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Prostate Cancer
Volume 2012 (2012), Article ID 302894, 12 pages
Review Article

Markers of Field Cancerization: Proposed Clinical Applications in Prostate Biopsies

1Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA
2New Mexico Cancer Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA

Received 6 February 2012; Accepted 8 March 2012

Academic Editor: Sandra M. Gaston

Copyright © 2012 Kristina A. Trujillo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Field cancerization denotes the occurrence of genetic, epigenetic, and biochemical aberrations in structurally intact cells in histologically normal tissues adjacent to cancerous lesions. This paper tabulates markers of prostate field cancerization known to date and discusses their potential clinical value in the analysis of prostate biopsies, including diagnosis, monitoring progression during active surveillance, and assessing efficacy of presurgical neoadjuvant and focal therapeutic interventions.

1. Introduction

1.1. Definitions of Field Cancerization

The term “field cancerization” or “field effect” was originally introduced by Dr. Slaughter and colleagues in 1953 in the context of oral squamous cell carcinoma [1]. It was used to describe the presence of histologically abnormal tissue surrounding primary cancerous lesions and was proposed to be the reason for the occurrence of multifocal tumors and for the development of locally recurrent cancer. Field cancerization was much later proposed for other organ systems, including prostate [27]. While its original clinical implication remained the same, that is, the occurrence of multifocality and cancer recurrence, it must be emphasized that the definition of field cancerization has changed over time. Of note, due to the tremendous progress in molecular biology and biotechnology since the 1950s, the description of field cancerization has changed from a largely histological to a more refined molecular perspective. This change is perhaps best reflected in the following definitions reported in the literature. Accordingly, the original intention by Slaughter and colleagues [1] was to describe: “The presence of histologically abnormal tissue surrounding cancerous lesions.” Höckel and Dornhöfer extended this definition by using the term “hydra phenomenon of cancer” [8]: “The monoclonal or multiclonal displacement of normal epithelium by a genetically altered but microscopically undistinguishable homologue.” In addition to the transition from a purely histological to a molecular description, another notable change is the introduction of the concept of histological normalcy as part of tissue pre-malignancy. Indeed, this newer definition is now established for organs developing solid tumors, including prostate cancer, and denotes the occurrence of molecular alterations in structurally intact cells that are part of histologically normal tissues.

Several aspects of prostate field cancerization remain unanswered. An immediate question is whether the “field” of molecular alterations is exclusively of precursor nature, or whether it is induced by the tumor. This is further complicated by the fact that this influence could affect all types of cells, including cells of the stroma. The latter has indeed been discussed as “reactive stroma”, which develops to support, or even induce oncogenesis and cancer progression [9, 10]. This heterotypic view has recently been proposed in the context of the tissue organization field theory as opposed to the well-established somatic mutation theory [11].

1.2. Prostate Field Cancerization and Multifocality

Prostate cancer tends to present as multifocal disease with reported rates of up to 90% of prostates containing two or more cancerous foci at the time of clinical diagnosis [12]. Multifocality is viewed as a major contributor to the complexity and inaccuracy of all aspects of prostate cancer clinical assessment and management [1215]. For example, it greatly complicates staging and grading because individual foci usually display extensive heterogeneity and thus could progress at different rates depending on the nature and extent of their genetic instability and their microenvironment. Fortunately, some of these challenges can be partially counteracted by sophisticated histological assessments, for example, the Gleason sum score which combines the first most common with the second most common grade of dedifferentiation, enhances the accuracy of prognosis and patient outcome and consequently defines the most optimal treatment modality [16].

Several mechanisms underlying the development of multifocality can be envisioned. Accordingly, different cancerous foci could evolve truly independently from each other; they can remain isolated or fuse if they are in close proximity to each other. The latter would explain the existence of different grades of dedifferentiation often found within one lesion, for example, the concomitant occurrence of the cancer precursor prostatic intraepithelial neoplasia (PIN) with cancer of different Gleason grades [6, 17]. Alternatively, multifocality could be explained by intraductal migratory cells undergoing dysplasia; in this case, intrafocal heterogeneity could be due to concomitant development of different genetic aberrations of different cell clones of an individual lesion. It is not inconceivable that prostate cancer multifocality could be due to a combination of these mechanisms occurring concomitantly. Regardless of the mechanisms that lead to prostate cancer multifocality, it is compatible with the concept of field cancerization. In fact, a field effect, defined as an underlying “predisposition” in areas of the prostate gland, has been proposed to play a causal role in the development of multifocal lesions [6, 12].

2. Field Cancerization: Possible Applications in Prostate Biopsies

The necessity to recover tissue from the prostate gland by transrectal or transperitoneal biopsy can be indicated for several reasons, including confirmatory diagnosis, monitoring progression during active surveillance, and assessing efficacy of presurgical neoadjuvant and focal therapeutic interventions. In this paper, we will make a case for the potential clinical value of field cancerization to several applications involving the use of biopsies. In particular, we will discuss the possibility that specific markers of field cancerization could be useful and complementary biomarkers for the accurate clinical assessment of prostate biopsy tissues. At least three excellent recent reviews have provided lists of molecular factors that are indicative of field cancerization in human prostate tissues [35]. Although research on field cancerization in prostate tissue is relatively new compared to other organ systems, including head and neck as well as breast [18, 19], this list has become quite impressive due to the increasing acceptance of this concept. To fully appreciate the diversity of markers of prostate field cancerization, we provide here an updated overview, inclusive of stromal markers that fit the definition of field cancerization (Table 1). This list emphasizes at least two important insights into the biology of field cancerization in prostate tissues: first, field cancerization is manifested at all levels of the biological information flow and molecular regulation, that is, at the genetic, epigenetic, transcriptional, and posttranscriptional level. Second, field cancerization encompasses several cellular processes, including proliferation, metabolism, inflammation, DNA repair, and stromal/epithelial interactions. In theory, these broad biological characteristics of prostate field cancerization should increase the potential clinical value of its markers, especially when used in combination with other clinically established indicators.

Table 1: Molecular markers that are in accordance with the definition of prostate field cancerization reported in the literature1.

