Prostatic Intraepithelial Neoplasia

A review article on prostatic intraepithelial neoplasia, the most likely precursor of prostate cancer.
by David G. Bostwick, M.D., M.B.A.

Introduction

High-grade prostatic intraepithelial neoplasia (PIN) is now accepted as the most likely pre-invasive stage of adenocarcinoma, a decade after its first formal description. PIN has a high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent invasive carcinoma. The only method of detection is biopsy; PIN does not significantly elevate serum PSA concentration or its derivatives and cannot be detected by ultrasound. Most studies suggest that most patients with PIN will develop carcinoma within ten years. PIN is associated with progressive abnormalities of phenotype and genotype that are similar to cancer rather than normal prostatic epithelium, indicating impairment of cell differentiation with advancing stages of prostatic carcinogenesis. Androgen deprivation therapy decreases the prevalence and extent of PIN, suggesting that this form of treatment may play a role in chemoprevention.

  • Do Men with PIN Have Prostate Cancer?

    The predictive value of high-grade PIN was evaluated in a retrospective case-control study of 100 patients with needle biopsies with high grade PIN and 112 biopsies without PIN matched for clinical stage, patient age, and serum PSA.(27) Adenocarcinoma was identified in 36% of subsequent biopsies from cases with PIN, compared with 13% in the control group. The likelihood of finding cancer increased as the time interval from first biopsy increased (32% incidence of cancer within one year, compared with 38% incidence in follow-up biopsies obtained after more than one year). High grade PIN, patient age, and serum PSA concentration were jointly highly significant predictors of cancer, with PIN providing the highest risk ratio (14.9). Other series have also found a high predictive value of PIN for cancer Table 3. (25, 33, 36, 38-47) These data underscore the strong association of PIN and adenocarcinoma and indicate that vigorous diagnostic follow up is needed.

    High grade PIN in transurethral resection specimens is also an important predictive factor for prostate cancer.(37, 38)(37,38) Among 14 patients with PIN and BPH followed for up to 7 years (mean, 5.9 years), three (21.4%) developed prostatic cancer.(37) Mean serum PSA concentration was higher than in those who did not develop cancer (8.1 ng/mL versus 4.6 ng./mL, respectively). All subsequent cancers apparently arose in the peripheral zone and were detected by needle biopsy. Thus, all tissue should be submitted by the pathologist for examination when high grade PIN is found in TURP specimens.(49) The high predictive value of PIN for the development of subsequent cancer warrants reporting the presence of PIN in TURP specimens, according to the Cancer Committee of the College of American Pathologists.(49) Conversely, a recent report showed that PIN in the transition zone and central zone from Norwegian men is not predictive of subsequent cancer development (50).

  • Does PIN Predict Cancer Recurrence?

    PIN was not predictive of PSA (biochemical) failure at 32 months in patients undergoing radical prostatectomy and androgen deprivation therapy (107).

  • Can Radiation Therapy Eliminate PIN?

    The prevalence and extent of PIN is decreased after radiation therapy.(116,117) However, one study paradoxically noted a higher incidence (70%) of PIN after radiation therapy than expected (118), but they failed to employ accepted diagnostic criteria for PIN, so their results are not comparable with others.

    Following radiation therapy, PIN retains the features characteristic of untreated PIN, and is readily recognized in tissue specimens.(116) The key pathologic features include nuclear crowding, nuclear overlapping and stratification, nuclear hyperchromasia, and prominent nucleoli. The basal cell layer is present, but often fragmented. The most common patterns of PIN are tufting and micropapillary, similar to those reported in untreated PIN (116).

