Advances in Anatomic Pathology:
Treatment Effects in the Prostate Including Those Associated With Traditional and Emerging Therapies
Evans, Andrew J. MD, PhD, FRCPC; Ryan, Paul MD; Van derKwast, Theodorus MD
Department of Pathology, Laboratory Medicine Program, University Health Network, Toronto General Hospital, Toronto, ON, Canada
The authors declare no conflict of interest. Reprints: Andrew J. Evans, MD, PhD, FRCPC, University Health Network, Laboratory Medicine Program, Toronto General Hospital, Eaton 11-444, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada (e-mail: email@example.com).
Classic treatment options for prostate cancer consist of radical prostatectomy, antiandrogen (or hormonal) therapy, and radiation therapy. Hormonal and radiation therapy, in particular, have well known, often profound effects on the histologic appearance of benign prostate tissue and prostatic carcinoma. The tissue changes induced by these treatments have been comprehensively described in several sources. Novel therapies ranging from focal ablative treatments to highly targeted molecular therapies are beginning to emerge and pathologists will play a central role in documenting the effects of these treatments on normal and malignant prostate tissue. It is therefore important that pathologists have access to basic treatment information and a solid working knowledge of the morphologic changes induced by these therapies. This will ensure accurate interpretation and reporting of posttreatment prostate specimens. This review is based on a presentation given by Dr A. Evans at the International Society of Urological Pathology Companion Society Meeting (Hot Topics in Urological Pathology) at The United States Canadian Academy of Pathology Meeting in Washington DC on March 20, 2010. This review will cover the histopathologic features seen in benign prostate tissue and prostatic carcinoma seen following: hormonal therapy, radiation therapy, ablative therapies such as vascular-targeted photodynamic therapy, interstitial laser thermotherapy, and high-intensity focussed ultrasound. An emphasis is placed on these specific modalities as they are currently in use as primary, salvage, or investigational therapy in the treatment of prostate cancer.
Therapies targeting the androgen-dependent nature of prostate cancer (Table 1) are widely used and can have profound effects on the histologic appearance of both benign and malignant prostate tissue.1–4 Endocrine-based therapies historically consisted of orchiectomy and/or estrogen therapy to treat locally advanced or metastatic disease.5 Maximal androgen blockade (MAB), with a combination of leuteinizing hormone-releasing hormone agonists and pure antiandrogens (steroidal, nonsteroidal, or nonclassic), is used to produce “chemical castration.”5,6 These agents are not strictly used in combination and can be used as monotherapy. Anti-androgen therapies have been more recently used in combination with radiotherapy7 and in neoadjuvant settings prior to radical prostatectomy.8 In terms of chemoprevention, the use of 5α-reductase inhibitors (5ARI) appears to reduce the risk of prostate cancer development.9–11 Since hormonal treatments are commonly used, pathologists must be aware of these morphologic changes when interpreting biopsies, transurethral resections of prostate (TURP's) or radical prostatectomy specimens from such patients. This is especially true when the specimen is not accompanied by accurate and complete clinical information.
