By David G. Bostwick M.D., M.B.A., Bostwick Laboratories, Richmond, Virginia
Reprinted from PCRI Insights February 2004 v7.1

Introduction
One of the most important and popular forms of treatment for prostate cancer, androgen deprivation therapy (ADT), has been in use for more than 50 years. In the past two decades, new forms of androgen deprivation have emerged with different mechanisms of action, including combined androgen blockade (gonadotrophin-releasing-hormone (GnRH)) agonist [e.g., goserelin and leuprolide combined with an androgen receptor antagonist [e.g., flutamide, bicalutamide, and nilutamide]), GnRH antagonists (e.g., abarelix), and 5-alpha-reductase inhibitors (e.g., finasteride and dutasteride). Androgen deprivation has been used for preoperative tumor shrinkage, symptomatic relief of metastases, cancer prophylaxis, and treatment of benign prostatic hyperplasia.

All modes of hormonal treatment induce programmed cell death of single cells (apoptosis) in benign and neoplastic prostatic epithelium. This apoptosis is characterized by fragmentation of tumor DNA, appearance of apoptotic bodies, and inhibition of cell growth. The altered epithelium displays involution and acinar atrophy, although the changes with finasteride appear to be less pronounced and variable than with other agents. Androgen deprivation therapy also induces significant histologic changes in prostatic intraepithelial neoplasia and adenocarcinoma, although this has been refuted by one study in needle biopsy specimens after finasteride treatment.1,2,3

The mechanism for emergence of androgen-independent cancer growth is unknown, but may result from loss of expression of the androgen receptor, structural abnormalities in the receptor, amplification of the androgen receptor gene, or androgen-independent pathways. Cancer cells may become habituated to an androgen-deprived environment or spawn androgen-independent clones as the result of genetic instability. Androgen-independent cells have a distinct growth advantage over the androgen-dependent cells that undergo growth arrest and die. This report describes the histopathologic and morphometric features of the benign and neoplastic prostate following finasteride therapy, and compares the findings with other forms of androgen deprivation therapy.

Histopathologic Findings After Finasteride in the Human Prostate
Finasteride inhibits the type 2 receptors of the 5-alpha-reductase enzyme, thereby blocking conversion of testosterone to the more-potent dihydrotestosterone and reducing hormonal stimulation of the prostate.

Benign and hyperplastic prostate. After finasteride treatment, prostatic volume is reduced by 20-30 percent, and there is a marked increase in the stroma/epithelial ratio when compared with untreated nodular hyperplasia; this was a near-constant finding in nine of ten published papers. Marks et al found a 55% decline in epithelial content after six months of treatment, and this decline correlated with prostate volume decrease.4 By 24 months, the epithelium had involuted further, contracting from 19.2% to 6.4% of mean tissue composition (6.0 cc vs. 2.0 cc overall mean epithelial volume; 3.2 stroma/epithelial ratio vs. 17.4 stroma/epithelial ratio).5 Interestingly, the epithelial involution was similar in different zones of the prostate. The treated secretory cells displayed shrunken nuclei, condensed chromatin, and inconspicuous nucleoli. Apoptotic bodies were occasionally present in the epithelial cells and lumens, but there were no mitotic figures.

The effects of finasteride in the ducts and acini were not homogeneously distributed, contrary to the results of combination androgen deprivation therapy.1,6,7,8 Similarly, Juniewicz et al9 observed that finasteride induced “incomplete atrophy” in the prostates of beagle dogs.

The lack of mitotic figures in the ducts and acini after finasteride indicates that there is no growth of the epithelial component as a result of this treatment. This is in agreement with the results of Bologna et al10 who assessed the effects of finasteride on the growth rate of the androgen-responsive LnCaP human prostate carcinoma cell line; they found that finasteride inhibited growth in a dose-dependent manner.

Prostatic Intraepithelial Neoplasia (PIN). The results of finasteride treatment in high-grade PIN are controversial and the cumulative number of cases studied is probably too small to draw firm conclusions. Two reports found no apparent effect on the histologic appearance or extent of high-grade PIN, whereas a third study of three cases described atrophy and involution with decreased prevalence.1,2,3

Prostatic Adenocarcinoma. Only two reports have evaluated the histopathology of prostate cancer after finasteride therapy. Civantos et al analyzed five radical prostatectomy specimens from patients treated for 3-24 months. They found that the finasteride effect was “very similar” to but “less prominent” than that of complete androgen blockade in Gleason primary grades 2 and 3 cancer, and was “minimal” in Gleason primary grade 4 cancer.1 They concluded that finasteride may induce some foci of lower grade cancer to resemble higher-grade cancer owing to cell loss and collapse of acini forming single rows of nucleated nuclei. They recognized the potential for grading bias, and noted that the effects of finasteride made it “difficult to recognize at low power and mimicking high Gleason grade owing to apoptosis with reduction in size and collapse of cancer gland. No Gleason grading…should be done; otherwise the report would indicate a worse grade tumor than it is.”2

Conversely, Yang et al prospectively studied 53 needle biopsy specimens with cancer and found no differences between finasteride-treated and untreated cases for a variety of histopathologic features, including Gleason score, number of cores involved with cancer, extent of cancer in the biopsies, atrophic changes in cancer cells, number of mitotic figures, amount of luminal mucin, and presence of prominent nucleoli.3 They noted that their results were limited by sampling variation, but cancer was readily identifiable after finasteride treatment.