    The long-term efficacy of radiation treatment may depend on eradication of cancer as well as precancerous lesions that may otherwise lead to evolution of secondary metachronous invasive cancers. Identification of residual or recurrent cancer portends a worse prognosis. The questions remain whether recurrent cancer after irradiation is due to regrowth of incompletely eradicated tumor or progression from incompletely eradicated PIN. Further studies of salvage prostatectomy specimens and post-RT needle biopsies are justified in an attempt to establish the significance of high-grade PIN as a source of long-term treatment failure among these patients. If PIN is associated with treatment failure, adjuvant chemoprevention strategies that ablate this lesion may reduce the risk of late cancer recurrence.

  • Can Androgen Deprivation Therapy Eliminate PIN?

    There is a marked decrease in the prevalence and extent of high grade PIN in cases after androgen deprivation therapy when compared with untreated cases Fig.12 Prevalence and extent of PIN following androgen deprivation. (107,109) This decrease is accompanied by epithelial hyperplasia, cytoplasmic clearing, and prominent glandular atrophy, with decreased ratio of glands to stroma. These findings indicate that the dysplastic prostatic epithelium is hormone dependent. In the normal prostatic epithelium, luminal secretory cells are more sensitive to the absence of androgen than basal cells, and these results indicate that the cells of high grade PIN share this androgen sensitivity. The loss of some normal, hyperplastic, and dysplastic epithelial cells with androgen deprivation is probably due to acceleration of programmed single cell death.

    Blockade of 5-alpha-reductase with finasteride appears to have little or no effect on PIN, unlike other forms of androgen deprivation therapy.(110) The incidence of PIN was unchanged in one study after one year of finasteride, and there was a significant increase in the number of patients with subsequent cancer on biopsy after this treatment (111).

  • What is the Evidence Linking PIN and Cancer?

    High grade PIN is strongly associated with prostate cancer, according to virtually all available evidence to date. The incidence and extent of PIN appear to increase with patient age.(8, 16, 19, 54, 55) An autopsy study of step-sectioned whole mount prostates from older men showed that the prevalence of PIN in prostates with cancer increased with age, predating the onset of carcinoma by more than five years Fig.7 Frequency of PIN with increasing age.(19) A similar study of young men revealed that PIN is first seen in men in their twenties and thirties (9% and 22% frequency , respectively), and precedes the onset of carcinoma by more than ten years.(54) Most foci of PIN in young men are low grade, with increasing frequency of high grade PIN with advancing age. The prevalence of PIN is similar in blacks and whites.(54) The volume of high grade PIN also increases with patient age (8).

    The frequency of PIN in prostates with cancer is greater than in prostates without cancer in men over 50 years of age (82% versus 43%, respectively); similarly, the severity of PIN is greater in prostates with cancer Fig.8 Freedom from cancer from time of first biopsy (3). The mean volume of PIN in prostates with cancer is 1.2- 1.32 cc, and the volume increases with increasing pathologic stage, Gleason grade, positive surgical margins, and perineural invasion.(8, 56) These findings underscore the close spatial and biologic relationship of PIN and cancer, and may result from an increase in PIN with increasing cancer volume.

    PIN and cancer are usually multicentric.(8, 13 53, 57, 59, 60) PIN is multicentric in 72% of radical prostatectomies with cancer, including 63% of those involving the non-transition zone and 7% of those involving the transition zone; 2% of cases have concomitant single foci in all zones.(8) The peripheral zone of the prostate, the area in which the majority of prostatic carcinomas occur (70%), is also the most common location for PIN.(8, 13, 16 53, 57, 58) Cancer and PIN are frequently multicentric in the peripheral zone, indicating a "field" effect similar to the multicentricity of urothelial carcinoma of the bladder (59).

