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Review: Molecular Pathogenesis of Premalignancy Series

Premalignancy in Prostate Cancer: Rethinking What We Know

Angelo M. De Marzo, Michael C. Haffner, Tamara L. Lotan, Srinivasan Yegnasubramanian and William G. Nelson
Angelo M. De Marzo
1Departments of Pathology
2Oncology
3Urology
4The Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center
5The Brady Urological Research Institute at Johns Hopkins, Johns Hopkins University, Baltimore, MD.
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  • For correspondence: ademarz@jhmi.edu
Michael C. Haffner
1Departments of Pathology
2Oncology
4The Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center
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Tamara L. Lotan
1Departments of Pathology
2Oncology
3Urology
4The Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center
5The Brady Urological Research Institute at Johns Hopkins, Johns Hopkins University, Baltimore, MD.
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Srinivasan Yegnasubramanian
1Departments of Pathology
2Oncology
3Urology
4The Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center
5The Brady Urological Research Institute at Johns Hopkins, Johns Hopkins University, Baltimore, MD.
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William G. Nelson
1Departments of Pathology
2Oncology
3Urology
4The Johns Hopkins University School of Medicine, The Sidney Kimmel Comprehensive Cancer Center
5The Brady Urological Research Institute at Johns Hopkins, Johns Hopkins University, Baltimore, MD.
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DOI: 10.1158/1940-6207.CAPR-15-0431 Published August 2016
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Abstract

High-grade prostatic intraepithelial neoplasia (PIN) has been accepted as the main precursor lesion to invasive adenocarcinoma of the prostate, and this is likely to be the case. However, in an unknown number of cases, lesions fulfilling the diagnostic criteria for high-grade PIN may actually represent intra-acinar or intraductal spread of invasive carcinoma. Intriguingly, this possibility would not contradict many of the findings of previous epidemiologic studies linking high-grade PIN to carcinoma or molecular pathologic studies showing similar genomic (e.g., TMPRSS2-ERG gene fusion) as well as epigenomic and molecular phenotypic alterations between high-grade PIN and carcinoma. Also, this possibility would be consistent with previous anatomic studies in prostate specimens linking high-grade PIN and carcinoma in autopsy and other whole prostate specimens. In addition, if some cases meeting morphologic criteria for PIN actually represent intra-acinar spread of invasive carcinoma, this could be an important potential confounder of the interpretation of past clinical trials enrolling patients presumed to be without carcinoma, who are at high risk of invasive carcinoma. Thus, in order to reduce possible bias in future study/trial designs, novel molecular pathology approaches are needed to decipher when an apparent PIN lesion may be intra-acinar/intra-ductal spread of an invasive cancer and when it truly represents a precursor state. Similar approaches are needed for lesions known as intraductal carcinoma to facilitate better classification of them as true intra-ductal/acinar spread on one hand or as precursor high-grade PIN (cribriform type) on the other hand; a number of such molecular approaches (e.g., coevaluating TMPRSS-ERG fusion and PTEN loss) are already showing excellent promise. Cancer Prev Res; 9(8); 648–56. ©2016 AACR.

Introduction

Prostate cancer is the most common noncutaneous cancer and the second leading cause of cancer-related death in men in the United States. While the death rate has been decreasing in some countries, including the United States, the aging population and the increasing “westernization” in a number of parts of the world is projected to produce an increasing burden of cases worldwide for the foreseeable future. Early detection, through serum prostate-specific antigen (PSA) screening coupled with improved treatment of localized disease, is likely responsible for much of the decrease in death rate (1). Nevertheless, as a result of the potential harmful side effects associated with radical treatment of men who do not necessarily need treatment, PSA screening is controversial (2). Thus, in addition to early detection with serum PSA screening and treatment of established disease, there has been great interest in developing strategies to prevent the disease altogether or to intercept the disease before it can progress to aggressive forms.

Attempts to prevent prostate cancer were conducted in two different large prospective randomized clinical trials (RCT) employing the 5-α reductase inhibitors finasteride (the Prostate Cancer Prevention Trial or PCPT; ref. 3) and dutasteride (Reduction by Dutasteride of Prostate Cancer Events or REDUCE; each vs. placebo; ref. 4). Both trials showed a reduction in the period-prevalence of prostate cancer of approximately 25%. However, in both trials, there was a small increase in the total number of patients diagnosed with higher grade disease; and, with long-term follow-up in the PCPT, there was no apparent survival advantage in patients in the treatment arm (5). Thus, neither of these agents are currently being employed widely for the chemoprevention of prostate cancer. A third large RCT (Selenium and Vitamin E Cancer Prevention Trial or SELECT) consisted of treatment with the antioxidants vitamin E and/or selenium which showed a lack of efficacy (6). A number of chemoprevention trials employed enrichment of men with high risk of cancer development because they were diagnosed with high-grade PIN, in which attempts were made to reduce the development of invasive disease with a variety of agents (reviewed in refs. 7, 8); such trials have not resulted in strong candidates for use as chemopreventative agents in any population to date (Table 1).

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Table 1.

Selected clinical trials for prostate cancer prevention

Proposed Alternative Prostate Cancer Precursor Lesions

In addition to the well-accepted lesion of high-grade PIN, a number of different histologic lesions have been proposed as potential precursor lesions for prostate cancer, such as adenosis (atypical adenomatous hyperplasia) and proliferative inflammatory atrophy (PIA). Adenosis may be a potential precursor to carcinomas arising in the transition zone, lesions which are often low grade and not generally thought to possess strong malignant potential (9). PIA, consisting of simple atrophy and postatrophic hyperplasia, that is often associated with inflammation, has been found to merge directly with small adenocarcinoma lesions in the peripheral zone, but this appears to be relatively rare (although very few systematic studies have been carried out to date; refs. 10–12). If PIA is a precursor (or “risk factor lesion”) for prostate cancer, it may do so indirectly by leading to carcinoma via PIN as PIA merging with PIN is quite common (10–12).

