Definition

Prostatic intraepithelial neoplasia (PIN) is the abnormal proliferation and cellular dysplasia of prostate epithelium within the prostatic ducts, ductules and large acini without stromal invasion.^{13, 14} In describing HGPIN, terms such as intraductal dysplasia, duct-acinar dysplasia, intraductal carcinoma and other denominations have been discouraged.¹⁵ PIN has previously been classified as low grade corresponding to former grade 1 and high grade (HG) referring to former grades 2 and 3.^{1, 16} Currently, conventional use of the term 'PIN' typically refers only to HGPIN.¹⁶ It is widely accepted that low-grade PIN should not be reported by pathologists because of its poor interobserver reproducibility, the resemblance to benign prostate and the lack of clinical significance.^{16, 17, 18} The interobserver agreement among several pathologists is considered to be excellent for the diagnosis of HGPIN.^{17, 19} It is important to note that many older studies included patients with low-grade PIN, and as such, interpretation is difficult.

Prevalence

The incidence of isolated HGPIN (that is not associated with cancer) can be assessed from biopsy, transurethral resection, transvesical prostatectomy and autopsy studies. Its incidence in prostatectomy and autopsy series describes its true incidence, while its detection on needle biopsy is most clinically relevant to its management.

Biopsy series

The incidence of HGPIN on needle biopsy varies from 0.7 to 25% (Table 1),^{3, 4, 5, 6, 7, 8, 9, 10, 11, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38} with a mean incidence of 9.55% (median 8.75%). Authors from the WHO Consensus Conference in 2000 also reported on the frequency of HGPIN, particularly on needle biopsy specimens, with a range of 0.8–23.9%.³⁹ In another review evaluating the incidence of HGPIN in prostate biopsy, the authors were not able to identify any apparent trend related to the type of practice setting (community hospital, commercial laboratory or academic institution) or the number of cores sampled and time (before versus after year 2000).¹ Conversely, Bostwick and Qian¹⁶ observed that the lowest likelihood of diagnosing HGPIN was in men participating in screening and early detection programs, with incidence ranging from 0.7 to 20%, whereas men seen by urologists in practice had a diagnosis of 4.4–25%.

Table 1 - Incidence of isolated HGPIN in prostate needle biopsy series.

Full table

Many factors can be responsible for the marked variation of the incidence in the literature, including the absence of strict diagnostic criteria and definitions, and differences in the non-standardized pathological techniques during the processing of the specimen.¹ Additionally, differences in age, ethnicity and familial predisposition among the studied populations, and disparities in the biopsy indications, contribute to the heterogeneity of these patients.

Transurethral resection of the prostate series

In a retrospective review of patients operated between 1974 and 1975, well before the prostate-specific antigen (PSA) era, a Norwegian group reported the incidence of HGPIN in transurethral resection of the prostate (TURP) and open prostatectomy specimen to be 50 and 65%, respectively, in patients without carcinoma, and 73 and 28%, respectively, in patients with concurrent carcinoma. These high numbers may be explained by the age of the study population (72.4 and 69.1 years for those with and without concurrent carcinoma, respectively) and different selection criteria.⁴⁰ In more contemporary series, the occurrence of HGPIN in TURP specimens has shown to be relatively uncommon (Table 2).^{40, 41, 42, 43} Based in two large retrospective series, the estimated incidence ranged between 2.3 and 4.2%.^{42, 43} The incidence in patients with and without cancer ranged from 3.2 to 10.2 and from 2.3 to 2.8%, respectively.^{42, 43} In the Mayo Clinic group, 21.4% of those with HGPIN and no carcinoma on TURP progressed into prostate cancer, with a mean follow-up of 6 years. None of these patients died during the follow-up period, and none of the patients without HGPIN developed carcinoma in 7 years.⁴³ The low incidence of HGPIN lesions in TURP specimens demonstrates its histopathologic similarity to prostate cancer, in that it is far more likely to occur in the peripheral zone, usually not well sampled during TURP.

Table 2 - Incidence of HGPIN in TURP series.