The clinical use, as specifically applied to prostate biopsies that could greatly benefit from well-characterized markers of field cancerization are discussed in the following sections. The markers of prostate field cancerization listed in Table 1 were extracted from the literature published in the PubMed database of the US National Library of Medicine of the National Institutes of Health (http://www.ncbi.nlm.nih.gov/pubmed/). The following key words were used in multiple combinations: “(bio)markers, prostate, biopsy, histologically normal, adjacent, field cancerization, field effect, diagnosis, prognosis, margins, active surveillance, neo-adjuvant therapy, and focal therapy.” Of note, the focused analysis of tissue adjacent to tumors in general is rare, as it is most often used as a mere control for analyses specific to the tumors [20]. Furthermore, the use of the terms “field cancerization” or “field effect” is new in prostate cancer research. Therefore, it is expected that some reports addressing such analyses may be missing herein. However, rather than providing a complete list of possible markers of field cancerization and details about their findings, we emphasize in this paper their potential as biomarkers in prostate biopsies.

2.1. Prostate Field Cancerization and Diagnosis

The risk of having prostate cancer is currently assessed by the triad of elevated serum prostate specific antigen (PSA; typically ≥3 ng/mL), abnormal digital rectal examination (DRE), and transrectal ultrasonography (TRUS) [21]. However, these indicators are per se not sufficient for the accurate diagnosis of cancer because of low sensitivity (especially for DRE and TRUS) and specificity (especially for PSA) [22, 23]. Rather, they justify the patient’s referral to the removal of biopsy cores for confirmatory diagnosis of cancer by histological assessment [21, 24]. Despite substantial controversy (further discussed in Section 2.2), PSA and DRE are often used to screen for prostate cancer leading to millions of analyzed needle biopsies each year in the USA [21, 24, 25]. A major problem inherent to biopsies is that 30–50% of men with subsequently confirmed prostate cancer experience an initial false-negative diagnosis [2527]. This is because biopsy core needles can easily miss smaller and inconspicuous lesions (Figure 1). Conceptually, it seems logical that this problem relates to the number of biopsies removed. However, the ideal number of biopsies necessary to accurately detect one or more cancer foci has been a controversial issue and has changed in the modern biopsy era. Under ultrasound guidance, 6 total cores were first recommended, three from each side of the prostate gland; this was termed “sextant biopsy.” In the late 1990s, this recommendation was changed to 10–12 cores taken from the mid and lateral peripheral zones because it was shown to increase cancer detection [28, 29]. However, since the problem of a high false-negative rate persisted, the concept of “saturation biopsy” was introduced thereafter [28, 30]. Saturation biopsy involves removing 20 to 40 cores, and its value for cancer detection is being investigated as both an initial procedure and as a secondary intervention (with a focus on lateral and apical cores; also see Section 2.4) for patients with negative initial biopsy but persistent elevated serum PSA levels. These patients are by definition at a higher risk of having cancer [28]. Regardless of the number of needle cores removed, a false-negative finding, either at first or subsequent biopsy, represents an important problem because it generates anxiety for the patient and represents a dilemma for the physician as to whether and what kind of further action is required, especially in the presence of persistently high PSA [2729]. Furthermore, an increased number of biopsy cores present the possibility of more complications and discomfort for the patient.

Figure 1: Improved diagnosis of prostate cancer by avoiding false negative biopsies through the use of markers of field cancerization. Biopsy cores (small circles) miss the two small cancer foci (white irregular structures; left); the field associated with the cancer foci (dashed circles) is detected by the biopsies (right).

The biological nature of field cancerization offers a potential means towards an improvement of this problem. The occurrence of molecular alterations that are associated with the presence of cancerous lesions, but that are not necessarily located in the same tissue area, potentially increases the target region of interest that can provide clinically meaningful information (Figure 1). This statement applies to both the traditional sextant biopsy, typically performed in the parasagittal plane between the lateral border and midline on both the right and left sides of the prostate gland as well as to the extended mode with cores removed more laterally in the anterior horns of the peripheral zone [30]. Depending on the nature of the field, that is, its extent and intensity, and on the discriminatory power of the marker(s) under investigation, it is not inconceivable that the necessity to detect histologically abnormal tissue or cells could become less important, especially when such markers are used in combination with other disease indicators such as PSA. The diagnostic value of markers of field cancerization is ideally tested in nested case-control studies, either prospectively or retrospectively. In this design, cases and controls are defined as patients with initially positive and negative biopsies, respectively. Retrospective studies offer many advantages with respect to the control of confounding factors: (i) patients derived from the same cohort can, and should be age-matched to control for potentially age related effects; (ii) the date of biopsy removal for cases and controls can be matched to account for changes in tissue quality over time; (iii) controls who remained free of cancer can be matched with cases who were at risk during the same time to assure the equal likelihood of cancer detection, which can be greatly confounded by many variables after an initial negative biopsy. This approach is termed “incidence density control sampling.” When properly designed, such optimizations lead to the determination of odds ratios that are accurate reflections of the true relative risk of having prostate cancer, as either determined at initial or after repeat negative biopsy (Figure 2) [5, 31]. Several of the factors listed in Table 1, when measured in negative biopsies, have been shown to predict the presence of cancer at prostatectomy (e.g., [32, 33]), indicating that all such markers have this diagnostic potential.