Diagnosis and Subtypes of PIN

High-grade PIN is characterized by atypical secretory luminal cells present within preexisting ducts and acini, with nuclear features similar to invasive adenocarcinoma (Fig. 1) (7, 9, 13). PIN has been proposed to arise with progressive morphologic abnormalities along a continuum from normal epithelium, to low-grade PIN to high-grade PIN and then to invasive carcinoma (7). However, as low-grade PIN has been deemed to be a diagnostic entity with poor interobserver reproducibility, and its clinical utility has not been demonstrated (7, 9), many studies of prostate cancer pathogenesis as well as randomized trials have not attempted to measure it.

Figure 1.
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Figure 1.

Models of prostate cancer development based on latest evidence. A, model of progression from normal to low-grade PIN (LGPIN) to high-grade PIN (HGPIN) to carcinoma. Thicker solid lines denote standard/canonical view. Note that there are only very limited data showing normal epithelium goes to low-grade PIN and that high-grade PIN arises from low-grade PIN. A subset of low- or high-grade PIN or invasive carcinoma may also arise from PIA, with the most likely route going from PIA to low- or high-grade PIN more commonly than going directly to carcinoma. Intraductal carcinoma is generally considered to arise after invasion, but has now been found in some cases to be present in prostates without invasive carcinoma and thus may arise directly from high-grade PIN at times or as a de novo lesion, which does occur in some mouse models of prostate cancer. The canonical view has been that lesions morphologically identifiable as high-grade PIN arise prior to invasive carcinoma development, but new evidence suggests that, at times, lesions morphologically identifiable as high-grade PIN may also arise as retrograde spread from invasive carcinoma. B, H&E images of morphologic entities indicated in A. B, normal (A), focal atrophy with inflammation/PIA (B), low-grade PIN (C), high-grade PIN (D), invasive adenocarcinoma (Gleason pattern 4 + 3 = 7; E), intraductal carcinoma and adjacent invasive adenocarcinoma (F). Lu, lumens of glands.

High-grade PIN shows a variety of architectural patterns, with the “tufted” pattern being the most common, occurring in >95% of cases (7). Other patterns include micropapillary and less commonly cribriform and flat. The diagnosis of high-grade PIN can be difficult at times, which is related to the fact that there are a number of both benign and malignant mimickers as well as borderline lesions (9). This has led to the fact that the diagnosis of high-grade PIN shows only moderate to good interobserver reproducibility (κ statistic of ∼0.41 through 0.6) among experts in the field (9).

Key Data Supporting High-Grade PIN as a Prostate Cancer Precursor

There is abundant data supporting the concept that high-grade PIN is a precursor to adenocarcinoma of the prostate (7, 9, 13, 14). For example, high-grade PIN cells resemble invasive adenocarcinoma cells morphologically, including having the key feature of nucleolar enlargement. Further evidence comes from zonal colocalization between high-grade PIN and carcinoma, the frequent multifocal occurrence of high-grade PIN and carcinoma, morphologic transitions between high-grade PIN and invasive “microcarcinomas,” morphometric measurements, phenotypic features (e.g., abnormal luminal cells expressing AR etc.), and a number of shared somatic genomic changes between high-grade PIN and carcinoma.

Perhaps the most cited finding for implicating high-grade PIN as the principal prostate cancer precursor comes from studies showing that fully embedded prostates containing carcinoma show a significantly increased prevalence (∼2 fold) and extent of high-grade PIN when compared with prostates without carcinoma (from autopsies, prostatectomies, or cystoprostatectomies; refs. 7, 9). While African-Americans tend to show increased rates of clinically diagnosed carcinoma, as well as increased death rates due to prostate cancer, they do not harbor more invasive carcinomas or high-grade carcinoma in autopsy studies when compared with age-matched men of non-African ancestry. However, they do tend to show an increase in the fraction of cases showing extensive high-grade PIN lesions (7, 9, 15).

A number of autopsy studies from different parts of the world indicate clearly that, similar to invasive carcinoma, the rates of high-grade PIN increase significantly with age. For example, a prevalence of 7% to 8% has been seen in the third decade of life and upwards of 60% to 86% in the eighth decade of life (9). Furthermore, the rates of high-grade PIN, like invasive carcinoma, appear to vary significantly throughout the world. For example, a relatively recent study of Caucasian Mediterranean men showed that the prevalence of high-grade PIN and carcinoma was lower than those from age-matched Caucasian North American and African-American men (16).

If high-grade PIN is a precursor lesion, one would expect that in autopsy studies PIN lesions would predate carcinoma. While this is the cases in some studies (e.g., ref. 16) it is not so in all, including a recent study from Hungary (17) and the most well-known studies conducted in North American men, where the increase in high-grade PIN with age was either delayed somewhat in relation to the increase in carcinoma or occurred at nearly the same time as invasive carcinoma (refs. 15, 18, 19; Fig. 2). In two highly cited studies (18, 19), only a single time period (in the third decade) was found in which the prevalence of PIN was higher than carcinoma, and, this predating of carcinoma was nearly exclusively due to low-grade PIN; high-grade PIN was first identified in the fifth decade of life (19).

Figure 2.
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Figure 2.

Prevalence of PIN and carcinoma in autopsy studies. A and B, prevalence of high-grade PIN and carcinoma across age groups in men from different ancestry (A, Whites; B, African American). Graphs were plotted using frequencies obtained as reported by Sakr and colleagues in the largest study to date of this kind (n = 525 autopsied med; ref. 15). C and D, similar plots obtained from frequencies reported by Sakr and colleagues (ref. 18 = 249 autopsied men).

In prostate needle biopsies from various populations, the prevalence of isolated high-grade PIN (no carcinoma present) ranges between 4% and 24% (mean of 9%; ref. 7). The rate of high-grade PIN in the placebo arm of the PCPT trial (men who never had an elevated PSA or abnormal digital rectal exam) was 7% (20).

The clinical significance of isolated high-grade PIN on prostate biopsy stems from its association with cancer on subsequent biopsies. However, this association has been decreasing over the years from approximately 30%–50% to approximately 20%. This decrease has been largely attributed to increased sampling from 6 to 12 or more cores which results in fewer cancers missed on the initial biopsy (7,21). In any case, focal high-grade PIN on needle biopsy no longer dictates the need for immediate repeat biopsy and most authors suggest a repeat biopsy at 1 year if there are no other clinical indications. The presence of multifocal high-grade PIN on prostate needle biopsy (involving 2 or more cores) still appears to represent a risk factor for detection of cancer on subsequent biopsies (9).