Effects of Maximal Androgen Blockade on Normal Prostate Tissue, Prostatic Carcinoma and High-grade Prostatic Intraepithelial Neoplasia
A spectrum of characteristic changes can be seen following MAB that varies in relation to the agent(s) and dose used as well as the duration of therapy. The vast majority of study describing the histopathologic changes associated with this therapy was published over a decade ago and there has been relatively little additional information published in this area since that time.1–4
In normal prostate tissue, one typically sees glandular atrophy, basal cell prominence, basal cell hyperplasia, and vacuolization of glandular epithelium. These treatment-induced changes are generally different between the peripheral and transition zones of the prostate, with basal cell hyperplasia predominating in the transition zone and glandular atrophy being more prominent in the peripheral zone (Fig. 1). The rupture of atrophic glands with extrusion of glandular secretions and corpora amylacea into the adjacent stroma may also be observed. The now outdated estrogen therapy is commonly associated with squamous metaplasia in normal glandular and ductal epithelium.12
MAB has historically been associated with a marked downstaging of prostatic carcinoma in roughly 50% of cases when used as neoadjuvant therapy before prostatectomy.13 This effect is largely attributed to shrinkage of the tumor(s) and is most pronounced in the setting of organ-confined (T2) disease. Tumor volume reductions in the order of 40% to 60% have been observed after 3 and 6 months of MAB respectively.14,15 Residual carcinoma in such prostatectomy specimens is frequently minimal in nature and may be quite challenging to identify (Fig. 2). No residual carcinoma may be identified in up to 8% of totally embedded prostates following MAB.13,16 In the absence of clinical information describing the use of neoadjuvant hormonal therapy, pathologists should always consider this possibility when confronted with an apparent “vanishing cancer” (pT0) that is associated with markedly atrophic peripheral zone tissue.3 An overall 22% reduction in extraprostatic extension has been observed in prostates after MAB. Margin involvement shows a roughly similar drop of approximately 20% on average, with reduced margin positivity being more pronounced in T2 as opposed to T3 disease.17,18 Significantly, fewer lymph node metastases are also found following MAB,19,20 even if serial sections and/or immunohistochemistry are employed.3 As several trials have failed to demonstrate a clinical benefit for neoadjuvant hormonal therapy before prostatectomy, this practice has largely been abandoned.21
The histologic appearance of prostate cancer can be drastically altered by MAB and this is well described in several sources.1–4 There is typically a decrease in the ratio of glands to stroma with the malignant glands decreasing in number and size. The malignant glands develop compressed, inconspicuous lumina and may appear as short chains or small clusters and cords of cells. It is also common to see single cells that resemble foamy histiocytes. Cytologically, the cancer cells develop clear, vacuolated cytoplasm with shrunken, pyknotic nuclei with inconspicuous nucleoli. It is not uncommon to observe a broad range of morphologic treatment effects in carcinoma in the same specimen (Fig. 3). Standard immunohistochemical staining using high molecular weight cytokeratin, p63, and alpha methyl acyl CoA racemase (AMACR) is usually effective in helping to confirm a diagnosis of prostatic carcinoma in challenging cases. Prostate specific antigen (PSA) staining is usually preserved, although it can be less intense than that seen in hormone-naive prostate cancer.
The morphologic changes associated with MAB typically become most pronounced after 3 months of sustained therapy; however, they are reversible over the same time period should the MAB be discontinued. In particular, nucleolar size tends to return to normal within 20 days of MAB cessation.15
Morphologic changes associated with MAB, such as the collapse of glandular structures and the arrangement of cells in solid sheets, would suggest a Gleason score in the range of 8 to 10/10. The bulk of available evidence indicates, however, that these tumor cells have a reduced proliferation capacity as shown by reduced mitotic activity22 and Ki-67/MIB-1 immunohistochemical staining.15 As such, it is generally accepted that tumor cells showing the effects of MAB do not possess the same potential for aggressive behavior as would truly high-grade, hormone-naive prostate cancer. The data available to date supports the notion that Gleason scores in this situation have no biological relevance, show poor reproducibility and, therefore, should not be assigned.1–4 Our approach has been to avoid assigning Gleason scores if the tumor uniformly shows pronounced treatment effect. If tumor showing treatment effect is admixed with foci showing no treatment changes, this can be indicated in a specific comment. If no treatment effect is noted despite the presence of clinical information indicating the use of MAB, this should similarly be indicated in a comment and a Gleason score can be assigned.
No method for providing reliable prognostic information for prostate cancer post-MAB has been developed, although an interesting classification scheme has recently been proposed by Efstathiou et al.23 These investigators recognized 3 architectural patterns in prostatectomy specimens in which preoperative androgen blockade was used: (1) single cells, cords and small clusters; (2) small, fused glands; and (3) cribriform growth with intraductal spread. Their review of 115 cases indicated that the presence of cribriform growth and intraductal spread were the strongest architectural predictors of PSA failure postprostatectomy.
Complete androgen-deprivation therapy has been found to decrease the incidence and extent of high-grade prostatic intraepithelial neoplasia (PIN).14,24–28 Vallancourt et al14 reported PIN as being present in fewer than 10% of prostates after complete androgen blockade. More recently, Kang et al27 noted that PIN was persistent in 16% of patients treated with androgen-deprivation therapy for >6 months and suggested that this provided evidence of variable sensitivity to antiandrogen therapy. It should be noted that the recognition of PIN may, however, become more difficult owing to the loss of nucleolar prominence that pathologists generally rely on to identify it. van der Kwast et al28 forwarded the idea that increases in nuclear size along with crowding and disordered nuclear arrangement could serve as adapted criteria for pathologists to use to recognize PIN following MAB.