    PIN is associated with progressive abnormalities of phenotype and genotype which are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis Fig.9 Genetic changes associated with progression of prostate cancer. There is progressive loss of some markers of secretory differentiation, including prostate-specific antigen, (60) Fig. 10A, B Progressive loss of markers of secretory differentiation prostatic acid phosphatase, secretory proteins (61-63), cytoskeletal proteins (63), glycoproteins such as blood group antigens (64), neuroendocrine cells (65), p-cadherin (66), fibroblast growth factor-2 (67), inhibin (68), prostate-specific transglutaminase (69), androgen receptor expression (70, 71), insulin-like growth factor binding protein-3(72), and telomerase.(73) A member of the CIP/KIP family of cyclin-dependent kinase inhibitory proteins, p27KIP1, also showed significant reduction in expression in PIN, cancer, and metastatic cancer when compared with benign prostatic epithelium.(74) Other markers show progressive increase, including including human glandular kallikrein 2 (hK2),(75) c-erbB-2 (Her-2/neu) and c-erbB-3 oncoproteins (67, 76,77), c-met proto-oncogene (78),bcl-2 oncoprotein (77, 79, 80), mutator (RER(+)) phenotype (81), epidermal growth factor and epidermal growth factor receptor (67, 82), type IV collagenase (83), Lewis Y antigen, TGF-alpha, apoptotic bodies (77, 81, 84, 85), mitotic figures (85), PCNA expression (86), Ki-67 expression (87), MIB-1 expression (71, 87), tenascin-C (88), aneuploidy and genetic abnormalities Fig.11.1, 11.2 Whole mount section of Prostate (71, 89-98), microvessel density, (99) Ep-Cam transmembrane glycoprotein (100), Insulin-like growth factor binding protein IGFBP-rP1 (101), and p53 mutations (102), although one group found no p53 expression immunohistochemically in PIN. (77) Prostate-specific membrane antigen, an abundant transmembrane glycoprotein, shows increased expression in PIN and cancer when compared with benign epithelium (103, 104), and this expression was unaffected by short-term androgen deprivation therapy.(104) Estrogen receptor alpha is present in up to 28% of cases of PIN and 43% of cancers, but estrogen receptor beta is absent (105); prolactin receptor expression is increased in PIN (106).

    A model of prostatic carcinogenesis has been proposed based on the morphologic continuum of PIN and the multi-step theory of carcinogenesis (4).

  • Can Transrectal Ultrasound Detect PIN?

    By transrectal ultrasound, PIN may be hypoechoic like carcinoma, although these findings have not been confirmed.(19, 20) Today, most urologists and radiologists do not believe that PIN is detectable by transrectal ultrasound because PIN is a microscopic finding which is below the detection threshold for this form of imaging.

  • Is Microvessel Density Increased in PIN?

    PIN is virtually always accompanied by a proliferation of small capillaries in the stroma, despite separation from the underlying vasculature by a basal cell layer and basement membrane. It is likely that PIN initially coopts adjacent vessels, similar to other tumors, and that these vessels soon regress, only to be followed by vigorous angiogenesis at the cancer's edge.(112) A critical balance exists between the pro-angiogenic vascular endothelial growth factor and the angiogenic antagonist angiopoietin-2.

    Microvessel density is higher in high grade PIN than in adjacent benign prostatic tissue (113,114), and the capillaries are shorter, more widely spaced, have more open lumina and curvaceous external contours, and are lined by a greater number of endothelial cells.(99) The degree of microvessel density in PIN is intermediate between benign epithelium and cancer, lending support to the concept of PIN as the precursor of prostate cancer. Inhibition of angiogenesis may be an effective method of chemoprevention, particularly for men at high risk such as those who have high grade PIN. It should be well tolerated in most adults because angiogenesis under typical conditions is needed only for reproduction and wound healing (115).

  • What are the Diagnostic Criteria of PIN?

    Prostatic intraepithelial neoplasia (PIN) refers to the putative precancerous end of the continuum of cellular proliferations within the lining of prostatic ducts, ductules, and acini. Fig 1.0 model of prostatic carcinogenesis The term prostatic intraepithelial neoplasia has been endorsed at multiple consensus meetings, and terms such as dysplasia, malignant transformation, and intraductal carcinoma are discouraged (9-12).