Figure 2: Nested case-control study design to investigate the diagnostic and prognostic potential of markers of field cancerization (FC) at the time of biopsy. Discrimination between positive and negative (or affected by benign prostatic hyperplasia, BPH) initial or repeat biopsies tests whether FC predicts the presence of cancer (left grey box). Discrimination between subsequently negative and positive biopsies after initial or repeat negative biopsies tests whether FC predicts development of cancer (bottom grey box). Prediction of cancer progression in initially positive biopsies indicating low-risk cancer during active surveillance tests whether FC is prognostic (top grey box).
2.2. Prostate Field Cancerization and Prognosis

The time of biopsy conceptually represents an ideal presurgical setting for clinical decision making for a patient at risk of having prostate cancer. However, even if the diagnosis of cancer can be achieved with high accuracy, a second related and as yet unresolved problem emerges at this point, that is, prognosis. While prognosis of progression is particularly powerful after surgical intervention, when the full extent of multifocality, distribution of grade, clinical staging (e.g., tumor volume), and analysis of surgical margins can be thoroughly performed, such assessment is much less accurate and often impossible in biopsies. Nevertheless, there is a growing consent among urologists that the detection of cancers in biopsies must be accompanied by the ability to determine the course of disease [16, 25]. Such conclusions are strongly supported by the large randomized trials of prostate cancer screening using the serum PSA test, that is, the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the American Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Although the primary focus of these studies was to study the association between screening and mortality, they also showed that the accompanying increased rate of cancer detection (70% and 22% higher in the ERSPC and PLCO, resp.) did not substantially improve mortality rates [89, 90]. These results show that diagnosis and prognosis are closely interrelated issues and ideally, should not be addressed separately. In fact, it is now recognized that increasing detection of cancer in biopsies without the ability of being able to discriminate between aggressive and indolent disease can lead to the clinical overtreatment of patients who may remain asymptomatic throughout their lifetimes. Such patients may experience unnecessary treatment at a high cost-to-benefit ratio, including a lower quality of life, and would benefit more from active surveillance programs [91] (further discussed in Section 2.3). Although often problematic and controversial, staging and grading information for prognosis is routinely assessed in biopsy tissue. For example, all biopsy cores containing cancerous tissue are analyzed for their level of de-differentiation by assigning a Gleason grade. In addition, parameters such as the number of cores affected by cancer, and within a single core, the percentage of tissue affected by cancer as well as the location (especially at the apex for saturation biopsies) are used to predict tumor focality, size, and extracapsular extension which are classical staging parameters [16, 25]. However, the assessment of these parameters in biopsy tissues is frequently compromised by mischaracterization of the cancer. This is evidenced by the persistent problem of stage and grade migration after prostatectomy [25].

As with diagnosis, markers of field cancerization could be helpful to predict the course of disease. In fact, it is well accepted that the entire microenvironment, including stromal cells, extracellular matrix, and growth factors is a critical determinant of tumor cell behavior for most cancers [92]. In prostate cancer, the microenvironment has even been shown to be a controlling factor and key driver of tumor initiation and progression [93]. Importantly, the interaction between tumor cells and its associated stroma not only pertains to the tumor area itself, but extends to areas surrounding the tumor at an increased distance. This implies that characteristic markers of tumor adjacent tissues have predictive value in determining tumor initiation or progression. Such markers could be highly informative in both initially negative and positive biopsies (Figure 2). In negative cases, even after repeat biopsies, these markers could indicate whether adenocarcinoma develops subsequently. The value of these markers in initially positive biopsies from men with low-risk cancer is discussed in the next section in the context of active surveillance.

2.3. Prostate Field Cancerization and Active Surveillance

One option for the management of low-grade (Gleason score of ≤6) and low-stage (T1c or T2a) prostate cancer with PSA levels of ≤10 ng/mL is to delay or forego more aggressive treatment unless evidence of an increased risk of disease progression exists. This approach is called active surveillance and aims at avoiding the substantial side effects that accompany radical prostatectomy and radiation therapy, such as incontinence, impotence, and bowel dysfunction [8991]. Active surveillance includes monitoring the patient’s cancer with PSA tests and digital rectal examinations every 3–6 months, and performing prostate biopsies every 12–24 months. The optimal strategy for the latter seems to be the “staging saturation biopsy” approach to monitor the possibility of pathological upgrading and clinical upstaging [25, 28].

Conceptually, the statements made earlier about the potential of markers of field cancerization to indicate a possible progression towards increased malignancy apply here, too. It can be easily acknowledged that the longer-term monitoring approach which is at the heart of active surveillance is ideal to determine indicative and clinically meaningful changes over time (Figure 2). Regardless of whether such molecular changes in histologically intact tissues indicate progressive instability towards further cancer development, or whether they reflect the influence of a new or already existing and progressing tumor, a marker that can be assessed dynamically and quantitatively over time with high resolution would be of great value. Lastly, because saturation biopsy covers a larger area of the prostate gland, the concerted information from several biopsy cores can be used to identify possible “geographical patterns” of molecular alterations and their change over time. Since research on prostate field cancerization is new, it has not been applied to specific clinical scenarios such as active surveillance. Specific examples of such markers in this particular setting are thus missing from the literature. However, the feasibility for the prognostic potential of markers of field cancerization is greatly supported by the fact that several of the factors listed in Table 1 have been shown (partly in biopsies) to correlate with adverse patient outcome, such as biochemical (PSA) recurrence after radical prostatectomy [48, 65].

2.4. Prostate Field Cancerization and Preoperative Assessment of Positive Margins

A positive surgical margin is defined as tumor cells touching the inked edge of the specimen. This finding is reported in approximately 25% of cases. Positive margins are one of the main determinants of biochemical (PSA) relapse and are associated with a doubled or tripled risk of failure, depending on their number and location at the inked edge [94]. Ideal prognostication of margin status would entail preoperative and highly informative biopsies to predict the risk of a positive surgical margin and as a consequence, an extraprostatic extension at radical prostatectomy. In fact, preoperative knowledge about margin status, combined with other indicators of aggressiveness determined at the time of biopsy could greatly influence the choice of further intervention. To explore this possibility, the deliberate positioning of biopsy cores for tissue removal at the apex or the base, and their association with positive margins at the time of prostatectomy were previously investigated [9598]. Interestingly, these investigations tend to be inconclusive with different studies reporting different outcomes. When individual core apical biopsies containing cancer were queried for their predictive value of positive surgical margin status and tumor involvement at the apex, it was less than 30% [97]. Similar results were reported when the incidences of a positive margin at both the apex and the base of the gland were analyzed for their association with the detection of positive or negative apical or basal biopsies [95]. In contrast, other studies determined the independent prognostic capability of positive preoperative apical biopsies for predicting positive surgical margins at the apex and reported positive predictive values of >70% [96]. Yet another study [98] reported conflicting results between apical and basal positive biopsies as predictors of positive surgical margins and extraprostatic extension. In this study, a positive biopsy at the base, but not at the apex, was predictive of a positive surgical margin and extraprostatic tumor involvement. Collectively, these studies show that the clinical value of preoperative analysis of apically and basally positioned biopsy needle cores to predict margin status remains inconclusive.