Effects of 5ARI Therapy on Prostate Histology
5ARI's (finasteride and dutasteride) block the enzyme 5α-reductase that catalyzes the conversion of testosterone into the more potent androgen dihydrotestosterone. Although 5ARI's have most commonly been used to reduce prostatic volume in symptomatic benign prostatic hyperplasia, these agents are now used to treat male-pattern baldness and there has been considerable interest in examining the ability of these agents to reduce the risk of developing prostate cancer.10,29,30 The Prostate Cancer Prevention Trial, published in 2003, reported a 24.8% reduction in the prevalence of prostate cancer in patents in the finasteride arm over the placebo group in the 7-year follow-up period of the trial. There was, however, a higher proportion of higher grade cancers (Gleason 7 to 10/10) found in the finasteride group compared with patients given placebo.9 This finding led to studies looking at the influence of 5ARI's on prostate cancer morphology31 and the possibility that Gleason scoring post-5ARI therapy might be unreliable. Studies based on blind histologic review have since indicated that 5ARI's are not likely to cause morphologic changes that create artifactually increased Gleason scores.32 There is currently no consensus recommendation for pathologists to avoid reporting Gleason scores in specimens obtained from patients exposed to 5ARI's. As such, pathologists should provide Gleason scores for such specimens even in the knowledge that 5ARI's have been used. Most of the available evidence suggests that the increased incidence of higher grade cancers found in the Prostate Cancer Prevention Trial were a result of reductions in biopsy sampling error associated with prostate shrinkage in the 5ARI group.33–35
Neuroendocrine Differentiation Following Maximal Androgen Blockade
Although neuroendocrine (NE) differentiation in the form of small cell carcinoma or large cell NE carcinoma can be a de novo occurrence,36 there is also a well-established association between the appearance of NE differentiation and the use of MAB for usual acinar type prostatic adenocarcinoma.37,38 Scattered NE cells can be found in essentially all conventional acinar-type prostate cancers and Abrahamsson et al39 showed long ago that the proportion of NE cells in acinar type carcinoma, based on chromogranin A staining, increases after antiandrogen therapy. The duration of antiandrogen therapy is typically in excess of 2 years before the emergence of NE carcinoma.38 The morphology and immunophenotype of these tumors will be identical to such tumors found in other body sites and transitional forms showing combined acinar-type and NE morphology will occasionally be present.38 In our experience, a typical clinical scenario associated with NE differentiation is the patient on long-term MAB with stable or undetectable serum PSA and a steadily expanding tumor burden, including metastases to sites not typical for acinar-type prostate cancer. The presence of NE carcinoma in these patients tends to be an incidental finding in palliative TURP specimens performed for malignant urinary obstruction.38 In some instances, NE carcinoma was admixed with acinar type carcinoma showing marked antiandrogen therapy effects along with transitional forms between acinar type and NE carcinoma (Fig. 4). When NE differentiation is identified by pathologists, Gleason scoring should not be applied.40 The true frequency with which NE carcinomas develop following MAB is unknown, although evidence from a rapid autopsy study appears to indicate that it happens in roughly 10% of cases.41 The patients will most often be treated with standard chemotherapy used for NE carcinoma; however, this will generally be for palliative purposes only.38,42 These tumors will commonly show negative immunoreactivity with PSA and prostate specific acid phosphatase,38 a point that can create a challenge for pathologists faced with a biopsy of a metastatic NE carcinoma for which the primary site is unknown.
Radiation therapy (RT) for prostate cancer, whether as primary therapy, neoadjuvant before prostatectomy, or adjuvant after prostatectomy, is typically provided by interstitial brachytherapy or external beam approaches. Brachytherapy, involving the implantation of radioactive seeds in the prostate to treat clinically localized disease, is associated with excellent outcomes.43 External beam RT, including conformal and intensity-modulated modalities (IMRT), is more commonly used against locally advanced prostate cancer44,45 and can be combined with various forms of antiandrogen therapy.46 Radiosurgery using Gamma Knife and Cyber Knife technology to deliver highly focused beams to selected targets while minimizing the damage to surrounding tissue is currently under development.47
The most common post-RT prostate specimen that pathologists will encounter will be prostate needle biopsies. These can be performed as part of clinical trials or in response to rising posttreatment PSA values. In our experience, these biopsies will most commonly be performed 18 to 24 months after the final RT treatment. Salvage prostatectomy after failed primary RT is a somewhat challenging procedure and is not commonly performed.48 The morphologic changes in prostate tissue obtained after RT, with or without additional changes induced by combined antiandrogen therapy, have been well described and can be quite pronounced. Proper clinical information concerning the treatment history is essential in order for the pathologist to accurately interpret post-RT biopsies. There is no evidence to suggest that the morphologic changes in normal and malignant prostate tissue will differ based on the particular modality used to deliver the RT.