    It is characterized by cellular proliferations within pre-existing ducts and acini with cytologic changes mimicking cancer, including nuclear and nucleolar enlargement. (3, 7) Fig. 2.1 and 2.2 Diagnostic criteria of high-grade prostatic intraepithelial neoplasia There are two grades of PIN (low grade and high grade), although the term "PIN" is usually used to indicate high grade PIN. The high level of interobserver variability with low grade PIN limits its clinical utility, and many pathologists do not report this finding except in research studies, including us. Interobserver agreement for high grade PIN is "good to excellent".

    The tufting pattern is the most common, present in 97% of cases, although most cases have multiple patterns. There are no known clinically important differencebetween the architectural patterns of high grade PIN, and their recognition appears to be only of diagnostic utility. Other unusual patterns of PIN include the signet ring-cell pattern, small cell neuroendocrine pattern Fig. 3.10 neuroendocrine cells, and mucinous pattern Fig. 3.11 PIN associated with copious mucin production,Fig 3.12 Alcain Blue staining highlighting mucin production. (14) The basal cell layer is usually fragmented in PIN but present, unlike cancer which lacks basal cell layer Fig. 3.13A,B Basal Cell Layer in PIN, Fig 3.14 Basal Cell Layer in PIN. The differential diagnosis of PIN includes numerous benign and malignant conditions of the prostate.

    PIN spreads through prostatic ducts in multiple different patterns, similar to prostatic carcinoma.(6, 15, 16) In the first pattern, neoplastic cells replace the normal luminal secretory epithelium, with preservation of the basal cell layer and basement membrane. This pattern often has a cribriform or near-solid appearance. Foci of high grade PIN are usually indistinguishable from ductal spread of carcinoma by routine light microscopy (15). In the second pattern, there is direct invasion through the ductal or acinar wall, with disruption of the basal cell layer. In the third pattern, neoplastic cells invaginate between the basal cell layer and columnar secretory cell layer ("pagetoid spread"), a very rare finding.

    Early stromal invasion, the earliest evidence of carcinoma, occurs at sites of acinar outpouching and basal cell disruption in acini with high grade PIN. Such microinvasion is present in about 2% of high power microscopic fields of PIN, and is seen with equal frequency with all architectural patterns (13).

  • Is PIN the Origin of Prostate Cancer?

    About 200,000 American men are diagnosed with prostate cancer each year, and millions more develop undiagnosed or hidden microscopic cancer. About 80% of men have microscopic prostate cancer by age 80 years, and the autopsy frequency of prostate cancer is remarkably similar in men around the world despite large differences in clinical detection. What is the origin of all of these prostate cancers? If we knew the answer to these questions, then effective measures could be developed to prevent cancer and thus conquer the second leading cause of cancer death among American men.

    High grade prostatic intraepithelial neoplasia (PIN) is the most significant risk factor for prostate cancer in needle biopsy specimens. Its role as the preinvasive stage of cancer was recently confirmed conclusively in two separate mouse models. (1, 2) PIN coexists with cancer in more than 85% of cases (3, 8) but retains an intact or fragmented basal cell layer, unlike cancer which lacks a basal cell layer.(5) The clinical importance of recognizing PIN is based on its strong association with prostatic carcinoma. PIN is strongly predictive of adenocarcinoma, and its identification in biopsy specimens of the prostate warrants further search for concurrent cancer. PIN alone has no apparent influence on serum PSA concentration, and it is not apparently visible by current imaging techniques Patients with PIN may be ideal candidates for chemoprevention trials.

  • Does PIN Elevate PSA?

    Biopsy remains the definitive method for detecting PIN and early invasive cancer, but non-invasive methods, including serum tests, are being evaluated.(17-23) Serum PSA concentration may be elevated in patients with PIN (17, 21), although these results have been refuted.(22, 23) There is a poor correlation of PIN and PSA density according to studies of radical prostatectomy specimens and preoperative serum.(22, 23) PSA increased from 8.4 to 11.6 ng/mL (mean) in patients with PIN who developed cancer within two years; patients with PIN who did not develop cancer during this interval had an increase in PSA from 4.8 to 5.9 ng/mL (5 patients) or decrease from 5.1 to 4.6 ng/mL; (24) however, these findings have not been confirmed (25)(25).