If markers of field cancerization are indicators of increased disease status, or indicators of extraprostatic cancer presence, it can be acknowledged that they could contribute to a more molecular and more refined interpretation of apical and basal biopsy material. Because research on prostate field cancerization is relatively new, examples specific to the assessment of positive margins are missing from the literature. However, the feasibility of such investigations has been announced [40], and given the importance of the zonal origin of biopsy cores taken from geographically distinct areas of the gland [99], it can be inferred from the studies on a variety of factors listed in Table 1.

2.5. Prostate Field Cancerization and Neo-Adjuvant Therapies

Neo-adjuvant intervention for prostate tumors is mostly indicated for high risk but localized organ-confined cancer. It can be applied as a monotherapeutic or multimodality approach and can entail radiotherapy, androgen ablation therapy, and chemotherapy [100]. The major goal of pre-surgical neo-adjuvant approaches is to improve the long-term outcome of subsequent prostatectomy with curative intent, as has been shown for all of the modalities listed above [101, 102]. An additional value of neo-adjuvant intervention is that it provides an opportunity for evaluating the activity and mechanism of action of neo-adjuvant new agents in correlative phase II clinical studies (Figure 3).

Figure 3: Study design to investigate the predictive potential of markers of field cancerization for pre-surgical neo-adjuvant therapies (black box), including the testing of novel agents in phase II clinical studies. Instead of applying surgical treatment with curative intent as a consequence of diagnosis of cancer at biopsy (white boxes), markers of field cancerization are assessed at the time of biopsy and after neo-adjuvant therapy (grey boxes) to determine its efficacy.

With respect to the latter, well-validated markers of field cancerization could function as surrogate endpoint indicators of therapeutic efficacy in biopsies removed before and after therapeutic intervention. Even when guided by ultrasound or other imaging techniques, it would be extremely difficult if not impossible to reliably resample the same premalignant tissue area in order to assess the effect of the therapeutic intervention. This is where markers of field cancerization could have a special advantage over markers that are specific for cancerous cells because they would be detected and quantitatively validated in structurally intact cells residing in histologically normal tissue associated with the lesion. In addition, assuming that the field is larger than the lesion itself (also see Figure 1), the exact position of the needle core biopsy would not matter as long as it is in the vicinity or area of the cancerous focus. Furthermore, as for most applications discussed in this paper, this possibility would be independent of whether the molecular alterations under investigation are precursors of the cancer or merely induced by its presence, as long as the field is representative of the tumor’s response to the therapeutic intervention. Reports on specific examples of markers of field cancerization applied to the validation of neo-adjuvant therapies are missing from the literature, but are expected to increase once distinct molecular markers have been better characterized and validated.

2.6. Prostate Field Cancerization and Focal Therapy

Organ-preserving therapy is widely accepted for several types of tumors where the lesions are found to be small, well-differentiated, and confined. Organ sparing approaches include partial as opposed to radical resection, as well as focal treatment by cryotherapy, laser ablation, and high-intensity focused ultrasound. The obvious goal is to specifically destroy cancerous tissue areas while leaving the majority of the organ and the surrounding tissues unscathed and functional, and thereby avoiding substantial side effects and reduced quality of life accompanying radical prostatectomy [103, 104]. Because of the tendency to present with multifocal disease (see Section 1.2 above), focal therapy was not considered suitable for prostate cancer. However, several reasons have shifted this view towards a more favorable one. For example, the very essence of active surveillance (described in Section 2.3) is based on the notion that most lesions within a gland are indolent in nature and will not progress. Coupled with ever improving imaging and energy-delivery techniques, it is becoming increasingly feasible to detect and treat the primary (index) lesion. While the latter approach bears the risk of ignoring smaller yet potentially more aggressive lesions, it does nevertheless offer additional tumor control for patients choosing active surveillance. However, the benefits of focal intervention will have to be determined in large trials before this approach can be recommended in all men with low-risk progression prostate cancer.

The biology of field cancerization conceptually opposes the use of focal therapy for the treatment of prostate cancer because the attempted eradication of histologically cancerous tissue would leave behind structurally intact yet molecularly altered and genetically compromised tissues that may contain cells with the potential to cause onsite recurrences and/or secondary tumors (Figure 4). However, at least three deviations from this view should be mentioned. First, if markers of field cancerization are able to discriminate with high accuracy histologically normal yet genetically compromised (i.e., field cancerized) from histologically and genetically intact (i.e., truly normal) tissues, the extent of the field associated with an individual lesion would become defined and could be included in the focal therapeutic approach (Figure 4). Second, if markers of field cancerization are predictive of progression (as discussed in Section 2.2), indolent lesions could be discriminated from more aggressive foci, thereby increasing the efficacy of focal therapy by guiding it towards foci with higher risk of progression. Lastly, if markers of field cancerization are merely indicators of the presence of cancer cells, as opposed to precursors of disease (as discussed in Section 1.1), they could be of value as predictive indicators for the efficacy of focal intervention (similar to their application described in Section 2.5).

Figure 4: A primary tumor (black irregular shape) is associated with a complex field of molecular alterations in structurally intact cells in histologically normal adjacent tissue (arrows and dotted lines; left). After focal therapy to the primary tumor (white dashed lined irregular shape), premalignant areas (grey irregular shapes) may in time lead to onsite or secondary tumors within the remaining field (upper right). If focal therapy is extended to include the field, onsite recurrences could be avoided (lower right).

