Prostatic Intraepithelial Neoplasia: An Update Liang Cheng1,2 Ryan F. Paterson2 Stephen D.W. Beck2 Jodi Parks1
of Pathology and Laboratory Medicine of Urology Indiana University School of Medicine Indianapolis 2Department
Clinical Prostate Cancer, Vol. 3, No. 1, 26-30, 2004 Key words: Adenocarcinoma, Chemoprevention, Needle biopsy, Prognosis, Prostate-specific antigen
Submitted: Jan 12, 2004; Revised: Mar 30, 2004; Accepted: Apr 9, 2004 Address for correspondence: Liang Cheng, MD Department of Pathology and Laboratory Medicine Indiana University Medical Center University Hospital 3465 550 North University Blvd Indianapolis, IN 46202 Fax: 317-274-5346; e-mail: [email protected]
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High-grade prostatic intraepithelial neoplasia (HGPIN) is commonly encountered on prostate needle biopsies and, based on epidemiologic, molecular, and animal models, has proven to be the most significant risk factor for prostate cancer and likely represents the premalignant phase of prostatic adenocarcinoma. This lesion is characterized by cellular proliferations within pre-existing ducts and glands, with nuclear and nucleolar enlargement similar to prostate cancer. However, unlike cancer, HGPIN retains a basal cell layer identifiable by immunohistochemistry with the basal cell–specific antibody cytokeratin 34βE12. The incidence of HGPIN identified in needle biopsies is as high as 25%, increases with age, and coexists with prostate cancer in approximately 85% of cases. There appears to be no causal relationship between HGPIN and serum prostate-specific antigen (total, percent free, or density) or radiographic characteristics on transrectal ultrasound. In a large series, the identification of HGPIN on initial needle biopsy is associated with about a 35% risk of prostate cancer on subsequent biopsies. Thus, the finding of HGPIN on prostate needle biopsy necessitates a second biopsy in a patient eligible for curative treatment. As a precursor lesion, HGPIN is currently a target for chemopreventive strategies, including antiandrogens and nutritional supplementation.
Prostatic intraepithelial neoplasia (PIN) consists of architecturally benign prostatic acini or ducts lined by cytologically atypical cells and is a common pathologic finding in routine prostate needle biopsies performed in response to an elevated serum prostate-specific antigen (PSA) level or an abnormal digital rectal exam. Prostatic intraepithelial neoplasia is most commonly found in the peripheral zone and is characterized by cellular proliferations within pre-existing ducts and glands with cytologic changes mimicking cancer. However, PIN retains an intact or fragmented basal cell layer with no stromal invasion unlike cancer, which lacks a basal cell layer. Prostatic intraepithelial neoplasia is divided into low- and high-grade categories. Low-grade PIN is no longer commented on in surgical pathology reports, as this diagnosis has questionable clinical significance with a significant interobserver variability in making the diagnosis.1-6 In contrast, high-grade prostatic intraepithelial neoplasia (HGPIN) has proved to be the most significant risk factor for prostate cancer and is considered a precursor for invasive cancer.2,3,7 In this review, we will discuss the epidemiology, pathology, and clinical management of HGPIN.
Figure 1 High-Grade Prostatic Intraepithelial Neoplasia A B
Proliferation of the luminal cell layer is evident as indicated by the red arrow (A). The neoplastic cells have large, hyperchromatic nuclei with prominent nucleoli, as indicated by the arrow in the enlarged region (B). Nuclear crowding and overlapping are present.