Changes in normal prostate tissue induced by RT include glandular atrophy, a marked increase in the amount of stroma relative glands, atrophy of the secretory epithelium, and prominence of basal cells, often with prominent cytologic atypia (Fig. 5).1,4,49–51 All of these features can usually be appreciated at low magnification. The degree of RT-induced change can vary markedly within a given biopsy and between patients.51 At intermediate magnification, the basal cells can display vacuolated cytoplasm and marked nuclear pleomorphism with hyperchromatic, smudged nuclei. They can also have macronucleoli mimicking those seen in invasive adenocarcinoma, which can be doubly alarming in appearance when the affected glands have a pseudoinfiltrative pattern. Paneth-cell, mucinous, and squamous metaplasia may also be seen when patients have been treated with RT alone or in combination with hormonal therapy.51 Finally, there can be variable amounts of stromal fibrosis along with marked vascular changes including luminal narrowing and fibrous obliteration. It has been the authors' experience that these changes can persist for >5 years after the final radiation treatment.
As is the case with MAB, the prevalence and extent of high-grade PIN is reduced in post-RT biopsies. When it can be recognized, the basic architectural patterns of high-grade PIN (flat, tufting, micropapillary, and cribriform) do not appear to be altered as a result of RT.1,51
The appearance of adenocarcinoma after RT can be highly variable, ranging from no obvious effects to alterations so profound that the affected glands and cells may be difficult to recognize as carcinoma.1,4,49,51 The complete range of RT-induced changes can be seen within a single needle core biopsy (Fig. 6). The recognition of such severely distorted malignant cells and glands can be made even more challenging when the specimen is not accompanied by information that mentions the history of radiotherapy. A heterogeneous appearance in terms of the degree of treatment-related change can certainly be present in needle biopsies, TURP's, or salvage prostatectomies. In all of these specimens, marked treatment effects typically manifest as haphazardly scattered glands or single cells with pale, vacuolated cytoplasm, and enlarged nuclei with prominent nucleoli (Fig. 6).1,4,49,51 The haphazard, infiltrative architecture appreciated at low-to-intermediate magnification is the key to distinguishing malignant glands with treatment effects from benign glands with radiation-induced atypia. Perineural invasion, if present, is another feature that can be helpful in identifying residual malignancy. In challenging cases, immunohistochemical staining with high molecular weight keratin and/or p63 and AMACR can be used to confirm the presence of malignancy (Fig. 6). Radiation effects do not change the expected staining patterns with these markers. In patients treated with combined RT and androgen-deprivation therapy, no additional treatment effects over and above those attributed to the RT will be observed if the patients are not receiving hormonal therapy at (or immediately before) the time of post-RT biopsy.51
Two-year post RT biopsy status has been shown to be strongly predictive of long-term disease-free survival.50 The features of greatest utility in this regard include the Gleason score and the degree of treatment effect.49,50 As with MAB, marked radiotherapy effects can result in apparent increases in Gleason score. Strategies for grading the degree of treatment effects and deciding on the applicability of Gleason scores have been developed; however, these should be regarded as experimental owing to lack of large-scale follow-up data. One method, developed by Bocking and Aufferman in 198752 and subsequently modified by Crook et al in 1997,49 includes an assessment of both cytoplasmic and nuclear features according to the details listed in Table 2. The cytoplasmic and nuclear features are graded separately and the individual scores are added together to give a combined score ranging from 0 to 6. Biopsies showing total grades 0 to 1 are the only category for which Gleason scores should be applied. The tumor morphology in these biopsies shows essentially no appreciable treatment effects and these cases are associated with local failure rates in excess of 55%.50 Biopsies showing tumor with combined treatment grades of 3 to 4 have local failure rates in the range of 30%.50 Carcinoma showing severe treatment effects, with total treatment grades of 5 to 6 on 24 month postradiation biopsies, have 5-year disease-free survival rates that are similar to negative biopsies according to a recent follow-up study by Crook et al.50 On the basis of this evidence, these investigators prefer to use the term “indeterminate” for tumor in the combined grade 5-6 category as opposed to referring to them as adenocarcinoma with marked treatment effects. For practical purposes, we recommend reporting the tumor as showing no-to-minimal, intermediate, or severe RT effects. We provide Gleason scores only in cases showing no to minimal RT change. This approach is consistent with general recommendations found in the urological pathology literature.1,4,51 For biopsies showing a spectrum of RT effects, we report these cases descriptively and indicate the approximate proportion of tumor showing each type of treatment change. Table 3 provides a summary of the most common diagnoses that we assign to post-RT biopsies. It has been our institutional experience that reporting the degree of RT effect is important for identifying patients who might benefit from salvage therapies in the setting of RT failure.
