Volume February 2005

From the Editor | Useful Definitions | New Trends in Gleason Grading | Prostatitis | Take-Home Points

From the Editor

Key Points discussed in this Issue:

• Every needle core should be assigned a separate Gleason grade. • Every core should have tumor quantification by percent cross sectional area and linear millimeters of tumor. • The worst Gleason grade equation should be used for clinical decision making. • Active chronic prostatitis defined as neutrophils in the secretory epithelium as well as chronic inflammation may explain mild elevations of serum PSA. • There is no known significance to finding mild chronic inflammation in the stroma which is often associated with BPH or atrophy with respect to cancer detection.

The mission of the Institute of Urological Pathology is three fold and includes: diagnostic service, education and research. This quarterly newsletter is directed toward health care professionals involved in the care of patients with urologic disorders and renal diseases including Urologists, Nephrologists, Pathologists, Nurses, and their support staff. It will aim to provide current up to date information on the evolving trends in urologic pathology and renal disease in a succinct and user friendly format. In this first issue Gleason grading and prostatitis are discussed with emphasis on issues important in interpreting and writing pathology reports. Upcoming issues will include topics such as high grade PIN, immunoperoxidase staining and predictive normograms as well as insights into disorders of the urinary bladder, testis and kidney, The news letter will be distributed quarterly and on occasion include contributions from invited guests, and nationally respected experts. I hope you find this a useful resource.

Kirk J. Wojno, M.D.
Director, Institute of Urological Pathology

Useful Definitions

1. Gleason grade is the number from 1 to 5 assigned to various histologic patterns of prostatic adenocarcinoma. One is the most favorable grade and 5 is the worst.
   
   
2. Gleason score as originally defined is the sum of the most common grade and the second most common grade. However, current practice in needle biopsies is to use the most common pattern and the worst pattern.
   
   
3. To have the complete information required for proper prognostication, one needs to have both Gleason grades and the Gleason score. For example Gleason grade 4 plus Gleason grade 3 equals Gleason score of 7. This is often abbreviated as Gleason grade 4+3=7. This mathematical equation provides all the required information in a succinct format. It is well known that not all Gleason score 7 tumors are alike with a Gleason grade 4+3=7 behaving more aggressively than a Gleason grade 3+4=7.
   
   
4. Prostatitis is inflammation of the prostate.
   
   
5. Active prostatitis is the infiltration of the secretory epithelium by neutrophils.

New Trends in Gleason Grading in the era of Extended Prostate Biopsies

Extended prostate biopsy strategies have lead to changes in the pathologists approach to Gleason grading on diagnostic biopsy specimens. The widespread use of local anesthesia has increased the tolerability and acceptance of taking many more needle cores than had been previously possible without general anesthesia. There appears to be only a limited need for geographic information (resolution) such that there seems to be little need fore more than 14-16 zones in the prostate proper with possible additional sampling of the seminal vesicles. In fact most urologists place specimens in 6 or 12 containers. However, many are placing more that one core in a container.

In addition to the inherent difficulties imposed on the histology lab by this practice, several questions arise:

• Should each core be assigned a separate Gleason grade?
  
• Does each core represent a separate tumor or biopsy sample of the same tumor?
  
• Does providing this information aid urologists?

It is well known that radical prostatectomy specimens are often under graded based on needle biopsy samples. Recent data suggests using the most common Gleason grade and the highest Gleason grade, rather than the second most common patterns helps to correct this problem.

Stage migration to smaller more multifocal tumors has occurred in the PSA era. At the time of prostatectomy there is an average of 4 separate tumors in the prostate gland with a range of 1 to 64. This is clearly a multifocal disease. It is only the occasional prostate that is found to have a single tumor at the time of radical prostatectomy. The Gleason grading system was originally developed at a time of larger more confluent tumors at diagnosis. This grading system is unique in that it uses an average of tumor grade, rather than the worst grade. It is not well established by rigorous scientific studies how to best assign a grade to a radical prostatectomy specimen that contains multifocal tumor of differing grades.

Several methods have been proposed. These include:

• assigning a grade to all the tumor in the prostate ignoring the multifocal nature
  
• grading the index tumor which is arbi- trarily chosen by the pathologist as the most important tumor
  
• grading each tumor nodule separately and using the worst grade or a weighted grade based on tumor volume

Two areas of tumor each on a separate core from a container with multiple cores. With each core graded separately this case was upgraded to a Gleason grade 5+4=9 by using the worst grade.

Understanding radical prostatectomy grading is critical to establishing the optimal grading on needle biopsies. We are currently studying this phenomenon in an ongoing study at the University of Michigan. Our preliminary data presented at the recent CAP meeting found that grading each tumor separately and using the worst grade best predicted biochemical failure after radical prostatectomy. This is an ongoing study which is in the process of looking at another population to validate these findings.

With this understanding of radical prostatectomy grading, we agree with others who have proposed that each needle core should be assigned a separate Gleason grade and the highest grade should be used for making clinical decisions. We currently report a separate Gleason grade equation for each needle biopsy. In our study we used 2mm of separation to define separate tumors. The question arises if two tumors of differing Gleason grade are found on a single core separated by more than 2mm should these be graded separately? This is a current area of investigation; however we have not implemented this practice yet.

Although not a definite predictor of small tumor volume, quantitative estimates of tumor on needle biopsy are good predictors of large tumor volumes and help prognostication and decisions regarding therapy. A quantitative estimate of tumor should be given (% and mm) for each needle core. Fragmentation of biopsies which comes from placing multiple biopsies in a single container have necessitated including % and mm in biopsy reports to give the most accurate representation of tumor volume.

Prostatitis

Benign prostate gland with active inflammation, i.e. neutrophils in the secretory epithelium.

Tissue biopsies are not often taken from patients with prostatitis; therefore, there is little histologic study in human specimens. There is controversy as to whether or not prostatic inflammation can cause elevations in serum PSA. The best study on the subject was done by Peter Humphrey and colleagues in the 1990’s. They showed that active inflammation, i.e. neutrophils in the secretory epithelium was most strongly correlated with elevations of serum PSA. Other forms of chronic inflammation did not have the same significance. We currently recommend that only abundent active inflammation (i.e. active chronic prostatitis) be reported in the pathology report. Mentioning other forms of inflammation may cause one to over interpret this as an explanation for an elevated PSA and a patient may not receive the appropriate follow-up. Therefore, the only inflammation that should be mentioned in a pathology report is active inflammation.

Take-Home Points

• Every needle core should be assigned a separate Gleason grade.

• Every core should have tumor quantification by percent and linear millimeters of tumor.

• The worst Gleason grade equation should be used for clinical decision making.

• Active chronic prostatitis which includes chronic inflammation along with neutrophils in the secretory epithelium may explain mild elevations of serum PSA.

• There is no known significance to finding mild chronic inflammation in the stroma which is often associated with BPH or atrophy.