3. Conclusions

Prostate cancer is an extensively heterogeneous disease with highly variable clinical outcome. The time of biopsy is an important milestone for a patient at risk of having cancer and progressing to a more advanced stage. Apart from confirmatory diagnosis, the information gained from biopsy cores is also crucial in determining further actions, especially the choice between active surveillance and more aggressive therapeutic interventions, including radical prostatectomy (Sections 2.1 to 2.4) [25, 105]. The procurement and analysis of biopsies also play a role during therapeutic intervention, such as in predicting and monitoring the efficacy of pre-surgical neo-adjuvant and focal therapy (Sections 2.5 and 2.6) [100, 104]. Therefore, the clinical management of prostate cancer leads to millions of biopsy cores that are removed by urologists and analyzed by pathologists each year in the USA [21, 24, 25], underscoring the importance of this type of material. Unfortunately, the analysis and interpretation of prostate biopsies is often complicated by limiting factors such as the number of cores affected by cancer, the amount of glandular tissue in an individual core, and the amount of tissue in general. In addition, there remains discordance, despite extended biopsy schemes, between the interpretation from biopsy material and information gained at prostatectomy, as evidenced by the frequency of upstaging and upgrading [25, 28].

Markers of field cancerization have the potential to overcome these important barriers. This is due primarily to the fact that molecular alterations that deviate from normalcy can be assessed in a larger target, defined as the tissue area adjacent to the tumor lesion, thus becoming more independent of the analysis of the lesion itself. However, key to such optimization is the choice of the proper controls for potentially field cancerized tissues, as the focus is shifted to what most investigators use as the control for the analysis of tumor tissues [20]. Tissues unrelated to cancer and similar conditions should be chosen and matched for age, body mass, and other factors to avoid detection of false positive molecular aberrations. This may be challenging due to intertissue heterogeneity and requires extensive characterization of the biomarker under investigation with respect to its association with cancer presence or development. The latter necessitates detailed knowledge about the nature and extent of the field associated with tumor foci. This knowledge, however, has just begun to be generated for men at risk of having or developing prostate cancer. Nevertheless, data in support of the potential of markers of field cancerization to help solve the “cancer biomarker problem,” as emphasized recently by leaders in the field [21, 106], is accumulating (Table 1) and warrants further research.


The authors are supported by the following funding agencies: The National Institutes of Health, the Department of Defense, and the American Cancer Society. The University of New Mexico Health Sciences Center Department of Biochemistry & Molecular Biology is greatly acknowledged for financial and administrative support.


