European Urology 48 (2005) 379–385
Prostatic Intraepithelial Neoplasia (PIN): Importance and Clinical Management S. Joniau, L. Goeman, J. Pennings, H. Van Poppel* Department of Urology, University Hospital of the Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium Accepted 10 March 2005 Available online 24 March 2005
Keywords: Prostate cancer; High grade prostatic intraepithelial neoplasia (HG PIN); Low grade prostatic intraepithelial neoplasia (LG PIN); Chemoprevention
1. Introduction Prostate cancer (PCa) is the most frequently diagnosed non-skin tumor in the western world in men. The lifetime risk of an American man to develop a clinically significant PCa is between 17 and 20% dependent on ethnic origin. In the western world, mortality from PCa varies between 2.82 and 4.73%. PCa is responsible for 12.7% of total cancer death in American men and is the second leading cause of cancer death after lung cancer . The incidence of PCa is increasing with age. The probability of being diagnosed with prostate cancer is 1 in 19,299 for men younger than 40 years, 1 in 45 for men aged 40 through 59 years, and 1 in 7 for men aged 60 through 79 years . Although there are considerable geographical differences in lifetime risk for clinically significant PCa, there seems to be an equal spread for microfocal PCa . In view of the increased life expectancy, the absolute number of clinically significant PCa’s will probably increase in the coming decades. In this way, to prevent an equal rise in mortality, early detection of PCa will become essential, as will the detection of premalignant lesions such as Prostatic Intraepithelial Neoplasia (PIN).
* Corresponding author. Tel. +32 16 346 687; Fax: +32 16 346 931. E-mail address: [email protected]
(H. Van Poppel).
2. What are the histopathological criteria of PIN? PIN lesions can only be diagnosed by histopathological examination of prostatic tissue. It is impossible to detect PIN clinically by DRE, PSA or ultrasound. The earliest reports on premalignant prostatic lesions date back to 1926 . No distinction between PIN and lesions resembling PIN was made at that time. In 1965, Mc Neal described different lesions with possible premalignant features in prostatic epithelium . But it would last until 1986 when Mc Neal and Bostwick described the first reproducible criteria for the diagnosis of ‘intraductal neoplasia’. A classification into 3 grades was proposed . One year later, Bostwick and Brawer proposed to change the terminology to Prostatic Intraepithelial Neoplasia . Finally, in 1989, at a workshop on premalignant lesions of the prostate, the classification was changed into Low Grade (former grade 1) and High Grade (former grades 2 and 3) . Cytologically, LG PIN and HG PIN have clear and reproducible features (Table 1). Histologically, however, different architectural variations exist for HG PIN (Fig. 1). At least four distinct patterns can be distinguished: flat, tufting, micropapillary and cribriform . Less frequent are signet cell pattern, small cell neuro-endocrine pattern, mucinous pattern and microvacuolar pattern. In the big majority of PIN-lesions, a tufting pattern can be found. Frequently, multiple patterns can be found at the same time. Kronz et al.
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Table 1 Prostatic Intraepithelial Neoplasia (PIN): Diagnostic criteria modified from Bostwick DG, Brawer MK Low Grade PIN
High Grade Pin
Epithelial cell crowding and stratification, with irregular spacing
Similar to Low Grade PIN; more crowding and stratification; 4 patterns: tufting, micropapillary, cribriform, and flat
Cytology Nuclei Chromatin Nucleoli
Enlarged, with marked size variation Normal Rarely prominent
Basal cell layer Basement Membrane
Enlarged; some size and shape variation Increased density and clumping Occasionally to frequently large and prominent, similar to invasive carcinoma; sometimes multiple May show some disruption Intact
described a link between risk of finding PCa in repeat biopsies and PIN pattern . Patients with HG PIN in only 1 initial biopsy, or a mainly flat/tufting pattern had clearly less risk of finding cancer in subsequent biopsies (risk 21–23.5%), compared to patients with HG PIN in more than 1 initial biopsy, or a micropapillary and/or cribriform pattern (risk 70–73%). Others have not been able to confirm a link between histological pattern and the risk of finding PCa in subsequent biopsies [10,11]. The incidence of isolated PIN in prostate biopsies varies considerably in the literature. The main reason for this finding is the variation in study-population. In a screening-population, incidences between 0.7 and 20%
can be suspected. In a urological practice, incidences between 4.4 and 25% can be found. The highest rates can be found in TURP-specimens, were incidences between 2.8 and 33% are seen . In young man, most PIN-lesions are low-grade. The incidence and volume of high-grade lesions increases with age and ethnical group. In Afro-Americans, the prevalence of HG PIN is higher and the lesions are more extensive . Although the histopathological criteria for LG and HG PIN are well defined, a great inter-observer variability seems to remain. Especially, the distinction between LG and HG lesions is problematic. Allam et al. studied this phenomenon and concluded that the
Fig. 1. (A) Micropapillary High Grade Prostatic Intraepithelial Neoplasia; (B) Low Grade Prostatic Intraepithelial Neoplasia.