Epidemiology of High-Grade Prostatic Intraepithelial Neoplasia A review of prostatic needle biopsy specimens reveals significant variation in the incidence of HGPIN (reported range, 0.7%-25%).8-12 This pronounced variation in the reporting of HGPIN in prostatic needle biopsy specimens likely results from differences in study populations, biopsy sampling and handling, and the judgment of individual pathologists in making the diagnosis.6,8,10 Rarely involving only the transition zone, HGPIN is not commonly found in transurethral resection specimens.13,14 In contrast, it is frequently encountered in radical prostatectomy specimens with a reported range of 59%-100%.6,8,10 High-grade prostatic intraepithelial neoplasia is considered to be a precursor to prostatic adenocarcinoma.7 Benign prostate glands are less likely to contain HGPIN than those prostate glands that contain adenocarcinoma.15 In an autopsy series consisting of whole mounted prostates, McNeal and Bostwick reported a 43% prevalence of PIN (low-grade and high-grade) in benign prostates in contrast to an 82% prevalence of PIN in glands containing adenocarcinoma when patients of similar age were compared.16 Desai and Borges evaluated 110 surgical prostate specimens and found an 85% incidence of HGPIN in prostates with adenocarcinoma.15 None of the benign prostates harbored HGPIN. The incidence of HGPIN rises with advancing age, but it has been detected in patients as young as 30 years of age.17-19 Incidence also varies with race: African-Americans and Brazilians have both a higher prevalence and a younger age at presentation than do Caucasians.8,10 High-grade prostatic intraepithelial neoplasia is an insidious condition; these neoplastic proliferations are remarkably quies-
cent and do not produce early warning signs. High-grade prostatic intraepithelial neoplasia does not significantly elevate the serum PSA level or PSA density or decrease the free-to-total serum PSA ratio. It does not induce a palpable lesion on digital rectal exam and it is not visible on transrectal ultrasound.8,20-23
Pathology of High-Grade Prostatic Intraepithelial Neoplasia High-grade prostatic intraepithelial neoplasia is characterized by architecturally normal prostatic acini and ducts lined by cytologically atypical cells. In PIN, the greatest cellular proliferation occurs on the luminal side of the acini and ducts in contrast to the predominantly basal proliferation of cells seen in benign glands. The cytologic features of HGPIN include prominent nucleoli, nuclear enlargement, nuclear crowding, and a fragmented and disrupted basal cell layer (Figure 1). Similar to prostatic adenocarcinoma,24 HGPIN is often multifocal and most commonly found in the peripheral zone.8,9,25 It is more common than adenocarcinoma in the apical region of the prostate. The identification of HGPIN on initial needle biopsy has been associated with a 50%-75% risk of subsequent prostate cancer.26-29 However, the largest contemporary studies report a risk of 23%-35%.30-33 If HGPIN is found on a biopsy sample of a prostate with a palpable lesion, the incidence of invasive cancer on subsequent biopsy increases significantly. In this setting, the correlation between a diagnosis of HGPIN and a later diagnosis of prostate cancer can be as high as 100%.8 In addition to the finding of HGPIN in needle biopsy specimens, HGPIN is even more frequently encountered in radical prostatectomy specimens in which HGPIN is commonly found in association with small-volume tumors. It is rarely found with large,
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Prostatic Intraepithelial Neoplasia poorly differentiated cancers; presumably, the larger, more aggressive tumors “overgrow” and obliterate the PIN lesions.6,10,21,22 There are 4 main patterns of HGPIN: tufted (the most common pattern, present in 97% of cases), micropapillary, cribriform, and flat.9 Most studies indicate that the PIN subtypes do not influence the risk of subsequent development of prostate cancer or the overall prognosis.22 However, Kronz et al recently reported that the micropapillary/cribriform pattern was more predictive of subsequent prostate cancer than the tufted or flat variants.32 These authors also contended that the only independent histologic predictor of a subsequent cancer diagnosis was the number of core biopsies with HGPIN. The risk of discovering cancer on subsequent biopsy was noted to be 30% with 1 or 2 cores, 40% with 3 cores, and 75% with > 3 cores. The differentiation of HGPIN from prostate cancer can be difficult, and immunostaining with antibodies directed against the basal cell–specific cytokeratin 34βE12 can be helpful. A discontinuous or fragmented basal cell layer also distinguishes HGPIN from adenocarcinoma, which lacks a basal cell layer.7 High-grade prostatic intraepithelial neoplasia, benign prostatic epithelium, and prostate adenocarcinoma are androgendependent tissues. However, immunohistochemical staining has shown that acinar lining (luminal surface) cells with PIN express less PSA than do benign acinar cells.34
High-Grade Prostatic Intraepithelial Neoplasia After Treatment The treatment of prostate cancer with androgen antagonists and radiation therapy results in a reduction in the prevalence and extent of HGPIN.35-38 This response is presumed to be caused by the induction of apoptosis (programmed cell death). However, underreporting of the lesion by pathologists is also a contributing factor. Interestingly, the observed morphologic changes caused by antiandrogen therapy are reversible, and HGPIN may flourish when re-exposed to androgens. There is a valid concern that the long-term use of antiandrogen therapy for chemoprevention (discussed herein) may lead to the emergence of androgen-insensitive clones.37,39,40 Blockade of 5-alpha reductase with finasteride appears to have little or no effect on PIN.41 Cote et al reported that the incidence of PIN was virtually unchanged on subsequent biopsy in a study group that took finasteride for a period of 1 year.41 Patients with adenocarcinoma who took finasteride had a significantly greater risk of persistence of prostate cancer on subsequent biopsy after 1 year (30%) than the men in the observation-only group (4%).41
