a Gleason 6 prostate cancer on one needle biopsy core only) appears to be relatively limited. However, the dilemma concerns the reliability of the initial biopsy report and this is where a subsequent staging saturation biopsy can help confirm the initial tumor volume and grade. Although low volume low grade disease (T1a) may or not be confirmed on the saturation biopsy, about 20% of these men may be seen to have an upstaging of their cancer and a still much smaller number of men,upgrading of their prostate cancer. Despite a slight potential for progression of T1a stage prostate cancer,the process of active surveillance will identify those men that demonstrate progression of their prostate cancer. Although documenting progression of disease, their prostate cancer will still be organ confined and these men will do well with focal treatment and cure of their cancer.  

Second Opinion
Seeking a second opinion may reassure you and your family that you have had the most accurate evaluation and that you have confidence in your diagnosis and your risk stratification and that your doctor has also reviewed the most precise treatment options for organ confined prostate cancer with you. Also,make sure you have a good understanding of Quality of Life (QOL) Issues that may result from your proposed treatment for localized prostate cancer. (see Quality of Life Issues from Prostate Cancer treatment).

Reliability Issues in Prostate Cancer Diagnosis

1. PSA.  The total prostatic specific antigen level is not very accurate for several of the reasons outlined earlier. The %free PSA appears more accurate.
2. DRE.  The rectal examination is not too accurate but still useful.The positive predictive value of an abnormal digital rectal examination(DRE) is between 39-50% due to subjectivity. Some very small prostate cancers can be picked up by DRE but the DRE commonly underestimates the tumor volume. Also, clinical overestimation of prostate cancer stage is common.
3.TRUS/Biopsy.  Whereas the most common ultrasound appearance of prostate cancer is a hypoechoic peripheral zone lesion,carcinoma is found in less than 20% of these. Also,the biopsy may miss early disease as only a small representative portion of the prostate is sampled during a sextant needle core TRUS/Biopsy. In other words the 12 core needle biopsy can have a significant false negative rate in that the 12 core biopsy has about a 70% accuracy. The saturation biopsy with over 20 cores has about an 80 to 90% accuracy. However, through active surveillance and close monitoring with PSA's,PCA3's and additional biopsies, the accuracy of a mans diagnosis can be underscored.
Additional areas of concern can be core contamination of the specimen with cancer cells on the needle from another area of the prostate already biopsied or in errors of specimen handling by staff.
  4. Pathology. Discrepancy between pathologists is not uncommon so having your slides reviewed by a reference laboratory with pathologists skilled in determining the presence, Gleason score and histological extent of your prostate cancer is invaluable. This is especially true when seeing a microfocus of cancer,small acinar proliferation or high grade PIN in your report. Also,there can be some under grading or over grading of the Gleason score amongst pathologists, especially for those men with a low to moderate Gleason score. In addition, more than 50% of prostate cancers exhibit at least 3 or more grades of prostate cancer and multiple Gleason grades can exist within the same lesion and not necessarily just a multifocal lesion. Finally,some pathologists do not make use of the immunohistochemistry stains that can be especially useful in determining the presence or absence of prostate cancer in a biopsy specimen.
5.Imaging. In addition to some subjectivity here also, most current imaging modalities (including CAT scans,bone scans and MRI's) are not very accurate in identifying microscopic invasion or spread of prostate cancer.

The bottom line is that there are some subjectivity concerns between individual pathologists in not only grading the prostate cancer and arriving at a Gleason score but also in estimating the volume of prostate cancer in the needle biopsy specimens. This is particularly so with low to moderate Gleason scores where there appears to be about a 25% either under grading or over grading of the score. Therefore,before you embark on a treatment option that may affect your Quality of LIfe you should have your pathology validated by a reference laboratory not only to confirm the presence of the cancer but also to confirm the Gleason score and the tumor volume.