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difference in expertise at different centres, the studyconditions, the subjective application of the histopathological criteria and the influence of colleagues are the main problems .
3. PIN and PSA Many contradictory reports exist on the influence of PIN on serum-PSA. Immunohistochemical studies show a lower PSA-expression in PIN-lesions compared to benign tissue and PCa . PIN-lesions are epithelial abnormalities. PSA produced by PIN lesions follows the road of least resistance and is excreted in the seminal fluid. PCa forms tissue islands without surrounding basal layer and basal membrane. PSA excreted by PCa cells diffuses into the blood stream . Alexander et al. studied 194 radical prostatectomy specimens. High Grade PIN was found in 88% of the cases. Cancer volume, prostate volume, gleason score and extraprostatic extension all correlated with serum PSA values. HG PIN did not contribute to serum PSA . Other studies showed similar results and even proved that the finding of HG PIN had no effect on percentage free PSA [18,19].
4. PIN and prostate carcinoma Many studies have been conducted to correlate HG PIN with PCa. These studies showed epidemiological, morphological, zonal, spatial and genetic arguments for the multi-step theory in which it is hypothesized that PIN lesions are premalignant. However, recent prospective trials were not able to confirm HG PIN as a clinical variable to predict the outcome of repeat biopsies [20,21]. Possible reasons for this were that they used a screening population as study group and that they used a different repeat biopsy protocol. 4.1. Epidemiological arguments PIN lesions precede PCa with more than a decade. The incidence and extent of PIN lesions increase with age and this increase is similar compared to the increase of the finding of PCa with age. In an autopsy study, Mc Neal and Bostwick studied 400 prostate specimens. HG PIN was found in 82% of prostates bearing cancer, compared to 43% of benign prostates in patients aged 50 or more . Thus, HG PIN is found significantly more frequently in prostates with cancer than without cancer. Furthermore, HG PIN lesions are more pronounced in prostates with cancer than in prostates without cancer .
4.2. Zonal arguments PIN and PCa are mostly multifocal and preferentially found in the peripheral zone of the prostate. In an autopsy study of Haggman, HG PIN was found in 63% solely in the peripheral zone, in 36% in the peripheral and the transition zone and in 1% solely in the transition zone . These finding are similar to the zonal distribution of PCa, which originates from the peripheral zone in 75–80% and from the transition zone in 20–25%. 4.3. Morphological arguments The transition of normal prostatic epithelium to invasive carcinoma is a morphological continuum. LG PIN represents mild dysplasia and HG PIN moderate to severe dysplasia and carcinoma in situ. In HG PIN, the basal cell layer is disrupted or fragmented as can be seen with 34bE12 cytokeratin immunostaining. In prostate carcinoma, there is a complete loss of the basal cell layer . In PIN and PCa, there is an elevated expression of collagenase type IV compared to normal epithelium. This enzyme is responsible for basal membrane degradation and facilitates invasion . PIN is accompanied by increased angiogenesis and during further progression to PCa, this phenomenon is even increasing . Many studies have described marked similarities in nuclear properties in PIN as well as in PCa, e.g. amount of DNA, chromatin texture, chromatin distribution, nuclear perimeter, nuclear diameter and nuclear abnormalities . 4.4. Genetic arguments Several genetic changes encountered in PCa cells can be found in PIN lesions. The most frequently found chromosomal anomalies are overexpression on chromosome 7p,7q, 8q, and inactivation on chromosome 8p, 10q,13q, 16q and 18q. Inactivation of tumor suppression genes such as NKX3-1 (8p) and PTEN (10q), and overexpression of oncogenes such as c-myc (8q) and bcl-2 play an important role in the initiation and progression of PCa [28,29]. In a study by Qian, c-myc amplification and numeric chromosomal anomalies were studied in multiple foci of PIN and cancer in 25 radical prostatectomy specimens. Within the same prostate, larger chromosomal anomalies and more copies of c-myc were present in the cancer cells compared to PIN, though the overall frequency of these anomalies in PIN and cancer foci were similar . Together with the histological association between PIN and PCa, these findings support the multi-step theory in which PIN is considered a precursor lesion of PCa. Progression in carcinogenesis is the result of the accumulation of