NEWLY EMERGING FOCAL/ABLATIVE THERAPIES
In addition to radical prostatectomy and RT, active surveillance/watchful waiting is now a viable option for patients with low-risk prostate cancer.53–56 Although this approach can avoid potentially unnecessary morbidity associated with definitive therapy, it is nonetheless limited by an inability to reliably identify all of the prostate cancers that are destined to behave aggressively. The concept that many men with low-risk prostate cancer are being either overtreated by radical prostatectomy and RT or undertreated by active surveillance has led to the development of minimally invasive, energy-based therapies that ablate the entire gland or only a portion of it. Precisely targeted ablative therapies aimed at locations from which positive cores were obtained after detailed mapping biopsies are also being developed in many centers (reviewed by Polascik and Mouraviev57 and Lindner et al58). These emerging treatment modalities include: high-intensity focused ultrasound (HIFU), vascular-targeted photo dynamic therapy (PDT), interstitial laser therapy, cryotherapy, and microwave thermotherapy (Table 4).None of them have been universally accepted as first-line therapies for prostate cancer and are currently best regarded as investigational treatments, particularly in the United States.
Information on the effects of these treatments on benign and malignant prostate tissue is now beginning to accumulate.4 It is likely that for the foreseeable future biopsy and prostatectomy specimens from such patients will only be encountered by pathologists working in specialized centers where these studies are conducted. Given the energy-based nature of these treatments, it follows that histologic changes will be largely confined to the areas that were targeted for ablation. Depending on the interval between treatment and when tissue is obtained after therapy, posttreatment samples will generally show relatively well-demarcated areas of coagulative necrosis, hemorrhage, granulation tissue, inflammatory/histiocytic infiltrates, and fibrosis in areas where the treatment has been effective.4 Ghosts of malignant glands may be appreciated in areas showing coagulative necrosis. Tissue obtained from untreated or suboptimally treated areas will show normal prostate tissue and/or adenocarcinoma with no apparent morphologic changes.
Cryotherapy causes localized tissue destruction as a result of ice ball formation and subsequent thawing. This causes direct cellular damage and secondary injury due to inflammation.58 Postcryotherapy biopsies are reported as being negative in 87% to 98% of patients.59 In 1 series, 92% of the positive biopsies after cryotherapy originated from the side opposite to one initially targeted for treatment. These were then retreated with another round of cryotherapy.60 Microwave thermotherapy creates tissue damage by exposing the prostate to temperatures in the range of 50 to 55°C for 5 to 15 minutes.61 Tissue necrosis and destruction of the prostatic urethra have been identified in radical prostatectomy specimens obtained 1 week after microwave therapy.61 Details on specific histopathologic changes seen in prostate tissue after cyrotherapy and microwave therapy are available.4 They will not be covered in detail in this study, as the authors do not have experience with tissue treated with these modalities. We do, however, have experience with biopsies obtained after HIFU and PDT and radical prostatectomy specimens obtained after interstitial laser therapy, as these modalities are currently either in use or are being evaluated our institution.