Full table

Autopsy series

The prevalence of HGPIN on autopsy is influenced by several factors, including age, PSA, race/ethnicity and the familiarity of the pathologist in recognizing HGPIN. These factors are probably the reason for the wide variability of prevalence in reported series (37.8–84.4%) demonstrated in Table 3.^{13, 44, 45, 46, 47} The largest study of this kind was performed by Sakr,⁴⁸ who retrospectively analyzed 370 prostates from Wayne State University in a population composed of African Americans (60%) and Caucasians (40%). He found HGPIN in 18, 31, 69, 78 and 86% of African-American men, and in 14, 21, 38, 50 and 63% of Caucasian men, in the 4th, 5th, 6th, 7th and 8th decades, respectively. Moreover, he observed that more extensive lesions were more prevalent in the African-American cohort, particularly below 50 years of age, compared with the matching group of Caucasian men. When compared with a large cohort of 345 men undergoing radical prostatectomy, the authors observed a similar age- and race-stratified distribution of HGPIN.⁴⁸ In the majority of autopsy cases, HGPIN was coexistent with prostate cancer. The frequency of isolated HGPIN was not reported.

Table 3 - Incidence of HGPIN in autopsy series.

Full table

Radical prostatectomy/cystoprostatectomy series

The review of radical prostatectomy series allows analysis of the association between HGPIN and clinically significant cancers. The incidence of HGPIN reported in radical prostatectomy specimen studies ranges from 52.7% up to 100% (Table 4).^{41, 47, 49, 50, 51, 52, 53, 54, 55, 56} The observation that the majority of patients with cancer have HGPIN is highly supportive of the premalignant nature of the lesion, and may suggest its importance in predicting significant disease.

Table 4 - Incidence of HGPIN in radical prostatectomy and cystoprostatectomy series.

Full table

Analyzing 100 cystoprostatectomy specimens, Troncoso and et al.⁵⁷ observed that all prostates with incidental carcinoma also presented HGPIN. Kim and Yang,⁵² studying another cystoprostatectomy group of patients, similarly reported that all men with incidental prostate cancer had HGPIN, whereas 63% of men without prostate cancer had isolated HGPIN. Wiley et al.,⁵⁶ studying the association of HGPIN and incidental carcinoma in 48 cystoprostatectomy specimens, observed a prevalence of 83% with HGPIN and 46% with incidental carcinoma. Interestingly, 91% of incidental prostate cancers were found in prostates with extensive or multifocal HGPIN, whereas only 11% of cancers occurred in prostates with absent or only focal HGPIN. In the study of Kim and Yang,⁵² extensive lesions were more likely associated with cancer as compared to focal lesions (65 and 31%, respectively, P=0.021). This pathologic data implicates HGPIN volume as a risk factor for occult cancer, with more extensive lesions predicting an increased likelihood of harboring histologic cancer.^{52, 56}

Age distribution

The incidence and extent of HGPIN increase with age.⁵³ While it is first reported in men in the third and fourth decade of life, most of these foci in young men are small in volume and unifocal.⁵⁸ With age there is an increasing incidence of HGPIN, comprising larger areas with increasing multifocality.^{58, 59} This supports the likelihood of a stage migration within men with isolated HGPIN who are biopsied at lower PSA and age.

Ethnic distribution

Epidemiologic studies reported an elevated incidence and extent of HGPIN in African-Americans compared to Caucasian men, similar to the findings in prostate cancer incidence. Autopsy series demonstrate that HGPIN occurs earlier, is more extensive and is more prevalent among African-American men when compared to Caucasians.⁶⁰ Billis⁴⁴ also found that in spite of having similar incidence, HGPIN was more diffuse and extensive at younger age in African-Brazilian group of men than in Caucasian natives. The incidence of HGPIN in Asians is lower than Caucasian or African cohorts, although its presence still represents an increased risk of diagnosing concurrent or subsequent prostate cancer, as observed by Fujita et al.⁵¹ in Osaka. Another Asian group from Singapore found low rate of HGPIN on needle biopsy (4.6%) relative to Western populations.³⁶ These findings are consistent with the premalignant nature of HGPIN and the known ethnic distribution of prostate cancer.

Family history

There has been only one study performed in the literature that addresses the issue of whether family history of prostate cancer is a significant predictor of cancer among men with isolated HGPIN, but the authors could not establish the relationship.⁶¹

Histology of HGPIN

Because PIN is defined by the abnormal proliferation of the secretory epithelium within prostatic ducts and acini without the invasion of the basement membrane, its diagnosis is ultimately based on findings of atypical nuclei in cells lining architecturally benign glands. The nuclear atypia, specifically the presence of prominent nucleoli, is the basic difference between low-grade PIN and HGPIN.¹ In addition, nuclear atypia associated with HGPIN may also demonstrate anisokaryosis, hyperchromasia, nuclear enlargement and crowding (Figure 1).⁶²

Figure 1.