  1. D. P. Slaughter, H. W. Southwick, and W. Smejkal, “Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin,” Cancer, vol. 6, no. 5, pp. 963–968, 1953.
  2. B. J. M. Braakhuis, M. P. Tabor, J. A. Kummer, C. R. Leemans, and R. H. Brakenhoff, “A genetic explanation of slaughter's concept of field cancerization: evidence and clinical implications,” Cancer Research, vol. 63, no. 8, pp. 1727–1730, 2003. View at Scopus
  3. G. D. Dakubo, J. P. Jakupciak, M. A. Birch-Machin, and R. L. Parr, “Clinical implications and utility of field cancerization,” Cancer Cell International, vol. 7, article 2, 2007. View at Publisher · View at Google Scholar · View at Scopus
  4. S. Halin, P. Hammarsten, H. Adamo, P. Wikstrm, and A. Bergh, “Tumor indicating normal tissue could be a new source of diagnostic and prognostic markers for prostate cancer,” Expert Opinion on Medical Diagnostics, vol. 5, no. 1, pp. 37–47, 2011. View at Publisher · View at Google Scholar · View at Scopus
  5. L. Nonn, V. Ananthanarayanan, and P. H. Gann, “Evidence for field cancerization of the prostate,” Prostate, vol. 69, no. 13, pp. 1470–1479, 2009. View at Publisher · View at Google Scholar · View at Scopus
  6. J. A. Squire, P. C. Park, M. Yoshimoto, et al., “Prostate cancer as a model system for genetic diversity in tumors,” Advances in Cancer Research, vol. 112, pp. 183–216, 2011.
  7. H. Chai and R. E. Brown, “Review: field effect in cancer-an update,” Annals of Clinical and Laboratory Science, vol. 39, no. 4, pp. 331–337, 2009. View at Scopus
  8. M. Höckel and N. Dornhöfer, “The hydra phenomenon of cancer: why tumors recur locally after microscopically complete resection,” Cancer Research, vol. 65, no. 8, pp. 2997–3002, 2005. View at Scopus
  9. J. A. Tuxhorn, G. E. Ayala, and D. R. Rowley, “Reactive stroma in prostate cancer progression,” Journal of Urology, vol. 166, no. 6, pp. 2472–2483, 2001. View at Scopus
  10. J. A. Tuxhorn, G. E. Ayala, M. J. Smith, V. C. Smith, T. D. Dang, and D. R. Rowley, “Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling,” Clinical Cancer Research, vol. 8, no. 9, pp. 2912–2923, 2002. View at Scopus
  11. A. M. Soto and C. Sonnenschein, “The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory,” BioEssays, vol. 33, no. 5, pp. 332–340, 2011. View at Publisher · View at Google Scholar · View at Scopus
  12. M. Andreoiu and L. Cheng, “Multifocal prostate cancer: biologic, prognostic, and therapeutic implications,” Human Pathology, vol. 41, no. 6, pp. 781–793, 2010. View at Publisher · View at Google Scholar · View at Scopus
  13. R. Arora, M. O. Koch, J. N. Eble, T. M. Ulbright, L. Li, and L. Cheng, “Heterogeneity of Gleason grade in multifocal adenocarcinoma of the prostate,” Cancer, vol. 100, no. 11, pp. 2362–2366, 2004. View at Publisher · View at Google Scholar · View at Scopus
  14. A. Villers, J. E. McNeal, F. S. Freiha, and T. A. Stamey, “Multiple cancers in the prostate. Morphologic features of clinically recognized versus incidental tumors,” Cancer, vol. 70, no. 9, pp. 2313–2318, 1992.
  15. G. J. Miller and J. M. Cygan, “Morphology of prostate cancer: the effects of multifocality on histological grade, tumor volume and capsule penetration,” Journal of Urology, vol. 152, no. 5, pp. 1709–1713, 1994. View at Scopus
  16. K. A. Iczkowski and M. S. Lucia, “Current perspectives on Gleason grading of prostate cancer,” Current Urology Reports, vol. 12, no. 3, pp. 216–222, 2011. View at Publisher · View at Google Scholar · View at Scopus
  17. D. G. Bostwick and L. Cheng, “Precursors of prostate cancer,” Histopathology, vol. 60, no. 1, pp. 4–27, 2012.
  18. C. M. Heaphy, J. K. Griffith, and M. Bisoffi, “Mammary field cancerization: molecular evidence and clinical importance,” Breast Cancer Research and Treatment, vol. 118, no. 2, pp. 229–239, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. C. R. Leemans, B. J. M. Braakhuis, and R. H. Brakenhoff, “The molecular biology of head and neck cancer,” Nature Reviews Cancer, vol. 11, no. 1, pp. 9–22, 2011. View at Publisher · View at Google Scholar · View at Scopus
  20. B. J. M. Braakhuis, C. R. Leemans, and R. H. Brakenhoff, “Using tissue adjacent to carcinoma as a normal control: an obvious but questionable practice,” The Journal of Pathology, vol. 203, no. 2, pp. 620–621, 2004. View at Publisher · View at Google Scholar · View at Scopus
  21. S. F. Oon, S. R. Pennington, J. M. Fitzpatrick, and R. W. G. Watson, “Biomarker research in prostate cancer—towards utility, not futility,” Nature Reviews Urology, vol. 8, no. 3, pp. 131–138, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. M. LaSpina and G. P. Haas, “Update on the diagnosis and management of prostate cancer,” The Canadian Journal of Urology, vol. 15, no. 41, pp. 3–13, 2008. View at Scopus
  23. J. H. Pinthus, D. Pacik, and J. Ramon, “Diagnosis of prostate cancer,” Recent Results in Cancer Research, vol. 175, pp. 83–99, 2007. View at Scopus
  24. B. Djavan, S. Milani, and M. Remzi, “Prostate biopsy: who, how and when. An update,” The Canadian Journal of Urology, vol. 12, supplement 1, pp. 44–48100, 2005. View at Scopus
  25. A. R. Patel and J. S. Jones, “Optimal biopsy strategies for the diagnosis and staging of prostate cancer,” Current Opinion in Urology, vol. 19, no. 3, pp. 232–237, 2009. View at Publisher · View at Google Scholar · View at Scopus
  26. D. A. Levy and J. S. Jones, “Management of rising prostate-specific antigen after a negative biopsy,” Current Urology Reports, vol. 12, no. 3, pp. 197–202, 2011. View at Publisher · View at Google Scholar · View at Scopus
  27. F. Rabbani, N. Stroumbakis, B. R. Kava, M. S. Cookson, and W. R. Fair, “Incidence and clinical significance of false-negative sextant prostate biopsies,” Journal of Urology, vol. 159, no. 4, pp. 1247–1250, 1998. View at Publisher · View at Google Scholar · View at Scopus
  28. N. B. Delongchamps and G. P. Haas, “Saturation biopsies for prostate cancer: current uses and future prospects,” Nature Reviews Urology, vol. 6, no. 12, pp. 645–652, 2009. View at Publisher · View at Google Scholar · View at Scopus
  29. K. Eichler, S. Hempel, J. Wilby, L. Myers, L. M. Bachmann, and J. Kleijnen, “Diagnostic value of systematic biopsy methods in the investigation of prostate cancer: a systematic review,” Journal of Urology, vol. 175, no. 5, pp. 1605–1612, 2006. View at Publisher · View at Google Scholar · View at Scopus
  30. J. C. Presti, “Prostate biopsy strategies,” Nature Clinical Practice Urology, vol. 4, no. 9, pp. 505–511, 2007. View at Publisher · View at Google Scholar · View at Scopus
  31. S. G. Baker, B. S. Kramer, and S. Srivastava, “Markers for early detection of cancer: statistical guidelines for nested case-control studies,” BMC Medical Research Methodology, vol. 2, no. 1, p. 4, 2002. View at Scopus