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multiple genetic changes . Chronic or recurrent prostate inflammation may initiate and promote this cancer development . 4.5. Potential clinical markers Apart from genetical changes, biochemical markers can be identified in PIN. These markers can possibly be used to develop diagnostic or even therapeutic strategies. 4.5.1. Fatty Acid Synthase (FAS) and PIN FAS is over expressed in several cancers (prostate, breast, colon, endometrium, etc) and is a key enzyme in the de novo production of fatty acids. Swinnen et al. showed that FAS enables cancer progression and invasion, and is gradually more expressed from LG PIN over HG PIN to PCa . 4.5.2. Glycoprotein A80 (A80) and PIN A80 is a membrane-bound glycoprotein that is related to exocrine differentiation. Very similar to FAS, A80 is gradually more expressed from LG PIN over HG PIN to PCa . 4.5.3. Alpha-MethylAcyl-CoA Racemase (AMACR) and PIN AMACR is an enzyme that plays a key role in the Beta-oxidation in fatty acids. Benign prostatic tissue does not express AMACR, contrary to PIN and PCa [33,34]. Rubin et al. studied AMACR expression using a sensitive immunofluorescence method and found expression of AMACR in LG PIN and in histologically benign prostate tissue, suggesting the possibility of an early molecular alteration preceding a morphologic alteration. 4.5.4. p63 Recently p63, a p53 homologue, has been shown to useful as a basal cell-specific marker, and it frequently is used in addition to 34 beta E12 in difficult cases to distinguish between PIN and PCa. The main advantage of p53 above 34 beta E12 is that there is less variable staining . 4.5.5. RNASEL Carpten provided evidence that the RNASEL gene may be a candidate gene for HPC1. This gene is in the 1q linkage peak, and deleterious mutations were identified in two of eight families with evidence for linkage to 1q24-25 markers . 4.5.6. Macrophage Scavenger Receptor 1 (MSR1) MSR1 gene were found in 4.4 percent of Caucasians who had prostate cancer, compared to 0.8 percent who
were found to be unaffected following prostate cancer screening. A different mutation of the gene was found in 12.5 percent of African-American men with prostate cancer, compared to 1.82 percent of unaffected men . 4.5.7. GSTP1 The measurement of GSTP1 methylation may be used to improve the accuracy for detecting early-stage prostate cancer. Study results also indicate that small biopsy tissues samples may be sufficient in methylated GSTP1 testing . 5. Clinical importance of PIN The presence of PIN in prostate biopsies is the most important risk factor of finding PCa in subsequent biopsies. Several reports have shown cancer incidences of 13–30% in LG PIN and 27–66% in HG PIN in repeat biopsies. Davidson et al. found a PCa incidence of 35% in repeat biopsies in comparison to 13% cancer incidence in a matched control group with BPH . Although many authors do not believe that the finding of LG PIN in initial biopsies has clinical implications, a study by Goeman et al. showed similar cancer incidence in repeat biopsies in LG PIN and HG PIN. In the LG PIN group, 30% of patients had cancer in the repeat biopsy cores versus 27% in the HG PIN group . The risk for finding PCa in repeat biopsies seems to increase with length of biopsy interval. Age, PSA and HG PIN were independent predictors for PCa in repeat biopsies, with prostatic intraepithelial neoplasia providing the highest risk ratio of 14.93. It remains unclear whether PIN volume, numbers of biopsies with PIN and histological PIN pattern are predictive for PCa . These findings have clear practical implications. First, the pathologist should not only look for PCa but has the responsibility to mention the presence of HG PIN in his pathology report. Also LG PIN can not be ignored. Second, the urologist needs to be aware of the consequences of the finding of PIN and should propose repeat biopsies to the patient. 6. Management of PIN In the United States 1.300.000 prostate biopsies are preformed annually to detect 230.000 new cases of PCa. There are approximately 115.000 cases of isolated HG PIN diagnosed each year, representing an estimated 9% of prostate biopsies .