Molecular Biology of PIN

A large number of molecular alterations have been identified in high-grade PIN lesions, many of which are also found in adenocarcinoma (reviewed in ref. 7, 22; Table 2 shows some well-known key changes in various lesions). Early examples include a study from Emmert-Buck and colleagues, showing that microdissected high-grade PIN had a similar rate and pattern of loss of one allele on chromosome 8p12–21 (90% in carcinoma and 63% in high-grade PIN) as compared with invasive adenocarcinoma; and that a region on 8p22 showed less frequent LOH in PIN than in carcinoma, implying that PIN is molecularly intermediate between normal and carcinoma (23). Others reported similar findings (24). Bostwick and colleagues reported that multifocal PIN often harbored similar loss of heterozygosity by alleotyping to that seen in concurrent invasive carcinoma lesions (25). Quin and colleagues used centromere-specific enumeration probes as well as a probe encompassing MYC at 8q24 to show that PIN frequently harbors similar chromosomal alterations as invasive carcinoma (26, 27). Not all studies, however, supported the concept that PIN lesions always behave as precursors as some PIN lesions near carcinoma actually harbor additional or different genetic changes not found in the adjacent carcinoma (23, 28, 29). Furthermore, not all studies have found evidence of high rates of chromosomal changes in PIN or found much lower rates than the earlier studies. For example, Bethel and colleagues found no allelic loss at chromosome 8p22 (LPL locus) in 19 isolated high-grade PIN lesions (30). Similarly, PTEN protein and allelic loss were recently found to be very common in intraductal carcinoma and atypical cribriform lesions, but not in isolated high-grade PIN (31, 32).

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Table 2.

Selected molecular alterations in atrophy, PIN, and intraductal carcinoma

ETS gene rearrangements, which are mostly characterized by the TMPRSS2-ERG fusion, can be detected in high-grade PIN in 5%–20% of men of European decent. This contrasts with a much higher frequency in carcinoma (∼50%; ref. 7). Furthermore, PIN lesions near carcinoma are much more likely to be TMPRSS2-ERG fusion positive than isolated high-grade PIN away from carcinoma, in which the frequency is very low (22, 33, 34), leading the authors to propose that TMPRSS2-ERG–positive PIN lesions are associated with clonal progression to carcinoma. In addition, some (albeit not all) studies have shown that ERG-positive high-grade PIN show a higher rate of cancer on repeat biopsy than ERG-negative cases (7, 35).

MYC is located on chromosome 8q24, a locus that frequently shows increased copy number in prostate cancer. Qian and colleagues have shown that 8q24 gain is commonly seen in at least some forms of high-grade PIN (27), although a separate study using a similar approach by Bethel and colleagues did not see 8q24 gain in any of 19 high-grade PIN lesions away from carcinoma (30). Despite the lack of 8q24 gain, Gurel and colleagues found a clear stepwise increase in MYC protein levels from normal epithelium to low-grade and then to high-grade PIN lesions; high-grade PIN was similar to invasive adenocarcinoma (30, 36).

Somatic DNA hypermethylation is a common occurrence in prostate cancer and a number of genes shown to be selectively hypermethylated in prostatic carcinomas, and not in benign tissues, are also frequently methylated in high-grade PIN. For example, the CpG island upstream of the GSTP1 gene is methylated in approximately 90%–95% of carcinomas, and in approximately 70% of high-grade PIN lesions (37, 38). Also Henrique and colleagues found a high prevalence and extent of hypermethylation of GSTPT1, RARB, and APC in high-grade PIN and invasive adenocarcinoma (39).

Telomeres have been shown in multiple studies to be paradoxically shortened in prostate tumor cells, compared with their normal counterparts, despite the fact that most of them have high levels of telomerase activity. In high-grade PIN, telomeres are also short in the vast majority of cases (40, 41). Interestingly, Vukovic and colleagues found that PIN lesions near carcinoma often showed shorter telomeres than PIN lesions away from carcinoma (41).

Phenotypically, a large number of immunohistochemical biomarkers have been shown to be altered in PIN. The most relevant are often similarly altered in carcinoma and these include MYC, as mentioned above, as well as proliferation markers such as Ki67, and differentiation markers such as PSA, and NKX3.1, which are somewhat decreased in PIN and carcinoma as compared with normal luminal cells (7, 9).

Intraductal Carcinoma

Intraductal carcinoma consists of malignant appearing epithelial cells expanding prostatic acini and/or ducts with retention of the basal cell layer. Intraductal carcinoma has been postulated to represent, in most cases, retrograde glandular colonization (intra-acinar/ductal spread), of preexisting invasive carcinoma that is usually high grade (Gleason grade 4 + 3 = 7 or higher). A number of studies have also shown that the presence of intraductal carcinoma is associated with adverse pathology at prostatectomy and worse outcomes after treatment (42). There are two main patterns of intraductal carcinoma: (i) solid or dense cribriform or (ii) lose cribriform or micropapillary. Guo and Epstein (2006) introduced strict morphologic criteria for the diagnosis of intraductal carcinoma on needle biopsy such that the pattern had to be either solid or dense cribriform or loose cribriform or micropapillary with either marked nuclear atypia (nuclear size 6 times normal or larger) or nonfocal necrosis (43). Isolated intraductal carcinoma is very rare on needle biopsy, but if found there is a general consensus that it should be treated similarly to high-grade invasive carcinoma (42, 44).

In addition to lesions that fit the Guo and Epstein criteria, pathologists have reported on the presence of atypical cribriform lesions with features intermediate between high-grade PIN and intraductal carcinoma. In a study that attempted to distinguish high-grade cribriform PIN from intraductal carcinoma, Han and colleagues observed that isolated atypical cribriform lesions were uncommon such that the overwhelming majority of them were associated with high-grade (Gleason score ≥ 7) and high-volume prostate cancer supporting the concept that they represent a spectrum within intraductal carcinoma (45).