  32. S. Isharwal, D. V. Makarov, H. B. Carter et al., “DNA content in the diagnostic biopsy for benign-adjacent and cancer-tissue areas predicts the need for treatment in men with T1c prostate cancer undergoing surveillance in an expectant management programme,” BJU International, vol. 105, no. 3, pp. 329–333, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. M. Slater, S. Danieletto, and J. A. Barden, “Expression of the apoptotic calcium channel P2X7 in the glandular epithelium is a marker for early prostate cancer and correlates with increasing PSA levels,” Journal of Molecular Histology, vol. 36, no. 3, pp. 159–165, 2005. View at Publisher · View at Google Scholar · View at Scopus
  34. P. Colanzi, A. Santinelli, R. Mazzucchelli, R. Pomante, and R. Montironi, “Changes in the normal-looking epithelium in prostates with PIN or cancer,” Advances in Clinical Pathology, vol. 3, no. 4, pp. 129–134, 1999. View at Scopus
  35. T. Mairinger, G. Mikuz, and A. Gschwendtner, “Nuclear chromatin texture analysis of nonmalignant tissue can detect adjacent prostatic adenocarcinoma,” Prostate, vol. 41, no. 1, pp. 12–19, 1999.
  36. R. W. Veltri, M. A. Khan, M. C. Miller et al., “Ability to predict metastasis based on pathology findings and alterations in nuclear structure of normal-appearing and cancer peripheral zone epithelium in the prostate,” Clinical Cancer Research, vol. 10, no. 10, pp. 3465–3473, 2004. View at Publisher · View at Google Scholar · View at Scopus
  37. J. A. Hanson, J. W. Gillespie, A. Grover et al., “Gene promoter methylation in prostate tumor-associated stromal cells,” Journal of the National Cancer Institute, vol. 98, no. 4, pp. 255–261, 2006. View at Publisher · View at Google Scholar · View at Scopus
  38. R. Henrique, C. Jerónimo, M. R. Teixeira et al., “Epigenetic heterogeneity of high-grade prostatic intraepithelial neoplasia: clues for clonal progression in prostate carcinogenesis,” Molecular Cancer Research, vol. 4, no. 1, pp. 1–8, 2006. View at Publisher · View at Google Scholar · View at Scopus
  39. A. Aitchison, A. Warren, D. Neal, and P. Rabbitts, “RASSFIA promoter methylation is frequently detected in both pre-malignant and non-malignant microdissected prostatic epithelial tissues,” Prostate, vol. 67, no. 6, pp. 638–644, 2007. View at Publisher · View at Google Scholar · View at Scopus
  40. J. Mehrotra, S. Varde, H. Wang et al., “Quantitative, spatial resolution of the epigenetic field effect in prostate cancer,” Prostate, vol. 68, no. 2, pp. 152–160, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. I. Krop, A. Player, A. Tablante et al., “Frequent HIN-1 promoter methylation and lack of expression in multiple human tumor types,” Molecular Cancer Research, vol. 2, no. 9, pp. 489–494, 2004. View at Scopus
  42. D. C. Malins, P. M. Johnson, E. A. Barker, N. L. Polissar, T. M. Wheeler, and K. M. Anderson, “Cancer-related changes in prostate DNA as men age and early identification of metastasis in primary prostate tumors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 9, pp. 5401–5406, 2003. View at Publisher · View at Google Scholar · View at Scopus
  43. D. C. Malins, N. K. Gilman, V. M. Green et al., “Metastatic cancer DNA phenotype identified in normal tissues surrounding metastasizing prostate carcinomas,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 31, pp. 11428–11431, 2004. View at Publisher · View at Google Scholar · View at Scopus
  44. D. C. Malins, N. K. Gilman, V. M. Green, T. M. Wheeler, E. A. Barker, and K. M. Anderson, “A cancer DNA phenotype in healthy prostates, conserved in tumors and adjacent normal cells, implies a relationship to carcinogenesis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 52, pp. 19093–19096, 2005. View at Publisher · View at Google Scholar · View at Scopus
  45. C. A. Fordyce, C. M. Heaphy, N. E. Joste, A. Y. Smith, W. C. Hunt, and J. K. Griffith, “Association between cancer-free survival and telomere DNA content in prostate tumors,” Journal of Urology, vol. 173, no. 2, pp. 610–614, 2005. View at Publisher · View at Google Scholar · View at Scopus
  46. A. M. Joshua, B. Vukovic, I. Braude et al., “Telomere attrition in isolated high-grade prostatic intraepithelial neoplasia and surrounding stroma is predictive of prostate cancer,” Neoplasia, vol. 9, no. 1, pp. 81–89, 2007. View at Publisher · View at Google Scholar · View at Scopus
  47. S. K. Watson, B. W. Woolcock, J. N. Fee et al., “Minimum altered regions in early prostate cancer progression identified by high resolution whole genome tiling path BAC array comparative hybridization,” Prostate, vol. 69, no. 9, pp. 961–975, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. E. G. Treat, C. M. Heaphy, L. W. Massie et al., “Telomere DNA content in prostate biopsies predicts early rise in prostate-specific antigen after radical prostatectomy for prostate cancer,” Urology, vol. 75, no. 3, pp. 724–729, 2010. View at Publisher · View at Google Scholar · View at Scopus
  49. C. M. Heaphy, T. M. Fleet, E. G. Treat et al., “Organ-wide telomeric status in diseased and disease-free prostatic tissues,” Prostate, vol. 70, no. 13, pp. 1471–1479, 2010. View at Publisher · View at Google Scholar · View at Scopus
  50. A. M. Joshua, E. Shen, M. Yoshimoto et al., “Topographical analysis of telomere length and correlation with genomic instability in whole mount prostatectomies,” Prostate, vol. 71, no. 7, pp. 778–790, 2011. View at Publisher · View at Google Scholar · View at Scopus
  51. R. L. Parr, G. D. Dakubo, K. A. Crandall et al., “Somatic mitochondrial DNA mutations in prostate cancer and normal appearing adjacent glands in comparison to age-matched prostate samples without malignant histology,” Journal of Molecular Diagnostics, vol. 8, no. 3, pp. 312–319, 2006. View at Publisher · View at Google Scholar · View at Scopus
  52. B. Reguly, J. P. Jakupciak, and R. L. Parr, “3.4 kb mitochondrial genome deletion serves as a surrogate predictive biomarker for prostate cancer in histopathologically benign biopsy cores,” Journal of the Canadian Urological Association, vol. 4, no. 5, pp. E118–E122, 2010. View at Scopus
  53. K. Robinson, J. Creed, B. Reguly et al., “Accurate prediction of repeat prostate biopsy outcomes by a mitochondrial DNA deletion assay,” Prostate Cancer and Prostatic Diseases, vol. 13, no. 2, pp. 126–131, 2010. View at Publisher · View at Google Scholar · View at Scopus
  54. Y. P. Yu, D. Landsittel, L. Jing et al., “Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy,” Journal of Clinical Oncology, vol. 22, no. 14, pp. 2790–2799, 2004. View at Publisher · View at Google Scholar · View at Scopus