HGPIN histology. (a) HGPIN with micropapillary pattern (hematoxylin–eosin, original magnification 200); (b) HGPIN showing enlarged nuclei with prominent nucleoli (hematoxylin–eosin, original magnification 400); (c and d) comparison between the acinus with HGPIN on the left and uninvolved acini on the right. Note multilayered epithelium with enlarged nuclei and prominent nucleoli in HGPIN (hematoxylin–eosin, original magnification 400).

Full figure and legend (180K)

There are four main patterns of HGPIN (tufting, micropapillary, cribriform and flat) as described by Bostwick et al.⁶³ in 1993. Most of the cases have multiple patterns, with tufting pattern representing the most frequent, present in 97% of cases. It has generally been believed that there is no difference in clinical outcome among the different histologic patterns.^{62, 63} Some contemporary studies have suggested, however, that the presence of micropapillary or cribriform patterns may represent a higher risk of progression to cancer.^{61, 64}

The histologic behavior of HGPIN is additional strong evidence of its premalignant nature. Pathologists can identify inversion of the normal orientation of epithelial proliferation in HGPIN lesions occurring in the luminal surface instead of in the basal cells, as it occurs in other neoplasms.¹⁶ Moreover, one can recognize the histologic similarities between HGPIN and prostate cancer, as both spread through the ducts, cancer may replace the normal secretory epithelium without disruption of basement membrane, and HGPIN may invade directly through the ductal or acinar wall with disruption of the basement membrane and basal cell layer.⁶³ Similar to prostate carcinoma, HGPIN is commonly characterized by multicentric lesions that apparently arise independently within the gland and support the hypothesis of an underlying 'field effect.'^{53, 65} These studies show that 63–98% of HGPIN lesions are found in the peripheral zone of the prostate and follow a predominantly multicentric pattern.^{39, 46, 53, 56}

The extent of HGPIN in the prostate correlates not only with the presence of prostate cancer but also with cancer volume.¹⁶ Although there is no consensus about the criteria regarding the extent of isolated HGPIN (definition of unifocal or multifocal), some authors have found that patients with high volumes of HGPIN in prostate biopsy specimens frequently show significant higher rates of prostate cancer in subsequent biopsies.^{34, 56, 61, 64} This observation asserts that not only the presence of HGPIN but also the volume of HGPIN is an important marker for concurrent or subsequent carcinoma of the prostate. Comparing monofocal and plurifocal isolated HGPIN detected on extended first biopsy, Roscigno et al.,³⁴ found that plurifocal HGPIN was the strongest independent predictive factor for prostate cancer diagnosis on repeat biopsy at a median of 11.4 months after baseline biopsy. Bishara et al.⁶⁴ also observed statistical difference between the risk of cancer in men whose first rebiopsy showed HGPIN on one core (0/9) compared to those with HGPIN seen on multiple cores (8/16), representing an increased risk (50%) of finding concurrent cancer in these cases. It is important to note that the studies demonstrating an increased risk of cancer on repeat biopsy of men with multifocal HGPIN have all been conducted with a relatively short interval from baseline biopsy to repeat sampling. This supports the idea that the volume of HGPIN on initial biopsy is predictive of the likelihood of associated undiagnosed cancer, but it does not tell us about its impact on the long-term risk of progression to cancer.

Given that HGPIN glands contain an intact or fragmented basal cell layer while cancer glands do not, the use of staining techniques for the basal layer is the key to its immunohistochemical diagnosis. There are several high molecular weight cytokeratins that are only expressed by prostate basal cells but not by secretory cells, such as cytokeratin 1, 5, 6, 10 and 14.²⁷ Using select antibodies anti-keratin such as 34E12 and p63, pathologists can stain for the basal membrane. Monoclonal basal cell-specific anti-keratin 34E12 stains virtually all the normal basal cells and is the most commonly used immunostain for prostatic basal cells.^{27, 66} P63, a recently discovered p53 homologue, is a nuclear protein that is also selectively expressed in prostate basal cells and may be very useful as an alternative to 34E12 stain for difficult lesions.⁶⁷ Increasing grades of PIN are associated with higher rates of basal cell layer disruption, which occurs in approximately 56% of HGPIN and is more frequent in acini that are adjacent to carcinomas.¹⁶ Early histologic carcinoma can be frequently found at sites of glandular outpouching and basal cell layer disruption associated with HGPIN.¹⁴