There is particular interest in the use of HIFU in many centers around the world as salvage therapy after failed RT or as primary therapy.57,62–65 HIFU therapy uses frequencies in the range of 0.8 to 3.5 MHz to ablate tissue by causing coagulative necrosis followed by cavitation as a consequence of alternating cycles of compression and rarefaction (reviewed by Lindner et al58). Focused HIFU beams held on target tissue for 3 seconds will raise the tissue temperature to >60°C and render it nonviable.66 HIFU operators use real-time visual feedback to assess tissue temperature during the procedure and to determine when the HIFU beam should be moved to the next target area.67 Although HIFU appears to provide acceptable short-term local control, it has not been approved as a primary therapy for prostate cancer by the United States Food and Drug Administration. Several devices including Albatherm (EDAP, Lyon, France) and Sonablate-500 (Focus Surgery, Indianapolis, IN) are in use for either focal or whole-gland therapy in men with low-intermediate risk prostate cancer. Biopsies obtained 3 to 6 months post-HIFU have been reported as being negative in up to 90% of patients, with no difference being identified between low and intermediate risk patients. Actuarial 5-year biochemical and disease-free survival rates after primary HIFU for localized disease have been reported as being 75% and 66% respectively. Upwards of 12% of men have gone on to have salvage hormonal therapy, RT, or radical prostatectomy in some series.57,62–65
Current literature contains only a few descriptions of the histologic changes seen in post-HIFU biopsies, TURP's, or radical prostatectomies. The earliest studies focused on acute tissue damage, such as coagulative necrosis and cystic cavitation, in canine prostates immediately after exposure to HIFU.68 Van Leenders et al69 subsequently described central necrosis and hemorrhage in prostatectomy specimens obtained from 9 patients 2 weeks after receiving HIFU therapy. These investigators also observed a loss of cytokeratin 8 expression in benign prostatic epithelium, indicative of severe tissue damage. Published information on the histopathologic features seen in post-HIFU biopsies is available in only 1 study of 25 patients who were biopsied at 6 months after primary HIFU treatment for low-to-intermediate risk prostate cancer (Gleason <7/10, pretreatment PSA <10 ng/mL, clinical stage T1-T2). Biermann et al70 noted chronic inflammation, reactive fibroblasts, glandular atrophy, hemosiderin deposition, acute inflammation, focal coagulation necrosis, stromal fibrosis, and stromal edema in benign post-HIFU tissue. Residual adenocarcinoma was identified in 44% of patients with cancer involving an average of 5% of the biopsy tissue. The adenocarcinoma showed no apparent treatment-related changes and Biermann et al70 recommended assigning Gleason scores to these biopsies. They also reported that immunohistochemical staining with high molecular weight cytokeratin remained useful in confirming the benign nature of atypical/reactive glands in post-HIFU biopsies.
We have recently completed a retrospective review of the histopathologic features seen in 30 sets of needle biopsies obtained ≥1 year after primary HIFU treatment for low-to-intermediate risk prostate cancer (manuscript in preparation). Of the 30 cases, post-HIFU biopsies were triggered by elevated posttreatment PSA values in 22 patients. The 8 remaining biopsies were performed as part of routine follow-up according to the practice of the urologists involved. Obvious HIFU-related effects manifesting as dense fibrosis and hemosiderin deposition was seen in 57% of the post-HIFU biopsy sets over a mean follow-up of 15.3 months. More extensive fibrosis (involving ≥50% of biopsy tissue) was associated a longer follow-up interval of 17.4 months. Foci of coagulative necrosis were found in only 4 cases (13%) at a mean follow-up interval of 8.5 months. In some of our cases, isolated corpora amylacea sitting in densely fibrotic stroma provided the only evidence of antecedent (likely benign) prostatic glands in the treatment area. Viable adenocarcinoma was found in 63% of the 30 post-HIFU biopsies in our series (Fig. 7). Although the vast majority of positive cases were associated with biopsies performed for elevated post-HIFU PSA (17 of 22 cases or 77%), viable carcinoma was also found in patients without elevated post-HIFU PSA (2 of 8 cases or 25%). As with the findings of Biermann et al,70 the residual post-HIFU adenocarcinoma in our series showed no treatment changes precluding the assignment of Gleason scores. The expected staining patterns of supporting immunohistochemical stains such as p63, 34βE12, and AMACR were unaffected by HIFU. In some instances a short course of antiandrogen therapy will be given 3 months before HIFU to shrink the prostate.64 Pathologists should be made aware of such a history in the event that morphologic changes associated with androgen-deprivation therapy are noted. This will likely to be relevant only in biopsies obtained soon after HIFU and within 3 to 4 months of the antiandrogen therapy.