Molecularly, intraductal carcinoma shows frequent loss of heterozygosity, indicative of genomic instability (46). Han and colleagues used FISH for ERG rearrangements and categorized the lesions into 2 groups, group A (meeting the Guo and Epstein criteria) and group B (atypical cribriform lesions nearby invasive high-grade carcinoma but that did not meet the Guo and Epstein criteria); they also studied cribriform high-grade PIN lesions that were isolated away from carcinoma (45). ERG rearrangements were not detected in isolated cribriform high-grade PIN but were present in 47% of group A and 48% of group B lesions (45). PTEN loss (usually by large-scale deletion and rarely by mutation) is common in prostate cancer and is enriched in high-grade aggressive disease. Lotan and colleagues found common loss of PTEN in both intraductal carcinoma (∼80%) as well as in atypical cribriform lesions that fall short of criteria for intraductal carcinoma (analogous to Han and colleagues' group B cases as described above; refs. 31, 32). In these studies, a total of 59 isolated high-grade PIN lesions were evaluated and none showed PTEN loss. Taken together, the data indicate that intraductal carcinoma and atypical cribriform lesions adjacent to carcinoma are quite distinct from isolated high-grade PIN, even cribriform high-grade PIN that is away from carcinoma.

While pathologists have largely accepted that intraductal carcinoma is usually the result of retrograde spread of carcinoma colonizing benign ducts and acini, until very recently, there was no unequivocal genetic evidence to support this. Recently, we used a novel molecular pathology approach to show this is indeed true, at least in some cases. The method involved the use of capture sequencing to determine case-specific TMPRSS2-ERG genomic breakpoints (geBACS) coupled with ERG IHC to identify the precise genomic breakpoint in ERG-rearranged cases to establish clonality in a given adenocarcinoma lesion (47). Then, we used the PTEN genomic status determined by IHC and FISH to show that only part of the invasive tumor lost PTEN, yet all of the intraductal tumor lost PTEN and had the identical TMPRSS2-ERG breakpoint, which established that the intraductal component arouse temporally after the invasive component (48). In another recent study, Lindberg and colleagues, recently published on a single case using whole-genome sequencing to show that an intraductal carcinoma was phylogenetically closer to lymph node metastases than were most areas of an adjacent carcinoma, also strongly indicating that the intraductal carcinoma likely arose after the invasive component (49). On the other hand, it has also become apparent recently that occasionally, lesions that are histologically diagnosed as intraductal carcinoma can be present in prostates without any invasive carcinoma (44), or, can be present away from invasive carcinoma (50). It appears, therefore, that histologic intraductal carcinoma may at times be a precursor lesion or occur in the absence of invasive carcinoma.

What about high-grade PIN? Interestingly, in the study by Haffner and colleagues (48), lesions meeting morphologic criteria for high-grade PIN (both cribriform and tufting) that were adjacent to carcinoma also showed evidence that they arose temporally after invasion commenced, suggesting that not all lesions regarded as PIN represent precursors, and at times, may represent invasive carcinoma colonizing benign glands in a retrograde manner (Fig. 1). Another frequent finding was that in cases of ERG-positive carcinoma, adjacent benign glands that were only partially involved with ERG-positive carcinoma cells were present (Fig. 3). This observation provides further morphologic evidence of common intraepithelial spread of carcinoma, at least near invasive lesions.

Figure 3.
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Figure 3.

ERG-positive carcinoma cells present in benign prostatic acini/ducts. An ERG-positive carcinoma (brown) is shown invading the prostatic stroma. Note 4 benign glands (numbers 1–4) with partial involvement with malignant ERG-positive cells.

A Way Forward

What are the implications of these findings? These types of molecular timing or “order of event” studies have been performed on a limited number of cases so far. Nevertheless, many of the same histologic, molecular, and epidemiologic findings used to support high-grade PIN as a bone fide precursor lesion are equally consistent with a scenario in which a significant fraction of lesions that are currently classified histologically as high-grade PIN actually represent invasive adenocarcinoma invading into the otherwise benign duct/acinar system. In addition, in an unknown number of cases, the results of clinical trials where patients are enriched for high risk of developing cancer by having high-grade PIN could be significantly confounded as many of the patients considered to have precursor lesions only would actually have unsampled invasive carcinoma. This further compounds the already well-known confounder of these trials that, due to the sampling problem occurring with blinded needle biopsies, many patients deemed to be negative for cancer (e.g., with entirely negative biopsies) actually have invasive carcinomas.

To address this confounding problem of carcinoma potentially mimicking PIN, additional studies need to be performed using molecular pathology approaches similar to those recently employed (48, 49) to obtain estimates of the fraction of high-grade PIN lesions that represent retrograde colonization by carcinoma. These combinatorial approaches include the integration of H&E histology of well-characterized specimens with IHC (including multiplex assays) and in situ hybridization–based methods (both FISH and RNA in situ), along with solution-based molecular approaches applied after laser capture microdissection, that are required to solve this issue. Such solution-based molecular approaches that employ high-throughput next-generation sequencing can be combined with molecular phylogenetic analyses to comprehensively decipher the temporal “order of events” to better understand precursor–progeny relations. In addition, if many of the cases of high-grade PIN studied with molecular tools to date actually represent invasive carcinoma mimicking PIN, it will be important to move beyond our reluctance for studying low-grade PIN and more systematically employ molecular pathologic tools to determine whether key molecular driver alterations indeed begin in these lesions. Table 2 shows some selected molecular lesions thought to be involved as key events in early prostate cancer formation. While the table is not exhaustive, it is quite clear that very limited data exist regarding molecular studies of low-grade PIN. Given the diagnostic challenges involved with low-grade PIN, we submit that the time is right for genitourinary pathologists to revisit the reproducibility of diagnosing low-grade PIN to facilitate future studies.