Pathologists have often observed histologic lesions that show a clear transition from a non-invasive lesion (HGPIN) to an invasive area of neoplasia.^{46, 68} The presence of small atypical glands places the patients at an even higher risk of subsequent cancer (50%), and the signification of the association between HGPIN and small atypical glands is still unknown.⁶⁹ When these two lesions are presented adjacent to each other (PINATYP), it becomes a challenge to the pathologist to rule out or to issue the diagnosis of cancer, but the risk of subsequent carcinoma is reported to be certainly higher than HGPIN alone (45% up to 63%).⁶⁹

Molecular characteristics

HGPIN and prostate cancer share a constellation of genetic and molecular events that recently have been targeted by scientists. These findings provide compelling evidence that HGPIN represents the main precursor of histologic cancer, not only pathologically but also genotypically. Examples of this association are the frequent allelic loss of chromosome 8p12–21,⁷⁰ loss of telomere length⁷¹ and gain in chromosomes 7, 8, 10 and 12,⁷² found in both prostate cancer and HGPIN. Using microarray analysis, Calvo et al.⁷³ described a wide profile of genes abnormally expressed in both cancer and HGPIN. Other molecular markers have also been shown to be abnormally regulated in HGPIN, such as C-erbB-2 (HER-2/neu) and C-erbB-3 oncoproteins,^{74, 75} c-met proto-oncogene,⁷⁶ bcl-2 oncoprotein,⁷⁷ -methylacyl-CoA racemase,⁷⁸ glycoprotein A-80⁷⁹ and apolipoprotein D,⁸⁰ among a number of other proteins involved in prostate carcinogenesis and cancer growth, such as androgen receptor,⁸¹ insulin-like growth factor binding protein 3 (IGFBP3),⁸² fibroblast growth factor 2⁷⁴ and telomerase.⁸³ Microvessel density has also been shown to be increased in the stroma adjacent to HGPIN.⁸⁴

These molecular observations have allowed proposal of models of the prostate carcinogenesis including a sequence of events involving genetic predisposition, oxidative damage, inflammatory response and chromosomal changes that create the genetic instability necessary for progression to invasive disease.^{85, 86, 87} Despite ongoing efforts, there is no reliable molecular marker of isolated HGPIN. Such a marker would undoubtedly be valuable in better defining populations at high risk for prostate cancer and would allow monitoring of progression or therapy.

Contemporary clinical management

Given the large body of evidence that HGPIN is a pre-malignant lesion, which identifies a population at high risk for associated prostate cancer, it is desirable for the clinician to define a clear clinical approach to men with isolated HGPIN on needle biopsy. Recent controversy surrounding the clinical significance of HGPIN has largely resulted from the stage migration to smaller volume HGPIN that has occurred with the widespread use of extended core biopsies. Better baseline sampling results in a lower likelihood of occult, undiagnosed cancer, but it does not likely impact on the long-term risk of prostate cancer progression. Among men with isolated HGPIN, this remains poorly defined. In establishing a clinical approach to men with isolated HGPIN, three fundamental goals exist: (1) to rule out occult malignancy at baseline presentation; (2) to monitor for development of clinically detectable prostate cancer over time; and (3) to define means by which the risk of prostate cancer over time might be reduced.

Risk of concomitant occult cancer

At the time of the original description of HGPIN, the primary clinical goal was to determine the presence of prostate cancer on immediate repeat biopsy. The risk of having a concomitant prostate cancer after a diagnosis of HGPIN has ranged from 22 to 79%, with a mean incidence close to 30%.^{8, 28, 29, 61, 64, 88, 89, 90, 91, 92} In the early 1991, Brawer et al.⁸⁹ performed a study in 21 men with previously diagnosed PIN (grade I, II or III), who underwent a repeat ultrasound-guided biopsy due to palpable prostatic abnormality. Twelve of them (57%) presented with prostate cancer, including 18% of the men with grade I PIN and 100% of men with grade II and grade III (HGPIN). They highlighted the significance of finding HGPIN at prostate biopsy and emphasized the need to rebiopsy these patients with HGPIN, owing to the higher likelihood of finding concurrent cancers missed due to the limited sampling. Similar results were reported by Weinstein et al.,⁹⁰ who analyzed 33 cases of HGPIN patients who underwent repeat biopsy. Of these, 73% had concomitant carcinoma detected in either a simultaneous (42%) or subsequent biopsy (31%). Again, the authors concluded that the finding of HGPIN at prostate needle biopsy represented a great likelihood of detecting concomitant cancer and recommended close follow-up, including rebiopsy.

