Case 8 -

Effects of Therapy (Radiation, Hormones and Chemotherapy) on the Prostate Gland Lawrence True MD University of Washington Seattle, WA, USA

Clinical History: This 62 year old male underwent needle biopsy of the prostate following a screening serum PSA of 22 ng/mL. The biopsy revealed Gleason combined score 4 plus 3 = 7 of 10 adenocarcinoma of the prostate. Since the patient was deemed to be at "high risk of recurrence", he was entered into a neoadjuvant trial of Mitaxantrone plus Taxotere, following which he underwent a radical prostatectomy with lymph node dissection. The section is from the prostatectomy sample. Case 8 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Pathological Findings: Histologically the prostate is characterized by clusters and cords of small cells with amphophilic to clear cytoplasm interspersed between benign prostate glands exhibiting atrophic epithelial cells changes. The differential diagnosis includes high-grade prostate carcinoma, prostate carcinoma exhibiting effects of exogeneous therapy, i.e. androgen deprivation, and (arguably) inflammation with a prominent population of small histiocytes. Diagnosis: Adenocarcinoma with therapy effects Discussion: Radiation therapy (external beam and brachytherapy) The effects of radiation on the prostate are more severe when delivered as seed implants (brachytherapy, typically either Iodine or Palladium) than by external beam. And, the changes, which can vary markedly within a single prostate, are more marked in benign glands than in cancer. These changes sinclude atrophy (flattening of the epithelium), stratification of the epithelium with assumption of a predominant basal cell phenotype (high MW keratin+, p63+, PSA-), marked atypia of individual epithelial cells, and (much less frequent than is seen in some other tissues) stromal changes – fibrosis, vascular ectasia and stromal cell atypia. Cancer glands appear as "collapsed" nests of cells or as single cells with small, often punctuate nuclei, inconspicuous nucleoli and voluminous, vacuolated cytoplasm. Distinguishing single cancer cells from normal stromal cells with a clear cytoplasm or from histiocytes can be very difficult using only H&E stains. Hence, immunostains for basal cells (high MW keratin) and for cancer cells (low MW keratin and PSA) can be very helpful for diagnosing or for ruling out carcinoma. Systems for grading the extent of radiation effect on prostate cancer have been proposed as a basis for estimating prognosis. One study provided evidence that biopsies showing no treatment effect have a worse prognosis. However, no system of grading radiation effect has been widely accepted. A question that is often raised is "Does radiation to the prostate predispose to sarcomatoid carcinoma of the prostate?" There is no compelling evidence of a causal association, which seems reasonable, given the rarity of sarcomatoid prostate carcinoma and the large number of men who have received radiotherapy as primary treatment of their prostate carcinoma. Hormone deprivation therapy The hypothalamic-pituitary-gonadal-prostate axis can be blocked at a number of steps. Similar to radiation effect, androgen deprivation also causes atrophy of both benign and malignant prostate glands. However, in contrast to epithelial stratification and individual cell atypia resulting from radiation, benign glandular epithelium is attenuated by androgen deprivation. Cells, both benign and malignant are shrunken, without atypia, to the point of being inconspicuous. Basal epithelial cells of benign glands are often focally prominent. Furthermore, some glands may exhibit marked squamous metaplasia. The most remarkable degree of squamous metaplasia results from estrogenic compounds. As with radiotherapy, in the androgen-deprived state, prostate cancer cells can become so inconspicuous (though without the marked vacuolization characteristic of irradiated cancer cells) as to pose a risk of underdiagnosis. As with radiation effect, immunostains for low MW keratin and PSA can help rule out cancer. An interesting hypothesis that is gaining credence is that "Residual levels of androgens in patients receiving Total Androgen Blockade are at a sufficient concentration to continue to activate androgen receptor activated pathways." Furthermore, there is preliminary evidence that prostate cancer cells might be able to synthesize androgens from cholesterol since they express the appropriate enzymes. Consequently, a term more appropriate than "Androgen Blockade" is "Androgen Deprivation." Chemotherapy We are seeing increasing numbers of patients whose prostate cancers have been treated with chemotherapy – either in a neoadjuvant manner (as in the present case) or as second or third line therapy for metastatic cancer. In the trial in which the present patient was entered, "high risk of recurrence" was defined as a cancer that has any of the following features: Clinical stage T2c or surgically resectable T3a, or serum PSA ³ 15 ng/ml or Gleason score ³ 4+3 (4+3, 4+4, or 5 + any secondary pattern, but not 3+4). No patterns that are as distinct as those described for radiation or androgen deprivation therapy have been consistently associated with specific chemotherapy regimens. Other investigators have observed patterns in patients on chemotherapy similar to those we observed: inconspicuous glands (55% of tumors), vacuolization of tumor cells (25%), intraductal carcinoma (20%), and cribriform (14%). In a relatively short-term follow-up, we found that the presence of intraductal carcinoma predicts a shorter progression-free survival. "Intraductal carcinoma", defined as cribriform glands filling architecturally "intact" glands with basal cells in a manner suggestive as invasion into the glands, is a controversial concept. Although the phenomenon is associated with voluminous, invasive prostate cancer in the untreated state, what is not resolved is the distinction between intraductal carcinoma and high-grade Prostatic Intraepithelial Neoplasia (PIN). In our series, the association of intraductal carcinoma with rapid progression of tumor in patients who did not have an intraductal histology in their initial, pre-therapy biopsies suggests that this histological pattern is of prognostic importance. At the University of Washington we have had the experience of doing autopsies on > 50 patients who died of metastatic prostate cancer despite multi-modality therapy, including androgen deprivation therapy, chemotherapy and radiotherapy. To date, we have not been able to establish a correlation between the histopathology of the cancer (tumor histology, necrosis, fibrosis) and the type and duration of therapy or length of survival. What has been useful is learning how different the histology of these end-stage, heavily treated cancers is compared with untreated primary prostate cancer. We have classified the histological patterns into the following categories: diffuse sheets of tumor cells, microacinar, microacinar, signet ring cell-like, and comedocarcinoma. We have not found a consistent correlation between tumor histology and the original tumor grade. Finally, H&E histology may, in the future, be routinely supplemented by immuno-histochemical stains to assess changes in protein expression that are otherwise not detectable. For example, members of our group have identified genetic signatures of ischemia that occur after devitalization of the prostate and prior to fixation. Grading Since the histological effects of systemic therapy of the prostate can be quite marked and since no studies have determined that the histological changes of treated cancer have prognostic or predictive power, the general opinion is that treated cancers should not be graded. An exception could be cancer that exhibits none of the features of therapy effect that have been discussed above. References: Radiation Effects: Crook J, Malone S, Perry G, Bahadur Y, Robertson S, Abdolell M. Postradiotherapy prostate biopsies: what do they really mean? Results for 498 patients. Int J Radiat Oncol Biol Phys. 2000;48(2):355-67. 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