Improvements in our ability to understand which PIN lesions represent true precursors, together with improvements in imaging localized disease, could ultimately aid patient management as approximately 50,000–70,000 new cases of isolated high-grade PIN are diagnosed per year in the United States. This combination of improved molecular diagnostics and imaging could also aid in terms of future chemoprevention clinical trials by enhancing the confidence in the classification of patients who do not have carcinoma at the start of the trial and truly following them for the effect of the selected agent on cancer development (this is likely a conservative estimate. This assumes the biopsy rate has been reduced from >1,000,000 per year to ∼800,000 per year after the USPTF recommendations in 2013, and an isolated high-grade PIN rate of 7% = 56,000 cases per year).

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed

  • Received December 14, 2015.
  • Accepted January 18, 2016.
  • ©2016 American Association for Cancer Research.

References

  1. 1.↵
    1. Schroder FH,
    2. Hugosson J,
    3. Roobol MJ,
    4. Tammela TL,
    5. Zappa M,
    6. Nelen V,
    7. et al.
    Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet 2014;384:2027–35.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Moyer VA
    , Force USPST. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012;157:120–34.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Thompson IM,
    2. Goodman PJ,
    3. Tangen CM,
    4. Lucia MS,
    5. Miller GJ,
    6. Ford LG,
    7. et al.
    The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215–24.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Andriole GL,
    2. Bostwick DG,
    3. Brawley OW,
    4. Gomella LG,
    5. Marberger M,
    6. Montorsi F,
    7. et al.
    Effect of dutasteride on the risk of prostate cancer. N Engl J Med 2010;362:1192–202.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Thompson IM Jr.,
    2. Goodman PJ,
    3. Tangen CM,
    4. Parnes HL,
    5. Minasian LM,
    6. Godley PA,
    7. et al.
    Long-term survival of participants in the prostate cancer prevention trial. N Engl J Med 2013;369:603–10.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Lippman SM,
    2. Klein EA,
    3. Goodman PJ,
    4. Lucia MS,
    5. Thompson IM,
    6. Ford LG,
    7. et al.
    Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 2009;301:39–51.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Bostwick DG,
    2. Cheng L
    . Neoplasms of the prostate. Urologic surgical pathology. Third edition: Saunders; 2014. p. 410.
  8. 8.↵
    1. Bosland MC,
    2. Ozten N,
    3. Eskra JN,
    4. Mahmud AM
    . A perspective on prostate carcinogenesis and chemoprevention. Curr Pharm Rep 2015;1:258–265.
    OpenUrlCrossRef
  9. 9.↵
    1. Merrimen JL,
    2. Evans AJ,
    3. Srigley JR
    . Preneoplasia in the prostate gland with emphasis on high grade prostatic intraepithelial neoplasia. Pathology 2013;45:251–63.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Putzi MJ,
    2. De Marzo AM
    . Morphologic transitions between proliferative inflammatory atrophy and high-grade prostatic intraepithelial neoplasia. Urology. 2000;56:828–32.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. De Marzo AM,
    2. Marchi VL,
    3. Epstein JI,
    4. Nelson WG
    . Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis. Am J Pathol 1999;155:1985–92.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Wang W,
    2. Bergh A,
    3. Damber JE
    . Morphological transition of proliferative inflammatory atrophy to high-grade intraepithelial neoplasia and cancer in human prostate. Prostate 2009;69:1378–86.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Montironi R,
    2. Mazzucchelli R,
    3. Lopez-Beltran A,
    4. Scarpelli M,
    5. Cheng L
    . Prostatic intraepithelial neoplasia: its morphological and molecular diagnosis and clinical significance. BJU Int 2011;108:1394–401.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Bostwick DG,
    2. Pacelli A,
    3. Lopez-Beltran A
    . Molecular biology of prostatic intraepithelial neoplasia. Prostate 1996;29:117–34.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Sakr WA,
    2. Grignon DJ,
    3. Haas GP,
    4. Heilbrun LK,
    5. Pontes JE,
    6. Crissman JD
    . Age and racial distribution of prostatic intraepithelial neoplasia. Eur Urol 1996;30:138–44.
    OpenUrlPubMed
  16. 16.↵
    1. Sanchez-Chapado M,
    2. Olmedilla G,
    3. Cabeza M,
    4. Donat E,
    5. Ruiz A
    . Prevalence of prostate cancer and prostatic intraepithelial neoplasia in Caucasian Mediterranean males: an autopsy study. Prostate 2003;54:238–47.
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Soos G,
    2. Tsakiris I,
    3. Szanto J,
    4. Turzo C,
    5. Haas PG,
    6. Dezso B
    . The prevalence of prostate carcinoma and its precursor in Hungary: an autopsy study. Eur Urol 2005;48:739–44.
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Sakr WA,
    2. Grignon DJ,
    3. Crissman JD,
    4. Heilbrun LK,
    5. Cassin BJ,
    6. Pontes JJ,
    7. et al.
    High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20–69: an autopsy study of 249 cases. In Vivo 1994;8:439–43.
    OpenUrlPubMed
  19. 19.↵
    1. Sakr WA,
    2. Haas GP,
    3. Cassin BF,
    4. Pontes JE,
    5. Crissman JD
    . The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients [see comments]. J Urol 1993;150:379–85.