The Natural History of Prostate Cancer and Patient Selection for Focal Therapy
The NATURAL HISTORY OF PROSTATE CANCER depends upon it's biological potential and this potential is extremely variable in individual men. Although prostate cancer increases in incidence with age,most elderly men will die with their disease rather than from it mainly because their disease is low volume and low grade. i.e. at the very low end of the D'Amico LOW RISK stratification group. The incidence of prostate cancer in these men was determined mainly from postmortem studies and their cancers were usually low volume and low grade and probably would have been too small to be picked up on DRE and PSA testing, and probably would not have been picked up on biopsies if they had been alive.
According to some studies,American men have about a 16% chance of having prostate cancer but only about a 3% chance of dying from it. Other studies have shown that the progression of prostate cancer for stage T1a or  MICROFOCUS of prostate cancer (5% or less of a Gleason 6 in one needle biopsy core only i.e. low volume,low grade) is generally limited but may show some low level of progression in stage but less so with grade. 
However,the usefulness of these postmortem studies and the poor design of other studies on the natural history of prostate cancer have made it difficult to retrieve meaningful information for accurate conservative patient management in those men diagnosed with the disease.
The natural history data does suggest that men with low volume low grade prostate cancer,particularly if they have a life expectancy of 10years or less or with significant co morbid disease,can be adequately managed with ACTIVE SURVEILLANCE with serial PSA's,DRE's and possibly PCa3's and biopsies and to re consider treatment should there be progression of their cancer. However,it would be inappropriate to manage those who have more extensive prostate cancer disease with active surveillance.
Again,because of the great variability in biological potential of prostate cancer,many men still die from the disease (about 28,000 per year in the US) so evaluation with a DRE and PSA are very important.
The big dilemma then, is in PATIENT SELECTION and identifying those men who would benefit from treatment of their prostate cancer. An even bigger dilemma is trying to identify those men who could benefit from FOCAL THERAPY and cure of their organ confined prostate cancer disease. This process of patient selection for focal therapy can at times difficult so that some men are not over treated while others are under treated or escape the active surveillance process altogether.
Patient selection for focal therapy should identify those men who have a 10 year or greater life expectancy and with low co morbid risk and who fall into the low or intermediate D'Amico risk stratification groups (outlined above). An added level of confidence and appropriateness for focal therapy can be assured by completing a STAGING SATURATION BIOPSY (as outlined above) to show that the margins of the prostate are clear of prostate cancer and that a man is a suitable candidate for focal therapy and cure.

In addition,because the same prostate biopsy specimen can be read differently by individual pathologists,it is important to get your biopsy validated by a reference laboratory before committing to a treatment. Also be sure to have a sound understanding of your proposed treatment and QOL issues for that treatment.

Shrinking or Downsizing your Prostate
The size of your prostate prior to treatment is important to know. Routinely we like to have your prostate volume at about 40g or less for more effective and timely treatment. Because the prostate as well as prostate cancer cells thrive on the androgen testosterone,the prostate cancer is arrested and the prostate shrinks or downsizes when testosterone is suppressed and the prostate is deprived of testosterone. This is called androgen deprivation therapy (ADT).
Therefore,Short Term ADT is often instituted before definitive treatment of localized prostate cancer for 2 reasons;
1. to shrink the size of the prostate to a more manageable volume.The patient can have the size of his prostate measured periodically through transrectal sonography till the size is appropriate for treatment.
2. in those men electing temporary postponement of definitive treatment for a few months.

Agents for Short Term ADT
a) LHRH agonists ie leuprolide/lupron and goseriline/zoladex
These agents bind to luteinizing hormone releasing hormone (LHRH) receptors in the pituitary and after an initial surge in luteinizing hormone (LH) release and testosterone production,suppress further LH release and testosterone production by desensitizing the pituitary.

The LHRH agonists do have some side effects but the benefits of prostate cancer arrest and prostate volume downsizing with these injections usually outweigh the following side effects:
i) hot flashes and breast discomfort/enlargement may be relieved with megace or effexor
ii) erectile dysfunction and decreased libido and possibly some penile wasting may be offset with medications such as cialis/levitra or viagra.
iii) emotional issues may arise but can be handled with antidepressants such as zoloft
iv) very unlikely with short term ADT are a type of metabolic syndrome ( increased subcutaneous fat raised triglycerides and decreased insulin sensitivity with a possible modest increased risk for cardiovascular disease) and bone loss. These issues are mainly seen in men on long term ADT for metastatic prostate cancer.

b) 5alpha reductase inhibitors
There are both type 1 and 2 and result in a decrease of dihydrotestosterone.
dutasteride/avodart (type 1 and 2)
finasteride/proscar (type 2)

These oral agents are effective in shrinking the prostate but their side effects can bring about temporary impotence,loss of libido and breast discomfort or enlargement.

Rising PSA after Treatment for Localized Prostate Cancer

Routine monitoring of men with PSA's after any treatment option for localized prostate cancer is important as no one treatment can guarantee complete obliteration of the cancer. A man who has a PSA that slowly continues to rise from a base line of 0.1/0.2 should undergo a prostate biopsy early in order to diagnose residual or recurrent prostate cancer so that it may be treated. Fortunately,HIFU can be repeated should the prostate cancer recur or HIFU can be performed should the cancer recur after surgery,radiation or cryoablation.

Biochemical Free Survival (BFS)
BFS usually parallels the criteria for cure.
The PSA nadir is the lowest level PSA that is achieved after any treatment for prostate cancer. Ideally that should be 0.2ng/ml or lower and is a good indicator of cure.
There are several definitions of biochemical failure:
i). ASTRO (American Society of Radiation Oncologists) which defines failure as 3 consecutive rises in PSA above the post treatment PSA nadir.
ii). Phoenix,nadir+2.0ng/ml PSA rise.
iii). Stuttgart,nadir+1.2ng/ml PSA rise and specifically designed to evaluate HIFU.
Concerns for treatment failure may then be evaluated with a prostate biopsy to determine whether there is residual cancer.