    The ratio of free to total PSA is the same for patients with high grade PIN and cancer, unlike low grade PIN and benign hyperplasia (17, 26), although this has also been refuted.(18) Many patients reported in these studies subsequently were found to have cancer, so the elevation in serum PSA concentration and its derivatives may have resulted from the undetected cancer.

  • Is PIN a Good Marker for Clinical Trials?

    PIN offers promise as an intermediate endpoint in studies of chemoprevention of prostatic carcinoma Fig.6 schema for chemoprevention. (51, 52) Recognizing the slow growth rate of prostate cancer and the considerable amount of time needed in animal and human studies for adequate follow-up, the non-invasive precursor lesion PIN is a suitable intermediate histologic marker to indicate subsequent likelihood of cancer (52).

  • How Should Men with High Grade PIN Be Treated?

    The clinical importance of recognizing PIN is based on its strong association with prostatic carcinoma. PIN has a high predictive value as a marker for adenocarcinoma, so its identification in biopsy specimens warrants further search for concurrent invasive carcinoma. If all procedures fail to identify coexistent carcinoma, close surveillance and follow-up are indicated.

    Follow-up biopsy is suggested at three to six month intervals for two years, and thereafter at twelve-month intervals for life.(7, 27) Some urologists have performed "saturation" biopsies, consisting of more than (12-15) biopsies in one session, often with brief general anesthesia in the operating theatre, in an effort to definitively exclude cancer. Most authors agree that the identification of PIN in the prostate should not influence or dictate therapeutic decisions.(7) The author is aware of 18 radical prostatectomies that were purposely (3 cases) or inadvertantly performed (15 cases) in patients whose biopsies contained only high grade PIN; all but two of the cases contained adenocarcinoma in the surgical specimen (DG Bostwick, personal communication, 1999).

  • How Often is PIN Found?

    The incidence of PIN varies according to the population of men under study.(28-36) The lowest likelihood is in men participating in PSA screening and early detection studies, with an incidence of PIN in biopsies ranging from 0.7- 20% Table 1. (28-36) Men seen by urologists in practice have PIN in 4.4- 25% of contemporary 18 gauge needle biopsies obtained by urologists Fig.5 200 consecutive needle biopsies. Those undergoing transurethral resections have the highest likelihood of PIN, varying from 2.8 – 33% Table 2. (35, 38-39) In such cases, all tissue should be examined, but serial sections of suspicious foci are probably not usually necessary. Select anti-keratin antibodies such as 34ß-E12 (high molecular weight keratin) may be used to stain tissue sections for the presence of basal cells, recognizing that PIN retains as intact or fragmented basal cell layer whereas cancer does not.(5) Unfortunately, needle biopsy specimens often fail to show the suspicious focus on deeper levels, precluding assessment by immunohistochemistry and compounding the diagnostic dilemma.

 

Summary

High grade PIN is the most likely precursor of prostatic adenocarcinoma, according to virtually all available evidence. PIN is associated with progressive abnormalities of phenotype and genotype which are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. There is progressive loss of some markers of secretory differentiation, whereas other markers show progressive increase.

The clinical importance of recognizing PIN is based on its strong association with prostatic carcinoma. PIN has a high predictive value as a marker for adenocarcinoma, and its identification in biopsy specimens of the prostate warrants further search for concurrent invasive carcinoma. Studies to date have not determined whether PIN remains stable, regresses, or progresses, although the implication is that it can progress. Androgen deprivation therapy decreases the prevalence and extent of high grade PIN, suggesting a role in chemoprevention.

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