    OpenUrlPubMed
  20. 20.↵
    1. Thompson IM,
    2. Lucia MS,
    3. Redman MW,
    4. Darke A,
    5. La Rosa FG,
    6. Parnes HL,
    7. et al.
    Finasteride decreases the risk of prostatic intraepithelial neoplasia. J Urol 2007;178:107–9.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Montironi R,
    2. Mazzucchelli R,
    3. Lopez-Beltran A,
    4. Cheng L,
    5. Scarpelli M
    . Mechanisms of disease: high-grade prostatic intraepithelial neoplasia and other proposed preneoplastic lesions in the prostate. Nature Clin Pract Urol 2007;4:321–32.
    OpenUrlCrossRef
  22. 22.↵
    1. Mosquera JM,
    2. Perner S,
    3. Genega EM,
    4. Sanda M,
    5. Hofer MD,
    6. Mertz KD,
    7. et al.
    Characterization of TMPRSS2-ERG fusion high-grade prostatic intraepithelial neoplasia and potential clinical implications. Clin Cancer Res 2008;14:3380–5.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Emmert-Buck MR,
    2. Vocke CD,
    3. Pozzatti RO,
    4. Duray PH,
    5. Jennings SB,
    6. Florence CD,
    7. et al.
    Allelic loss on chromosome 8p12–21 in microdissected prostatic intraepithelial neoplasia. Cancer Res 1995;55:2959–62.
    OpenUrlAbstract/FREE Full Text
  24. 24.↵
    1. Haggman MJ,
    2. Wojno KJ,
    3. Pearsall CP,
    4. Macoska JA
    . Allelic loss of 8p sequences in prostatic intraepithelial neoplasia and carcinoma. Urology 1997;50:643–7.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Bostwick DG,
    2. Shan A,
    3. Qian J,
    4. Darson M,
    5. Maihle NJ,
    6. Jenkins RB,
    7. et al.
    Independent origin of multiple foci of prostatic intraepithelial neoplasia: comparison with matched foci of prostate carcinoma. Cancer 1998;83:1995–2002.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Qian J,
    2. Bostwick DG,
    3. Takahashi S,
    4. Borell TJ,
    5. Herath JF,
    6. Lieber MM,
    7. et al.
    Chromosomal anomalies in prostatic intraepithelial neoplasia and carcinoma detected by fluorescence in situ hybridization. Cancer Res 1995;55:5408–14.
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    1. Qian J,
    2. Jenkins RB,
    3. Bostwick DG
    . Detection of chromosomal anomalies and c-myc gene amplification in the cribriform pattern of prostatic intraepithelial neoplasia and carcinoma by fluorescence in situ hybridization. Mod Pathol 1997;10:1113–9.
    OpenUrlPubMed
  28. 28.↵
    1. Sakr WA,
    2. Macoska JA,
    3. Benson P,
    4. Grignon DJ,
    5. Wolman SR,
    6. Pontes JE,
    7. et al.
    Allelic loss in locally metastatic, multisampled prostate cancer. Cancer Res 1994;54:3273–7.
    OpenUrlAbstract/FREE Full Text
  29. 29.↵
    1. Ruijter ET,
    2. Miller GJ,
    3. van de Kaa CA,
    4. van Bokhoven A,
    5. Bussemakers MJ,
    6. Debruyne FM,
    7. et al.
    Molecular analysis of multifocal prostate cancer lesions. J Pathol 1999;188:271–7.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Bethel CR,
    2. Faith D,
    3. Li X,
    4. Guan B,
    5. Hicks JL,
    6. Lan F,
    7. et al.
    Decreased NKX3.1 protein expression in focal prostatic atrophy, prostatic intraepithelial neoplasia, and adenocarcinoma: association with gleason score and chromosome 8p deletion. Cancer Res 2006;66:10683–90.
    OpenUrlAbstract/FREE Full Text
  31. 31.↵
    1. Lotan TL,
    2. Gumuskaya B,
    3. Rahimi H,
    4. Hicks JL,
    5. Iwata T,
    6. Robinson BD,
    7. et al.
    Cytoplasmic PTEN protein loss distinguishes intraductal carcinoma of the prostate from high-grade prostatic intraepithelial neoplasia. Mod Pathol 2013;26:587–603.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Morais CL,
    2. Han JS,
    3. Gordetsky J,
    4. Nagar MS,
    5. Anderson AE,
    6. Lee S,
    7. et al.
    Utility of PTEN and ERG immunostaining for distinguishing high-grade PIN from intraductal carcinoma of the prostate on needle biopsy. Am J Surg Pathol 2015;39:169–78.
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Furusato B,
    2. Tan SH,
    3. Young D,
    4. Dobi A,
    5. Sun C,
    6. Mohamed AA,
    7. et al.
    ERG oncoprotein expression in prostate cancer: clonal progression of ERG-positive tumor cells and potential for ERG-based stratification. Prostate Cancer Prostatic Dis 13:228–37.
  34. 34.↵
    1. Perner S,
    2. Mosquera JM,
    3. Demichelis F,
    4. Hofer MD,
    5. Paris PL,
    6. Simko J,
    7. et al.
    TMPRSS2-ERG fusion prostate cancer: an early molecular event associated with invasion. Am J Surg Pathol 2007;31:882–8.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. Park K,
    2. Dalton JT,
    3. Narayanan R,
    4. Barbieri CE,
    5. Hancock ML,
    6. Bostwick DG,
    7. et al.
    TMPRSS2:ERG gene fusion predicts subsequent detection of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia. J Clin Oncol 2014;32:206–11.
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    1. Gurel B,
    2. Iwata T,
    3. Koh CM,
    4. Jenkins RB,
    5. Lan F,
    6. Van Dang C,
    7. et al.
    Nuclear MYC protein overexpression is an early alteration in human prostate carcinogenesis. Mod Pathol 2008;21:1156–67.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Brooks JD,
    2. Weinstein M,
    3. Lin X,
    4. Sun Y,
    5. Pin SS,
    6. Bova GS,
    7. et al.
    CG island methylation changes near the GSTP1 gene in prostatic intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev 1998;7:531–6.
    OpenUrlAbstract/FREE Full Text
  38. 38.↵
    1. Nakayama M,