Prostate Cancer Grading After Finasteride and Androgen Deprivation Therapy
An international consensus conference held at Mayo Clinic in 1996 considered prostate cancer grading after ADT. The group, consisting of about 30 leading pathologists and urologists specializing in prostate cancer around the world, concluded that grading after therapy is not validated, of no practical value, and should not be used to avoid misinterpretation by clinicians.11 This position has been recently reaffirmed by Bostwick and Gleason in response to the published results of the Prostate Cancer Prevention
Trial (personal communication).

The Prostate Cancer Prevention Trial (PCPT)
The PCPT trial study followed 18,882 men 55 years of age or older at relatively low risk for prostate cancer (serum PSA below 3.0 ng/ml; asymptomatic; negative digital rectal examination) for up to seven years, and found a 24.8% reduction in the needle biopsy risk of prostate cancer (24.4% vs. 18.4% for finasteride vs. placebo, respectively).12 Tumors of Gleason score 7 or higher were reportedly more common in the finasteride group (37% of all cancers in this group) than in the placebo group (22.2% of cancers).

The disproportionate frequency of Gleason scores 7 and higher is mostly due to a shift from a Gleason pattern of 3 to a pattern of 4, leading to a score of 7 or 8. As discussed by Civantos et al,1 the results seen in PCPT are therefore probably attributable to grading bias rather than an increased risk of aggressive cancer.3 Furthermore, the relative over-interpretation of Gleason score 7 and higher in the finasteride arm is more pronounced in years 1 and 2 of PCPT. Thus, it is more likely due to treatment-induced architectural changes rather than to the de novo development of more aggressive cancer. Were the latter to be the case, one should expect increases in Gleason score 7 and higher cancer as years of treatment increased, but this was not observed in PCPT.

I suggest that cancer aggressiveness after therapy should be determined by other, more objective measures to avoid the likely influence of grading bias. Certainly, finasteride’s remarkable 24.8 percent improvement in chemoprevention of prostate cancer indicated in the PCPT study should not be withheld based on safety concerns about the emergence of aggressive prostate cancer when these concerns are based on available data that is quite likely to be attributable to grading bias.

What You Should Have Learned From This Article
All forms of androgen deprivation therapy, including finasteride, induce distinctive histologic changes in benign and malignant prostatic epithelial cells. Treated cancer has a significantly higher architectural (Gleason) grade, lower nuclear grade, and smaller nucleolar diameter than untreated controls, thus creating the potential for grading bias. The effects of finasteride may be less pronounced than other forms of therapy, with variable distribution throughout the prostate; further, there may be greater sensitivity of low and intermediate-grade cancer than high-grade cancer. The Gleason grading system for cancer should not be used after finasteride treatment as it is not validated in this setting and is likely to overestimate the biologic potential of high-grade cancer observed after therapy. Chemoprevention trials with agents such as finasteride that alter morphology should not rely on cancer grading as a secondary endpoint owing to grading bias.

References
1. Civantos F, Watson RB, Pinto JE, et al. Finasteride effect on benign prostatic hyperplasia and prostate cancer. A comparative clinico-pathologic study of radical prostatectomies. J. Urol. Pathol. 6:1-8, 1997.
2. Montironi R, Pomante R, Diamanti L, et al. Evaluation of prostatic intraepithelial neoplasia after treatment with a 5-alpha-reductase inhibitor (finasteride). A methodologic approach. Anal Quant Cytol Histol 18:461-70, 1996.
3. Yang XJ, Lecksell K, Short K, et al. Does long-term finasteride therapy affect the histologic features of benign prostatic tissue and prostate cancer on needle biopsy? PLESS Study Group. Proscar Long-Term Efficacy and Safety Study. Urology 53:696-700, 1999.
4. Marks LS, Partin AW, Gormley GJ, et al. Prostate tissue composition and response to finasteride in men with symptomatic benign prostatic hyperplasia. J Urol 157:2171-8, 1997.
5. Marks LS, Partin AW, Dorey FJ, et al. Long-term effects of finasteride on prostate tissue composition. Urology 53:574-80, 1999.
6. Monrtironi R, Diamanti L. Morphologic changes in benign prostatic hyperplasia following chronic treatment with the 5-alpha-Reductase inhibitor Finasteride. J. Urol. Pathol. 4:123-35, 1996.
7. Finasteride (MK-906) in the treatment of benign prostatic hyperplasia. The Finasteride Study Group. Prostate 22:291-9, 1993.
8. Monrtironi R, Muzzonigro G, Magi Galluzzi C, et al. Effect of LHRH agonist and flutamide (combination endocrine therapy) on the frequency and location of Proliferating Cell Nuclear Antigen and apoptotic bodies in benign prostatic hyperplasia. J. Urol. Pathol. 2:161-71, 1994.
9. Juniewicz PE, Hoekstra SJ, Lemp BM, et al. Effect of combination treatment with zanoterone (WIN 49596), a steroidal androgen receptor antagonist, and finasteride (MK-906), a steroidal 5 alpha-reductase inhibitor, on the prostate and testes of beagle dogs. Endocrinology 133:904-13, 1993.
10. Bologna M, Muzi P, Biordi L, et al. Finasteride dose-dependently reduces the proliferation rate of the LnCap human prostatic cancer cell line in vitro. Urology 45:282-90, 1995.
11. Algaba F, Epstein JI, Aldape HC, et al. Assessment of prostate carcinoma in core needle biopsy – definition of minimal criteria for the diagnosis of cancer in biopsy material. Cancer 78:376-381; 1996
12. Thompson IM, Goodman PJ, Tangen CM, et al: The influence of finasteride on the development of prostate cancer. N. Eng J Med 349:211-20, 003

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