PDT involves the intravenous administration of a bacteriochlorophyll derived pharmacologically inactive photosensitzers (WST-09 Tookad, STEBA Biotech, The Netherlands and WST-11, Stakel, STEBA Biotech) that absorb light maximally in the visible portion of the spectrum ranging from 732 to 763 nm.58,71,72 Activating light is delivered to the prostate triggering the formation of reactive oxygen species. This causes thrombosis and coagulation in the vascular bed exposed to the light source, resulting in localized necrosis in the adjacent prostate tissue.58 PDT has been investigated as salvage therapy after failed primary RT at University Health Network.71,72 Biopsies obtained 6 months after PDT show tissue damage characterized by a sharp demarcation from the surrounding untreated tissue (benign or malignant) (Fig. 8). It has been our experience that the boundary between treated and untreated tissue is much more distinct with PDT than with HIFU. The areas of damage are characterized by well demarcated areas of dense fibrosis often with an absence of prostatic glands at 6 months post-PDT. Less commonly, organizing granulation tissue or coagulative necrosis is present. Areas of viable adenocarcinoma located immediately adjacent to the foci of damage show no obvious morphologic changes that would preclude the use of Gleason scoring. It should be noted that the size of the areas of damage induced by PDT are a function of the dose of photosensitizer, the number of optical fibers placed in the prostate and the light dose per fiber. It is possible to ablate the entire gland by this method.72
Interstitial laser ablation is currently under investigation at our institution as a primary focally ablative therapy for low-risk prostate cancer.58,73,74 Laser fibers are inserted into the prostate by the perineum. Magnetic resonance imaging guidance is used to confirm proper placement of the fibers and to obtain real-time temperature monitoring during treatment.72 Four radical prostatectomy specimens obtained 1 week after focal laser therapy showed well-demarcated foci of necrosis corresponding to the areas targeted for therapy. The necrosis is surrounded by a small rim of hemorrhage. These same basic features will be seen in needle biopsies performed within 6 months of treatment (Fig. 9). Viable carcinoma in untreated areas of the gland shows no obvious morphology changes that would preclude assigning Gleason scores. Vital staining, based on immunoreactivity with cytokeratin 8, shows no viable glandular tissue (benign or malignant) in the treated area.73
CHEMOTHERAPY AND TARGETED MOLECULAR THERAPIES
Chemotherapy has traditionally been reserved for hormone-refractory metastatic disease and is generally used as a palliative measure. The agents used include, but are not limited to, mitoxantrone, etoposide, cisplatin, vinblastine, estramustine, paclitaxel, and docetaxel. As these tissues are not commonly the subject of biopsies or review by pathologists, there is little information concerning the effects of these agents on the morphology of prostatic carcinoma (particularly, over and above changes that would be expected after any previously administered antiandrogen therapy). There are many new drugs at various stages of development75,76 including those that target growth factor and signal transduction pathways, apoptosis and differentiation, angiogenesis and immunologic therapies and novel cytotoxic agents. It has been our limited experience, however, that these agents have essentially no effect on normal or malignant prostate tissue when given on a short-term neoadjuvant basis before radical prostatectomy (unpublished observations).
NUTRITIONAL AND HERBAL SUPPLEMENTS
The use of vitamins D and E as well as nutritional supplements such as soy, selenium, tomato products, and green tea as potential preventative agents for prostate cancer is currently under investigation. No significant morphologic changes in either normal prostate tissue or prostate cancer have been reported to date and the use of these agents will likely have no impact on the ability of pathologists to accurately diagnose and grade prostate cancer in biopsies, TURP, or prostatectomy specimens.3 The same would appear to apply to herbal supplements used to promote prostate health, such as saw palmetto berry extract.
The treatment options currently available for prostate cancer are frequently associated with morphologic changes in benign and malignant prostate tissue, some of which have implications with respect to assigning Gleason scores and directing additional treatment for the patients involved. Knowledge of these treatment-related changes and access to basic treatment information are essential to ensure accurate interpretation and reporting of posttreatment prostate specimens by pathologists. With the evolution of new chemotherapies and targeted molecular therapies, there will be a need for new information on the effects of these agents on prostatic tissue and pathologists will most certainly play a valuable role in this process.77
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