The relatively high incidence of concomitant prostate cancer noted in early studies was likely due, in part, to the typical limited sextant sampling generally employed at that time. Contemporary series report lower rates of cancer detection on follow-up biopsy after diagnosis of isolated HGPIN (Table 5).^{2, 3, 6, 8, 10, 11, 21, 28, 32, 33, 34, 64} Upon implementation of extended core biopsies into clinical practice, Lefkowitz et al.² postulated that immediate repeat biopsy among men with HGPIN may be unnecessary after a 12-core biopsy, given the better baseline sampling of the gland. Among 43 men biopsied with 1 year of a 12-core biopsy demonstrating HGPIN, cancer was found in one (2.3%). Subsequently, others have validated the findings of Lefkowitz et al. by showing a risk of subsequent carcinoma ranging from 10 to 27%^{8, 64, 93} among men with isolated HGPIN on extended core biopsy. These authors concluded that the risk of cancer on immediate repeat biopsy was no greater among men with isolated HGPIN than among those with benign baseline biopsy. The lower rate of cancer detection on immediate repeat biopsy observed in contemporary series may also be a function of stage migration owing to the use of biopsy in men with lower PSA levels, younger age and the implementation of population-based screening.

Table 5 - Rate of cancer detection on follow-up biopsy after diagnosis of isolated HGPIN.

Full table

Based on the earlier observations of Lefkowitz et al., the National Comprehensive Cancer Network (NCCN) made general recommendations on the management of isolated HGPIN in the Prostate Cancer Early Detection Guideline v.1.2006 (electronic access at http://www.nccn.org/professionals/physician_gls/
PDF/prostate_detection.pdf). It was recommended that while men with isolated HGPIN in an initial sextant needle biopsy should undergo repeat extended core biopsy, those with baseline biopsy of 10 or more cores could be considered for simple observation. In our practice, we have generally recommended that the decision for immediate repeat biopsy be made on the number of baseline cores, the location of baseline cores and the level of suspicion based on PSA level and rectal exam. In those individuals who have had <10 cores, no sampling of the far lateral peripheral zone, or PSA10 ng/ml, a repeat biopsy might be considered. Sampling of the transition zone should be used for men with PSA10 ng/ml, but does not appear necessary among men with isolated HGPIN alone, as there is no suggestion that HGPIN in the peripheral zone predicts a higher risk of isolated prostate cancer in the transition zone.

Long-term risk of prostate cancer

While the association of HGPIN with prostate cancer is well studied, there is limited knowledge regarding the long-term natural history of HGPIN, its risk of progressing to cancer or its timeline to cancer initiation. If in fact, isolated HGPIN represents a precancerous lesion, then one would expect a continued risk of progression to cancer over time. Pacelli and Bostwick⁴³ reported on the long-term risk of progression to cancer among 14 men diagnosed with HGPIN on TURP. At a median follow-up of 5.9 years, 21.4% (3/14) developed prostate cancer. In this study, men did not receive routine follow-up prostate biopsies. As such, the incidence of progression to cancer over time is likely underestimated.

Lefkowitz et al.¹⁰ empirically biopsied 31 men 3 years after the diagnosis of HGPIN on a minimum 12 core sampling. 25.8% of men were found to have cancer suggesting either a de novo progression of HGPIN to cancer or progression of clinically undetectable foci of cancer to a clinically detectable state. Within this study, the authors found no relationship of change in PSA to the likelihood of prostate cancer. Amount of HGPIN, histologic pattern and baseline PSA were not evaluated as independent risk factors, given the small sample size. Interestingly, all men diagnosed with cancer were found to have clinically localized disease, and those undergoing radical prostatectomy had pathologically confined disease.¹⁰ This study suggests that men with isolated HGPIN on 12-core biopsy have an increased risk of cancer 3 years after baseline biopsy (25.8%), as compared to the first year after baseline biopsy (2.3%).^{2, 10} Furthermore, the likelihood of cancer could not be predicted by PSA.

The risk of subsequent cancer development in the HGPIN population was also noted by Abdel-Khalek et al.³ in 2004. The authors found cancer in 4 of 21 (19%) patients with HGPIN, rebiopsied at a mean follow-up of 36 months. All patients in that series, however, underwent repeat biopsy because of either concerning changes in Digital Rectal Examination (DRE) or an increased PSA velocity. As such, this may underestimate the true prevalence of progression to cancer, which would probably be higher if all patients were rebiopsed regardless of changes in the DRE or PSA serum levels.