Clinical Management of Patients with High-Grade Prostate Intraepithelial Neoplasia on Needle Biopsy Recently, the World Health Organization consensus conference on premalignant lesions in the genitourinary tract published recommendations for the management of patients with HGPIN.3,8,10 The panel recommended that only patients
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considered candidates for curative treatment of localized prostate cancer should undergo additional investigations following a diagnosis of HGPIN on initial biopsy. When HGPIN is noted in the initial prostate needle biopsy specimen in a patient eligible for curative treatment, repeat prostate biopsy should be recommended. Since HGPIN is often multifocal, subsequent biopsy should include the sextant regions of the prostate as well as the regions where PIN was found initially. If the second biopsy is normal, annual serum PSA tests and digital rectal exams are recommended. Repeat biopsy should then be performed if the PSA rises. On the other hand, if HGPIN is found on the second biopsy, the risk of invasive prostate cancer should be discussed with the patient. In this scenario, another biopsy within a year can be considered.8 Notably, the presence of HGPIN alone on repeat biopsy does not warrant curative treatment but does mandate careful follow-up.8,27,33 In recent years, there has been a significant decline in the predictive value of confirming a diagnosis of cancer following an initial diagnosis of HGPIN.42-45 In a multi-institutional study, Sakr et al showed that the probability of confirming prostate cancer on follow-up biopsy of isolated HGPIN was only 27%.42 Gokden et al studied 221 men with HGPIN in needle biopsy and found the detection rate of prostate cancer upon repeat biopsies had dropped to 28%.43 In a recent study by Schlesinger and Bostwick, the cancer detection rate was only 22% after an initial diagnosis of HGPIN.44 Prostate cancer was found in only 25% of patients with an isolated HGPIN after extended-core sampling in another study.45 The recent trend toward lower cancer detection rates after a diagnosis of HGPIN, as compared with those previously reported in unscreened populations, may be attributed to stage migration, lower cancer volume in highly screened populations, more extensive tissue sampling, and the use of new biopsy strategies with the addition of more lateral biopsies. These findings may have implications in designing follow-up plans for patients with the diagnosis of an isolated HGPIN. Other factors, such as patient’s age, family history of prostate cancer, serum PSA levels, digital rectal examination findings, and certain histopathologic attributes of HGPIN, should be considered in clinical management. High-grade prostatic intraepithelial neoplasia is commonly encountered in radical prostatectomy specimens. The presence of HGPIN in tandem with adenocarcinoma should not alter the postoperative management of the patient.22 Balaji et al reported that the presence of HGPIN in a radical prostatectomy specimen was not predictive of a postoperative rise in PSA.36 This study included 50 patients who underwent radical prostatectomy and 3 months of neoadjuvant hormone therapy. The median postoperative interval was 32 months.
Chemoprevention Autopsy studies suggest that PIN may precede the development of invasive prostate cancer by 5-10 years.17-19 Methods of early detection and possible treatment modalities for PIN are therefore areas of active research. Chemoprevention involves
Liang Cheng et al the administration of drugs or other agents to prevent the development of prostate cancer or to halt the progression of early prostate cancer to clinically significant disease. Multiple studies are currently under way to investigate the potential benefits of chemoprevention in patients with HGPIN.22 The Southwest Oncology Group S9917 phase III trial will compare treatment with placebo to treatment with a selenium supplement for men with HGPIN (Figure 2). The objectives of the trial are to compare the effects of selenium versus placebo on the 3-year incidence rate of prostate cancer in patients with HGPIN and the effects of these regimens on the rate of PSA increase in these patients. Androgen deprivation therapy (250 mg per day of flutamide) and nutritional supplementation (selenium, vitamin D, or vitamin E) are being compared to placebo in double-blind, randomized phase II trials.46,47 However, because of the risks of both side effects and the emergence of androgen-insensitive clones, these experimental treatments should be given only to patients with HGPIN enrolled in clinical trials.
Conclusion High-grade prostatic intraepithelial neoplasia likely represents the premalignant phase of prostatic adenocarcinoma and is commonly encountered in prostate needle biopsy specimens. Aggressive investigation (repeat biopsy) of patients felt to be candidates for curative treatment of localized prostate cancer is warranted in this setting. The presence of HGPIN in radical prostatectomy specimens should not alter postoperative management. Currently, chemotherapeutic strategies to prevent prostate cancer by treating its neoplastic precursor are being tested in clinical trials.
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Figure 2 Treatment Schema for SWOG S9917
Patients with HGPIN and PSA levels ≤ 10 ng/mL
R A N D O M I Z E
Selenium 200 μg p.o. daily for 3 years
Placebo 200 μg p.o. daily for 3 years
Abbreviations: HGPIN = high-grade prostatic intraepithelial neoplasia; PSA = prostate-specific antigen; SWOG = Southwest Oncology Group
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44. 45. 46.
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