    2. Bennett CJ,
    3. Hicks JL,
    4. Epstein JI,
    5. Platz EA,
    6. Nelson WG,
    7. et al.
    Hypermethylation of the human glutathione S-transferase-pi gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: a detailed study using laser-capture microdissection. Am J Pathol 2003;163:923–33.
    OpenUrlCrossRefPubMed
  39. 39.↵
    1. Henrique R,
    2. Jeronimo C,
    3. Teixeira MR,
    4. Hoque MO,
    5. Carvalho AL,
    6. Pais I,
    7. et al.
    Epigenetic heterogeneity of high-grade prostatic intraepithelial neoplasia: clues for clonal progression in prostate carcinogenesis. Mol Cancer Res 2006;4:1–8.
    OpenUrlAbstract/FREE Full Text
  40. 40.↵
    1. Meeker AK,
    2. Hicks JL,
    3. Platz EA,
    4. March GE,
    5. Bennett CJ,
    6. Delannoy MJ,
    7. et al.
    Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis. Cancer Res 2002;62:6405–9.
    OpenUrlAbstract/FREE Full Text
  41. 41.↵
    1. Vukovic B,
    2. Park PC,
    3. Al-Maghrabi J,
    4. Beheshti B,
    5. Sweet J,
    6. Evans A,
    7. et al.
    Evidence of multifocality of telomere erosion in high-grade prostatic intraepithelial neoplasia (HPIN) and concurrent carcinoma. Oncogene 2003;22:1978–87.
    OpenUrlCrossRefPubMed
  42. 42.↵
    1. Shah RB,
    2. Zhou M
    . Atypical cribriform lesions of the prostate: clinical significance, differential diagnosis and current concept of intraductal carcinoma of the prostate. Adv Anat Pathol 2012;19:270–8.
    OpenUrlCrossRefPubMed
  43. 43.↵
    1. Guo CC,
    2. Epstein JI
    . Intraductal carcinoma of the prostate on needle biopsy: Histologic features and clinical significance. Mod Pathol 2006;19:1528–35.
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. Robinson BD,
    2. Epstein JI
    . Intraductal carcinoma of the prostate without invasive carcinoma on needle biopsy: emphasis on radical prostatectomy findings. J Urol 2010;184:1328–33.
    OpenUrlCrossRefPubMed
  45. 45.↵
    1. Han B,
    2. Suleman K,
    3. Wang L,
    4. Siddiqui J,
    5. Sercia L,
    6. Magi-Galluzzi C,
    7. et al.
    ETS gene aberrations in atypical cribriform lesions of the prostate: Implications for the distinction between intraductal carcinoma of the prostate and cribriform high-grade prostatic intraepithelial neoplasia. Am J Surg Pathol 2010;34:478–85.
    OpenUrlCrossRefPubMed
  46. 46.↵
    1. Dawkins HJ,
    2. Sellner LN,
    3. Turbett GR,
    4. Thompson CA,
    5. Redmond SL,
    6. McNeal JE,
    7. et al.
    Distinction between intraductal carcinoma of the prostate (IDC-P), high-grade dysplasia (PIN), and invasive prostatic adenocarcinoma, using molecular markers of cancer progression. Prostate 2000;44:265–70.
    OpenUrlCrossRefPubMed
  47. 47.↵
    1. Weier C,
    2. Haffner MC,
    3. Mosbruger T,
    4. Esopi DM,
    5. Hicks J,
    6. Zheng Q,
    7. et al.
    Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer. J Pathol 2013;230:174–83.
    OpenUrlCrossRefPubMed
  48. 48.↵
    1. Haffner MC,
    2. Weier C,
    3. Xu M,
    4. Vaghasia A,
    5. Gurel B,
    6. Gumuskaya B,
    7. et al.
    Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization. J Pathol 2015;238:31–41.
    OpenUrlPubMed
  49. 49.↵
    1. Lindberg J,
    2. Kristiansen A,
    3. Wiklund P,
    4. Gronberg H,
    5. Egevad L
    . Tracking the origin of metastatic prostate cancer. Eur Urol 2015;67:819–22.
    OpenUrlCrossRefPubMed
  50. 50.↵
    1. Miyai K,
    2. Divatia MK,
    3. Shen SS,
    4. Miles BJ,
    5. Ayala AG,
    6. Ro JY
    . Heterogeneous clinicopathological features of intraductal carcinoma of the prostate: a comparison between "precursor-like" and "regular type" lesions. Int J Clin Exp Pathol 2014;7:2518–26.
    OpenUrlPubMed
  51. 51.
    1. Paltsev M,
    2. Kiselev V,
    3. Muyzhnek E,
    4. Drukh V,
    5. Kuznetsov I,
    6. Pchelintseva O
    . Safety and tolerability of DIM-based therapy designed as personalized approach to reverse prostatic intraepithelial neoplasia (PIN). EPMA J 2014;5:18.
    OpenUrlCrossRefPubMed
  52. 52.
    1. Taneja SS,
    2. Morton R,
    3. Barnette G,
    4. Sieber P,
    5. Hancock ML,
    6. Steiner M
    . Prostate cancer diagnosis among men with isolated high-grade intraepithelial neoplasia enrolled onto a 3-year prospective phase III clinical trial of oral toremifene. J Clin Oncol 2013;31:523–9.
    OpenUrlAbstract/FREE Full Text
  53. 53.
    1. Marshall JR,
    2. Tangen CM,
    3. Sakr WA,
    4. Wood DP Jr.,
    5. Berry DL,
    6. Klein EA,
    7. et al.
    Phase III trial of selenium to prevent prostate cancer in men with high-grade prostatic intraepithelial neoplasia: SWOG S9917. Cancer Prev Res 2011;4:1761–9.
    OpenUrlAbstract/FREE Full Text
  54. 54.
    1. Fleshner NE,
    2. Kapusta L,
    3. Donnelly B,
    4. Tanguay S,
    5. Chin J,
    6. Hersey K,
    7. et al.
    Progression from high-grade prostatic intraepithelial neoplasia to cancer: a randomized trial of combination vitamin-E, soy, and selenium. J Clin Oncol 2011;29:2386–90.
    OpenUrlAbstract/FREE Full Text
  55. 55.
    1. Zanardi S,
    2. Puntoni M,
    3. Maffezzini M,
    4. Bandelloni R,
    5. Mori M,
    6. Argusti A,
    7. et al.
    Phase I-II trial of weekly bicalutamide in men with elevated prostate-specific antigen and negative prostate biopsies. Cancer Prev Res 2009;2:377–84.
    OpenUrlAbstract/FREE Full Text
  56. 56.
    1. Joniau S,
    2. Goeman L,
    3. Roskams T,
    4. Lerut E,
    5. Oyen R,