Based on the initial study by Lefkowitz et al., we have continued to recommend empiric delayed interval biopsy at a 3-year interval to men with isolated HGPIN and no upward trend in serum PSA. Among those with rising PSA, follow-up biopsy is generally recommended sooner on the assumption that an occult cancer may be present. To date, we have performed a 3-year delayed interval biopsy in 101 men with isolated HGPIN and a delayed 6-year biopsy in 28 men, demonstrating cancer detection rates of 23.2 and 28.6%, respectively (SS Taneja, unpublished data). The same trends persist with no suggestion that change in PSA between biopsies can predict a higher likelihood of cancer. Additionally, all cancer diagnosed appear clinically significant by conventional criteria,⁹⁴ and 41.4% of patients are found to have Gleason 7/10 disease. Despite this, all cancers have been found to be clinically and pathologically confined, suggesting that 2–3 years is not an excessive interval of observation. While these data suffer from the lack of control group of men rebiopsied without a history of HGPIN, others have similarly demonstrated a lower likelihood of cancer on repeat biopsy among men with a benign baseline biopsy, as compared to those with baseline HGPIN. Over a mean follow-up of 72 months, Eggener et al.⁹⁵ reported a 35% likelihood of cancer in follow-up of men with HGPIN as compared to 16% among those with a stable PSA and benign biopsy. These findings further validate the increased long-term risk of cancer among men with isolated HGPIN.

Factors predicting progression to prostate cancer

Relationship to PSA

Very few investigators have been able to link serum PSA level with risk of prostate cancer among men with isolated HGPIN on needle biopsy.^{8, 91, 96} Raviv et al.⁹¹ found that PSA was relatively elevated in men with isolated HGPIN, who had a cancer in a repeat biopsy taken 3–6 months after baseline sextant biopsy, as compared to those men who did not. Two additional studies identified a predictive value for the level of PSA elevation at the initial biopsy with HGPIN, but did not observe any significant change in PSA prior to repeat biopsy.^{8, 96} This relationship has not been observed by others,^{10, 33, 61, 93, 97, 98, 99} and controversy still remains regarding the ability of PSA level to predict the presence of both HGPIN and prostate cancer among men with HGPIN.

PSA velocity also has not proved to be a good marker of progression of HGPIN. We previously reported our experience with 3 years delayed interval prostate biopsy, after a first diagnosis of HGPIN in an extended 12-core biopsy scheme, and serum PSA change was not significant for those in which cancer was found on the second biopsy.¹⁰ Similar results were found by Kronz et al.,⁶¹ who found no relationship between PSA velocity and the risk of subsequent prostate cancer among 245 men who underwent repeat biopsy. Borboroglu et al.¹¹ studied PSA velocity and also investigated the role of free PSA, but similar to others,⁸ could not find any significance related to the presence of HGPIN. More recently, Loeb et al.¹⁰⁰ have suggested that among men with isolated HGPIN on sextant biopsy, PSA velocity is higher in those diagnosed with cancer on repeat biopsy (PSAV=0.2 ng/ml/year) as compared to those without (PSAV=-0.6 ng/ml/year). In this study, men were rebiopsied at a median of 8 months from baseline, 46/51 (90.1%) cancers diagnosed were found on first repeat biopsy, and very few men (16/50) had more than one repeat biopsy. A clear problem with this study is the undersampling of patients with baseline biopsy resulting in high rates of cancer detection on immediate repeat biopsy. It is questionable as to whether this observation would apply to men who are well sampled at baseline and followed for longer periods of time. Finally PSA density has also been evaluated, but only one study was able to show it was predictive of cancer on rebiopsy.³

Imaging

There is no imaging exam available to date that can identify HGPIN or the risk of cancer on subsequent biopsy in men with HGPIN. Most do not believe that HGPIN is detectable by ultrasound, although it could be theoretically represented by hypoechoic regions, particularly in association with prostate cancer. In evaluation of men undergoing repeat biopsy for HGPIN, transrectal ultrasound abnormality did not predict a higher risk of subsequent cancer.⁶¹ Magnetic resonance spectroscopic imaging has been also evaluated recently, but failed to identify those patients with HGPIN in the prostate.¹²

Histology

Kronz et al. have proposed that the histologic outcome of repeat biopsy may predict the long-term risk of progression to cancer among men with isolated HGPIN. Men with benign histology, HGPIN or atypia on repeat biopsy had a 10, 25.9 and 57.1% risk of cancer, respectively.⁶¹ It is important to note that this study was carried out retrospectively, and the interval to third or fourth biopsy, the number of biopsy cores and the technique of biopsy were not standardized. As such, it is unclear as to whether the histologic pattern on repeat biopsy is truly predictive of progression to cancer, or if it is predicting the likelihood of associated undiagnosed cancer. In the same study, the authors demonstrated that the number of cores harboring HGPIN was predictive of cancer on first repeat biopsy, but the pattern of HGPIN was not. Contrarily, the presence of micropapillary or cribriform HGPIN on repeat biopsy predicted a higher risk of subsequent cancer in third or fourth biopsy. In our follow-up studies at New York University, we have demonstrated that the likelihood of cancer on second delayed interval biopsy (performed at a mean of 64.2 months from baseline) is not influenced by the presence or absence of HGPIN on first delayed interval biopsy (performed at a mean of 33.3 months from baseline) (SS Taneja, unpublished data).