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6.1. Number of cores on initial biopsy Lefkowitz et al. has shown that if isolated HG PIN is found in a 12-core biopsy protocol, the cancer incidence in immediate 12-core repeat biopsy will only be 2.3%. This is in sharp contrast to the 27–30% cancer detection rate in repeat biopsies following initial sextant or octant biopsies . It is now generally accepted that initial sextant biopsies will miss an estimated 30% of cancers. But taking too many biopsies, can raise the concern of finding too many insignificant cancers (volume <0.5 ml and Gleason score less than 7), which may lead to overtreatment . Another concern is the increased morbidity with taking multiple site biopsies. Damiano et al. proposed an 8-biopsy regimen which clearly outperformed the standard sextant regimen in cancer detection rate (93 vs. 77%). The detection rate was only 3.1% lower than a 14-biopsy regimen . 6.2. Number of cores in repeat biopsy The jury is still out concerning the best repeat biopsy strategy following the diagnosis of isolated HG PIN in the initial biopsy. Sextant repeat biopsies have shown similar cancer detection rates as multiple zone repeat biopsies [25–75% vs. 33–47% respectively) . It is remarkable that the cancer detection rate will not decrease until the 5th set of rebiopsies. 6.3. Timing of repeat biopsy The time between repeat biopsies should depend on the initial amount of biopsies. Lefkowitz showed that repeat biopsy at a 3-year interval following an initial 12-core biopsy demonstrated a cancer detection rate of 25.7% versus 2.3% in early repeat biopsies. These data are in favour of a close follow-up with interval biopsies . Our group showed that an early repeat octant biopsy detected PCa in 20% in an initial octant biopsy protocol, and most were significant cancers on radical prostatectomy specimen. Three months later, a second repeat octant biopsy detected an additional 15% of PCa, but on final pathology, 60% had a tumor volume <0.5 ml and 90% had a gleason score of 6 or less . The ideal length of the interval still needs to be established in larger prospective studies. 6.4. Treatment of PIN 6.4.1. Dietary modifications A considerable amount of data suggests that the diet consumed in Western societies may be one of the main environmental factors affecting progression from microscopic to clinically significant PCa. The occidental diet is characterized by a high intake of energy, total fat and animal products (specifically milk and meat) and is positively linked to PCa mortality. Traditional
oriental cuisine uses more vegetables, cereals, soy, fruit, nuts and fish; there is a negative relationship to mortality from carcinoma of the prostate . Thus, it is hypothesized that adapting one’s diet could possibly have an effect on PCa incidence and development of premalignant lesions. The easiest way to achieve a change in diet is to add nutritients. Our group has performed a prospective 6-month follow-up study in patients with High Grade PIN. 100 men with isolated HG PIN in octant biopsies were included in a prospective trial, evaluating the effects of a short term Selenium-Vitamin E-Isoflavonoids supplement. Patients underwent repeat biopsies at 3 and 6 months. The risk of finding PCa after a 6-months follow-up period was 35.5%. Interestingly, in a large subgroup (64%), PSA decreased under supplement therapy. In this subgroup, the overall risk of finding cancer was only 24.5% compared to 55.6% in a smaller subgroup of patients (36%) in whom the PSA continued to rise under supplements . These data suggest that PSA becomes a useful clinical marker in the follow-up of HG PIN, if the patient is started on supplement therapy. Furthermore, is seems that continuation of supplements is only advocated in the patient group with a PSA response. 6.4.2. Androgen deprivation A marked decrease in the extent and prevalence of HG PIN occurs in patients treated with androgen ablation therapy compared to untreated patients. This is accompanied with epithelial hyperplasia, cytoplasmic clearing and glandular atrophy. This suggests that the dysplastic epithelium is sensitive to Hormonal Therapy (HoT) [46,47]. It is however unclear whether the histopathologic and immunohistochemical changes after HoT are clinically important. The underlying genotypic instability may be still be untouched and PIN might repopulate the prostate soon after androgen deprivation is stopped. 5-alfa reductase blockade with finasteride does not seem to have any effect on the incidence of PIN . In a study by Slem et al, the incidence of PIN was unchanged after 1 year substitution of finasteride and there even was a significant increase in the number of patients with cancer on subsequent biopsies after this treatment . 6.4.3. Radiation therapy The prevalence and extent of PIN lesions decreases significantly after RT. Following radiation therapy, PIN retains the typical characteristics of untreated PIN and is readily recognised on histopathology . The question remains if recurrent cancer after irradiation
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is due to regrowth of incompletely eradicated tumor or progression of incompletely eradicated PIN.
available evidence. The finding of isolated HG PIN in prostate biopsies should prompt the clinician to perform repeat biopsies. If no cancer is found on repeat biopsies, HG PIN might be considered for chemoprevention trials, based either on dietary modifications or pharmaceutical compounds.
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