    6. Van Poppel H
    . Effect of nutritional supplement challenge in patients with isolated high-grade prostatic intraepithelial neoplasia. Urology 2007;69:1102–6.
    OpenUrlCrossRefPubMed
  57. 57.
    1. Bunker CH,
    2. McDonald AC,
    3. Evans RW,
    4. de la Rosa N,
    5. Boumosleh JM,
    6. Patrick AL
    . A randomized trial of lycopene supplementation in Tobago men with high prostate cancer risk. Nutr Cancer 2007;57:130–7.
    OpenUrlCrossRefPubMed
  58. 58.
    1. Price D,
    2. Stein B,
    3. Sieber P,
    4. Tutrone R,
    5. Bailen J,
    6. Goluboff E,
    7. et al.
    Toremifene for the prevention of prostate cancer in men with high grade prostatic intraepithelial neoplasia: results of a double-blind, placebo controlled, phase IIB clinical trial. J Urol 2006;176:965–70.
    OpenUrlCrossRefPubMed
  59. 59.
    1. Alberts SR,
    2. Novotny PJ,
    3. Sloan JA,
    4. Danella J,
    5. Bostwick DG,
    6. Sebo TJ,
    7. et al.
    Flutamide in men with prostatic intraepithelial neoplasia: a randomized, placebo-controlled chemoprevention trial. Am J Ther 2006;13:291–7.
    OpenUrlCrossRefPubMed
  60. 60.
    1. Bettuzzi S,
    2. Brausi M,
    3. Rizzi F,
    4. Castagnetti G,
    5. Peracchia G,
    6. Corti A
    . Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res 2006;66:1234–40.
    OpenUrlAbstract/FREE Full Text
  61. 61.
    1. Mohanty NK,
    2. Saxena S,
    3. Singh UP,
    4. Goyal NK,
    5. Arora RP
    . Lycopene as a chemopreventive agent in the treatment of high-grade prostate intraepithelial neoplasia. Urol Oncol 2005;23:383–5.
    OpenUrlCrossRefPubMed
  62. 62.
    1. Kucuk O,
    2. Sarkar FH,
    3. Sakr W,
    4. Djuric Z,
    5. Pollak MN,
    6. Khachik F,
    7. et al.
    Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy. Cancer Epidemiol Biomarkers Prev 2001;10:861–8.
    OpenUrlAbstract/FREE Full Text
  63. 63.
    1. Cote RJ,
    2. Skinner EC,
    3. Salem CE,
    4. Mertes SJ,
    5. Stanczyk FZ,
    6. Henderson BE,
    7. et al.
    The effect of finasteride on the prostate gland in men with elevated serum prostate-specific antigen levels. Br J Cancer 1998;78:413–8.
    OpenUrlCrossRefPubMed
  64. 64.
    1. Hanson JA,
    2. Gillespie JW,
    3. Grover A,
    4. Tangrea MA,
    5. Chuaqui RF,
    6. Emmert-Buck MR,
    7. et al.
    Gene promoter methylation in prostate tumor-associated stromal cells. J Natl Cancer Inst 2006;98:255–61.
    OpenUrlAbstract/FREE Full Text
  65. 65.
    1. Brikun I,
    2. Nusskern D,
    3. Gillen D,
    4. Lynn A,
    5. Murtagh D,
    6. Feczko J,
    7. et al.
    A panel of DNA methylation markers reveals extensive methylation in histologically benign prostate biopsy cores from cancer patients. Biomark Res 2014;2:25.
    OpenUrlCrossRefPubMed
  66. 66.
    1. Lotan TL,
    2. Gurel B,
    3. Sutcliffe S,
    4. Esopi D,
    5. Liu W,
    6. Xu J,
    7. et al.
    PTEN protein loss by immunostaining: analytic validation and prognostic indicator for a high risk surgical cohort of prostate cancer patients. Clin Cancer Res 2011;17:6563–73.
    OpenUrlAbstract/FREE Full Text
  67. 67.
    1. Yoshimoto M,
    2. Cutz JC,
    3. Nuin PA,
    4. Joshua AM,
    5. Bayani J,
    6. Evans AJ,
    7. et al.
    Interphase FISH analysis of PTEN in histologic sections shows genomic deletions in 68% of primary prostate cancer and 23% of high-grade prostatic intra-epithelial neoplasias. Cancer Genet Cytogenet 2006;169:128–37.
    OpenUrlCrossRefPubMed
  68. 68.
    1. Schneider TM,
    2. Osunkoya AO
    . ERG expression in intraductal carcinoma of the prostate: comparison with adjacent invasive prostatic adenocarcinoma. Mod Pathol 2014;27:1174–8.
    OpenUrlCrossRefPubMed
  69. 69.
    1. Bettendorf O,
    2. Schmidt H,
    3. Staebler A,
    4. Grobholz R,
    5. Heinecke A,
    6. Boecker W,
    7. et al.
    Chromosomal imbalances, loss of heterozygosity, and immunohistochemical expression of TP53, RB1, and PTEN in intraductal cancer, intraepithelial neoplasia, and invasive adenocarcinoma of the prostate. Genes Chromosomes Cancer 2008;47:565–72.
    OpenUrlCrossRefPubMed
  70. 70.
    1. Tsuzuki T
    . Intraductal carcinoma of the prostate: a comprehensive and updated review. Int J Urol 2015;22:140–5.
    OpenUrlCrossRefPubMed
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Cancer Prevention Research: 9 (8)
August 2016
Volume 9, Issue 8
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Premalignancy in Prostate Cancer: Rethinking What We Know
Angelo M. De Marzo, Michael C. Haffner, Tamara L. Lotan, Srinivasan Yegnasubramanian and William G. Nelson
Cancer Prev Res August 1 2016 (9) (8) 648-656; DOI: 10.1158/1940-6207.CAPR-15-0431

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Premalignancy in Prostate Cancer: Rethinking What We Know
Angelo M. De Marzo, Michael C. Haffner, Tamara L. Lotan, Srinivasan Yegnasubramanian and William G. Nelson
Cancer Prev Res August 1 2016 (9) (8) 648-656; DOI: 10.1158/1940-6207.CAPR-15-0431
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  • Article
    • Abstract
    • Introduction
    • Proposed Alternative Prostate Cancer Precursor Lesions
    • Diagnosis and Subtypes of PIN
    • Key Data Supporting High-Grade PIN as a Prostate Cancer Precursor
    • Molecular Biology of PIN
    • Intraductal Carcinoma
    • A Way Forward
    • Disclosure of Potential Conflicts of Interest
    • References
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