Bishara et al.⁶⁴ studied a combined cohort of 200 men with HGPIN from two independent institutions. Men (50%) with HGPIN in multiple cores on repeat biopsy had prostate cancer on subsequent biopsy, compared to 0/9 rebiopsied with a single core of HGPIN. Mean interval to cancer diagnosis was 10.6 months. Naya et al.³² biopsied 1086 men and found that 226 had isolated HGPIN. In follow-up, the number of cores with HGPIN did not predict the likelihood of prostate cancer on repeat biopsy. The conflicting literature likely relates to the adequacy of sampling at baseline. Others have previously demonstrated that the amount of HGPIN in prostates removed for bladder cancer correlates with the likelihood and amount of incidental prostate cancer.⁵⁶ Given the short interval to repeat biopsy in the studies of Kronz and Bishara,^{61, 64} the presence of multifocal HGPIN likely corresponds to higher risk of concomitant, undersampled prostate cancer. It is not clear from the available literature as to whether this predicts a higher long-term risk of progression to cancer.

It is important to note that the presence of atypia or atypical small acinar proliferation on follow-up biopsy is distinct from HGPIN. A number of studies have demonstrated a high risk of prostate cancer in the region of the atypical glands, and focal repeat saturation of the suspicious area is recommended, even when co-existent with HGPIN.^{1, 21, 64, 69} It is interesting to note that in a recent study, 100% of men with atypical glands who decided to have a radical prostatectomy were found to have prostate cancer on final pathology.¹⁰¹

Role of chemoprevention

Given the strong evidence supporting the high risk of prostate cancer progression among men with isolated HGPIN, it is desirable to offer some form of intervention for prevention of cancer initiation and/or treatment of co-existing malignancy. To date, there is no published experience with primary surgery or radiotherapy for HGPIN. Such interventions are probably ill-advised given the relative morbidity of treatment, the limited data regarding the long-term risk of HGPIN and the suggestion that, even when diagnosed at delayed intervals, cancer initiation is generally identified at an early stage. As such, a number of clinical trials evaluating potential preventive strategies in isolated HGPIN have emerged. In this capacity many modalities can be considered, including dietary modifications, supplements or hormonal manipulations.⁵⁹

It has been suggested that HGPIN, similarly to prostate cancer, is sensitive to androgen deprivation.¹⁰² A substantial reduction in the expected incidence of HGPIN was seen following neoadjuvant hormone deprivation using either Luteinizing Hormone-Releasing Hormone (LHRH) agonists or antiandrogens prior to radical prostatectomy.¹⁰³ At present, there are ongoing clinical trials evaluating the efficacy of antiandrogens (hydroxyflutamide) and 5- reductase inhibitors (dutasteride) in the prevention of prostate cancer. While the biologic rationale for use of an antiandrogen in the treatment of HGPIN is strong, the secondary effects on sexual function, muscle mass, bone density and cardiovascular health make broad application of such prevention strategies unlikely.

A 5- reductase inhibitor (finasteride) has already been tested for efficacy in prostate cancer prevention. In the Prostate Cancer Prevention trial, a 24.8% reduction in cancer incidence over 7 years was noted among men at low risk of prostate cancer (normal PSA and exam) treated with finasteride.¹⁰⁴ Enthusiasm over the study result was dampened owing to an observed increase in the risk of high-grade disease within the study arm. This effect has subsequently been explained as the result of increased sampling among glands shrunken by finasteride. Nonetheless, prevention strategies employing 5- reductase inhibitors have failed to gain popularity. Interestingly, Yang¹⁰⁵ and the PLESS study group (Proscar Long-term Efficacy and Safety Study group) did not observe any effect of 5- reductase inhibitors on HGPIN.

