Dr. Epstein provides a comprehensive review of the pathology of prostatic carcinoma and its importance in guiding the clinical management of treatment for our patients with abnormal prostates and prostate cancer. Prostate cancer, its evaluation, screening, and treatment, remain in many aspects the most controversial for the urologic oncologist. Clearly, our decisions on how we treat patients with elevated PSA's, abnormal prostate exams, and a diagnosis of prostate cancer is influenced greatly by the interpretation of the pathologist of biopsies and radical prostatectomy specimens. In short, the oncologist and urologist are unable to make intelligent and accurate recommendations without accurate pathologic review.
Who Needs a Repeat Biopsy?
Although it may seem odd, one of the most frustrating situations is a patient with an elevated or rising PSA, an abnormal digital rectal examination, a good candidate for curative therapy, and a negative prostate biopsy. The risk of prostate biopsy is small. However, when one considers the overall cost of the procedure, time off from work, and the anxiety caused to the patient, a recommendation to repeat the biopsy must not be taken lightly.
As Dr. Epstein so clearly points out, certain criteria help us decide which men should undergo repeat biopsy and which should be followed conservatively. Without question, high grade PIN is one of these criteria. Like the Hopkins group, Brawer and associates found that men with high grade PIN but no cancer on original prostate biopsy have an extremely high risk of prostate cancer on subsequent biopsy . In a previous series of 21 men with PIN, all 10 patients with grade 2 or 3 PIN had carcinoma on repeat biopsy, whereas only 2 of 11 had positive subsequent biopsies when their original biopsy showed grade 1 PIN . In the gentleman with a completely negative biopsy, I tend to use physical exam and, more importantly, the velocity of PSA change over time. Carter et al, found an annualized PSA increase of 0.75ng/mL/year to be a significant cut-off in determining which men harbored cancer with a previous negative biopsy.
Catalona demonstrated that men with PSA determinations of greater than 10ng/mL with a previous negative biopsy had approximately a 41% chance of having carcinoma found on subsequent biopsy . Those men that have a subsequent negative second biopsy are unlikely to have carcinoma found on a third biopsy, and therefore, in my opinion, should not be rebiopsied unless their PSA continues to rise at a rapid rate or their physical examination changes significantly, which occurs in only 4% to 8% of patients.
Who Needs Treatment?
Once cancer is diagnosed the clinician treating the patient needs to make recommendations based on information received from the pathologist. This decision is influenced greatly by the pathologist's interpretation of grade, the number and percentage of each biopsy involved, and the location of these biopsies. As a urologic oncologist who sees many men for treatment or second opinion after the diagnosis is already established, it is extremely difficult when pathologic reports do not contain all of this information. Several studies have now established algorithms that help predict stage based on biopsy grade, the number, location, and amount of cancer in each biopsy obtained, and PSA value.5 This is extremely important information in counseling and guiding a patient about the advisability of several aspects of treatment:
Is a bone scan necessary?
Is nerve sparing radical prostatectomy appropriate?
Is watchful waiting appropriate?
Does radiotherapy have a reasonable chance for cure?
Should neoadjuvant hormonal therapy be used?
Will this patient require a lymph node dissection?
Will this patient likely have pathologic disease outside the prostate, and possibly require adjuvant radiation or hormonal therapy after definitive therapy?
Dr. Epstein points out, as have other authors, that grade is very important in determining the overall prognosis and success of therapy. In 1994, the Hopkins group attempted to define which men might be able to be followed safely with watchful waiting  based on several criteria, including grade, number of biopsies positive, amount of cancer per biopsy, and PSA density. The problem with this algorithm is that prostate biopsies with low grade most often have the greatest error in determining the final pathologic grade. Bostwick reported 316 patients diagnosed with prostatic adenocarcinoma by the 18 gauge automatic spring loaded biopsy gun and found that prostate biopsies underestimate the radical prostatectomy specimen grade in 40% of cases. In addition, those cases most likely to be in error were those with the least amount of tumor found on prostate biopsy and those with the lowest grade . In a recent analysis of 88 patients biopsied with the 18 gauge gun at the City of Hope National Medical Center, we found that 28 patients (32%) had their final total Gleason score upgraded by at least two points .
In short, I think that healthy men with good life expectancy, despite having supposed low grade and low volume prostate cancer should undergo definitive therapy because higher grade and higher volume disease commonly appear on final pathologic review. The vast majority of these men will be cured. In addition, this practice spares them the chronic anxiety of carefully watching their PSA value while the cancer remains untreated.
Treatment of Men with pT3 and Node Positive Disease
Dr. Epstein points out that the incidence of positive margins in radical prostatectomy specimens varies widely from institution to institution. In addition, adjuvant therapy for these gentlemen with locally advanced disease (pT3) is controversial. Accurate pathologic interpretation of positive margins and seminal vesical involvement is extremely important as these men need careful guidance as to options of possible adjuvant therapy, available prospective randomized trials, and the increased risk of biochemical recurrence and eventual metastatic disease.
The treatment of men with pT3 disease with adjuvant radiotherapy is controversial. To date, no definite benefit has been proven. In my opinion, these men should be placed on the SWOG/RTOG intergroup study (SWOG-3794) studying the benefit of adjuvant external beam radiotherapy so that this question can be answered.
One of the most controversial areas is the treatment of men with positive micro-metastases to regional lymph nodes found on frozen section. Dr. Epstein points out in the Hopkins' series that men with a Gleason sum less than 8 on needle biopsy have a relatively prolonged interval before distant metastases appear. He advocates radical prostatectomy in these patients. However, he states that men with Gleason's grade of 8 to 10 with positive lymph node metastases will not benefit from radical prostatectomy.
Zincke, and others, reported 370 patients in 1992 with Stage D1 disease who had undergone radical retropubic prostatectomy with or without adjuvant hormonal therapy with a follow-up of up to 22 years . Those patients with diploid tumors had a significantly improved survival equal to that of their normal life expectancy when treated with immediate hormonal therapy following radical prostatectomy. Although ploidy correlates with grade, not all men with Gleason's score 8 to 10 will have aneuploid or tetraploid tumors. Those men with diploid tumors and Gleason's score 8 may significantly benefit from radical prostatectomy and early adjuvant hormonal therapy despite their node positive status. In addition, those men that have undergone pelvic lymph node dissection and have micro-metastases without radical prostatectomy are often plagued with symptoms of local progression, not to mention the anxiety caused by knowing that they will eventually progress. Since the morbidity of radical prostatectomy is low , it is justifiable to control the disease locally and give these men the benefit of the doubt from immediate hormonal therapy in addition to radical prostatectomy.
In summary, Dr. Epstein provides an excellent review of the pathologic evaluation of prostatic carcinoma. In addition, he personally has provided clinicians with invaluable information by his research and contributions in this field. The role of the pathologist is crucial when treating the patient with prostate cancer. However, the questions of who needs treatment and what kind, can only be determined by the clinician and his overall evaluation of the patient. For example, two men of the same chronologic age and same pathology report may require two completely different treatment plans based on other factors such as comorbidities, voiding and sexual function or body habitus. Although we are able to make broad statements about how men of certain pathologic stage generally do, we must always tailor the treatment to the individual.