Estrogens have also been implicated in the development or progression of prostate cancers. The influence of estrogens on prostate epithelium is transduced contrarily through two receptors: estrogen receptor (ER) and . Agents that stimulate ER-, such as soy protein or specific isoflavones, exert a selective antiproliferative effect. The use of soy and soy derivatives is actively in study for chemoprevention, but not within the specific context of HGPIN.¹⁰⁶ Alternatively, stimulation of ER- could in theory produce a proliferative response. In practice, administration of estrogens usually results in pharmacologic castration through secondary suppression of the pituitary–testis axis. In the castrate host, estrogens do not exert a proliferative response in prostate epithelium.

Selective ER modulators are capable of differential tissue effects through binding of the ER. As such, depending on the structure of a selective ER modulator, it may result in a proliferative or antiproliferative effect in the prostate. Toremifene is a selective ER modulator approved by the Food and Drug Administration for the treatment of breast cancer. Pre-clinical studies have demonstrated that at low doses, toremifene (Acapodene, Gtx Inc, Memphis, TN, USA) selectively inhibits ER- in the prostate, theoretically exerting an antiproliferative effect.¹⁰² In the transgenic adenocarcinoma of mouse prostate (TRAMP) model, toremifene delayed the development of prostate cancer and reduced prostate cancer incidence greatly among those animals treated.¹⁰⁷ In a phase IIb evaluation of toremifene in 514 men with isolated HGPIN, patients were treated with either placebo or one of the three escalating doses of daily toremifene (20, 40 and 60 mg). A 48% reduction in cancer incidence at 1 year of follow-up was observed among men treated with 20 mg toremifene as compared to placebo.¹⁰⁸ Higher dose of toremifene did not reveal a significant reduction in cancer progression, suggesting that selective inhibition of ER- may truly occur at only low doses.¹⁰⁸ These provocative results have prompted an ongoing randomized phase III trial of 20 mg toremifene in 1200 men with isolated HGPIN. Men will be biopsied yearly for a total of 3 years to assess the preventive effect of the drug.

Dietary modification is another appealing means of exerting a preventive effect in the prostate. Agents including soy protein, vitamin E, selenium and lycopene have been implicated as preventive agents in prostate cancer. This is largely based on observations from large epidemiologic cohorts. At present, within the National Cancer Institute of Canada, there is an ongoing trial of selenium and vitamin E in combination for the prevention of prostate cancer in men with isolated HGPIN (N Fleshner, personal communication). No interim analysis has yet been presented.

Recommended approach

Based on the existing literature and our own preliminary observations, we have proposed a general clinical strategy for the management of isolated HGPIN on prostate biopsy, although clinical discretion is advised on its practical application (Figure 2). Among men who are diagnosed with a biopsy of <10 cores, an immediate repeat extended biopsy should be performed to provide adequate baseline sampling of the gland. Among those with isolated HGPIN identified on an extended core biopsy, if the serum PSA is markedly elevated (>10 ng/ml) or there is strong suspicion based on clinical history, then a repeat saturation biopsy with sampling of the transition zone is warranted. In those men with isolated HGPIN identified on extended core biopsy, in whom there are no high-risk features, we would recommend observation with PSA measurement every 6 months and a delayed interval biopsy at 3 years of follow-up. Among men with rising PSA following the biopsy, an earlier delayed interval biopsy (1–3 years) might be considered. At the time of delayed interval biopsy in men with stable serum PSA, we do not feel routine transition zone sampling is likely to improve cancer detection. As chemoprevention strategies emerge, use of non-toxic preventive agents within the periods of observation would be ideal.

Figure 2.

Management algorithm of HGPIN.

Full figure and legend (32K)

Conclusions

The increasing use of prostate biopsy in clinical practice has resulted in a stage migration toward earlier detection of disease. A secondary effect of this is increased detection of isolated HGPIN on biopsy. There is an abundance of compelling evidence to suggest that HGPIN is a precursor of prostate cancer, and as such, the presence of HGPIN identified a cohort of men very likely at higher long-term risk of prostate cancer. The need for immediate repeat biopsy is highly dependent on the adequacy of baseline prostate sampling. Men with HGPIN diagnosed on an extended core sampling do not require immediate repeat biopsy. While there is limited data regarding the long-term risk of prostate cancer among men with isolated HGPIN, it does appear that delayed interval biopsy monitoring is warranted, even among men with stable serum PSA. Given the absence of non-invasive monitoring techniques for HGPIN, repetitive biopsy at delayed intervals is warranted. Chemoprevention strategies for HGPIN, currently in development, are highly desirable and they may ultimately define the paradigm by which men with isolated HGPIN are managed.

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