  55. U. R. Chandran, R. Dhir, C. Ma, G. Michalopoulos, M. Becich, and J. Gilbertson, “Differences in gene expression in prostate cancer, normal appearing prostate tissue adjacent to cancer and prostate tissue from cancer free organ donors,” BMC Cancer, vol. 5, article 45, 2005. View at Publisher · View at Google Scholar · View at Scopus
  56. I. Popa, Y. Fradet, G. Beaudry, H. Hovington, G. Beaudry, and B. Têtu, “Identification of PCA3 (DD3) in prostatic carcinoma by in situ hybridization,” Modern Pathology, vol. 20, no. 11, pp. 1121–1127, 2007. View at Publisher · View at Google Scholar · View at Scopus
  57. F. Rizzi, L. Belloni, P. Crafa et al., “A novel gene signature for molecular diagnosis of human prostate cancer by RT-qPCR,” PLoS One, vol. 3, no. 10, Article ID e3617, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. B. Furusato, C. L. Gao, L. Ravindranath et al., “Mapping of TMPRSS2-ERG fusions in the context of multi-focal prostate cancer,” Modern Pathology, vol. 21, no. 2, pp. 67–75, 2008. View at Publisher · View at Google Scholar · View at Scopus
  59. C. M. Haaland, C. M. Heaphy, K. S. Butler, E. G. Fischer, J. K. Griffith, and M. Bisoffi, “Differential gene expression in tumor adjacent histologically normal prostatic tissue indicates field cancerization,” International Journal of Oncology, vol. 35, no. 3, pp. 537–546, 2009. View at Publisher · View at Google Scholar · View at Scopus
  60. Z. Zhao, J. Liu, S. Li, and W. Shen, “Prostate stem cell antigen mRNA expressionin preoperatively negative biopsy specimens predicts subsequent cancer after transurethral resection of the prostate for benign prostatic hyperplasia,” Prostate, vol. 69, no. 12, pp. 1292–1302, 2009. View at Publisher · View at Google Scholar · View at Scopus
  61. H. Bonkhoff, U. Stein, C. Welter, and K. Remberger, “Differential expression of the pS2 protein in the human prostate and prostate cancer: association with premalignant changes and neuroendocrine differentiation,” Human Pathology, vol. 26, no. 8, pp. 824–828, 1995. View at Scopus
  62. E. O. Olapade-Olaopa, E. H. MacKay, N. A. Taub, D. P. S. Sandhu, T. R. Terry, and F. K. Habib, “Malignant transformation of human prostatic epithelium is associated with the loss of androgen receptor immunoreactivity in the surrounding stroma,” Clinical Cancer Research, vol. 5, no. 3, pp. 569–576, 1999. View at Scopus
  63. S. Zha, W. R. Gage, J. Sauvageot et al., “Cyclooxygenase-2 is up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma,” Cancer Research, vol. 61, no. 24, pp. 8617–8623, 2001. View at Scopus
  64. S. M. Henshall, D. I. Quinn, C. S. Lee et al., “Altered expression of androgen receptor in the malignant epithelium and adjacent stroma is associated with early relapse in prostate cancer,” Cancer Research, vol. 61, no. 2, pp. 423–427, 2001. View at Scopus
  65. G. Ayala, T. Thompson, G. Yang et al., “High levels of phosphorylated form of Akt-1 in prostate cancer and non-neoplastic prostate tissues are strong predictors of biochemical recurrence,” Clinical Cancer Research, vol. 10, no. 19, pp. 6572–6578, 2004. View at Publisher · View at Google Scholar · View at Scopus
  66. R. Dhir, B. Vietmeier, J. Arlotti et al., “Early identification of individuals with prostate cancer in negative biopsies,” Journal of Urology, vol. 171, no. 4, pp. 1419–1423, 2004. View at Publisher · View at Google Scholar · View at Scopus
  67. H. Uetsuki, H. Tsunemori, R. Taoka, R. Haba, M. Ishikawa, and Y. Kakehi, “Expression of a novel biomarker, EPCA, in adenocarcinomas and precancerous lesions in the prostate,” Journal of Urology, vol. 174, no. 2, pp. 514–518, 2005. View at Publisher · View at Google Scholar · View at Scopus
  68. V. Ananthanarayanan, R. J. Deaton, X. J. Yang, M. R. Pins, and P. H. Gann, “Alpha-methylacyl-CoA racemase (AMACR) expression in normal prostatic glands and high-grade prostatic intraepithelial neoplasia (HGPIN): association with diagnosis of prostate cancer,” Prostate, vol. 63, no. 4, pp. 341–346, 2005. View at Publisher · View at Google Scholar · View at Scopus
  69. V. Ananthanarayanan, R. J. Deaton, X. J. Yang, M. R. Pins, and P. H. Gann, “Alteration of proliferation and apoptotic markers in normal and premalignant tissue associated with prostate cancer,” BMC Cancer, vol. 6, article 73, 2006. View at Publisher · View at Google Scholar · View at Scopus
  70. A. S. Merseburger, J. Hennenlotter, P. Simon et al., “Activation of the PKB/Akt pathway in histological benign prostatic tissue adjacent to the primary malignant lesions,” Oncology Reports, vol. 16, no. 1, pp. 79–83, 2006. View at Scopus
  71. D. E. Hansel, A. M. DeMarzo, E. A. Platz et al., “Early prostate cancer antigen expression in predicting presence of prostate cancer in men with histologically negative biopsies,” Journal of Urology, vol. 177, no. 5, pp. 1736–1740, 2007. View at Publisher · View at Google Scholar · View at Scopus
  72. A. Santinelli, R. Mazzucchelli, F. Barbisan, et al., “alpha-Methylacyl coenzyme A racemase, Ki-67, and topoisomerase IIalpha in cystoprostatectomies with incidental prostate cancer,” American Journal of Clinical Pathology, vol. 128, no. 4, pp. 657–666, 2007.
  73. D. Huang, G. P. Casale, J. Tian et al., “Quantitative fluorescence imaging analysis for cancer biomarker discovery: application to β-catenin in archived prostate specimens,” Cancer Epidemiology Biomarkers and Prevention, vol. 16, no. 7, pp. 1371–1381, 2007. View at Publisher · View at Google Scholar · View at Scopus
  74. P. Wikström, J. Marusic, P. Stattin, and A. Bergh, “Low stroma androgen receptor level in normal and tumor prostate tissue is related to poor outcome in prostate cancer patients,” Prostate, vol. 69, no. 8, pp. 799–809, 2009. View at Publisher · View at Google Scholar · View at Scopus
  75. S. Waalkes, P. Simon, J. Hennenlotter et al., “Altered expression of Akt signaling pathway parameters in prostate needle biopsies derived from benign, adjacent and cancerous tissue,” Oncology Reports, vol. 23, no. 5, pp. 1257–1260, 2010. View at Publisher · View at Google Scholar · View at Scopus
  76. C. Hägglöf, P. Hammarsten, A. Josefsson, et al., “Stromal PDGFRbeta expression in prostate tumors and non-malignant prostate tissue predicts prostate cancer survival,” PLoS One, vol. 5, no. 5, Article ID e10747, 2010.
  77. P. Hammarsten, A. Karalija, A. Josefsson et al., “Low levels of phosphorylated epidermal growth factor receptor in nonmalignant and malignant prostate tissue predict favorable outcome in prostate cancer patients,” Clinical Cancer Research, vol. 16, no. 4, pp. 1245–1255, 2010. View at Publisher · View at Google Scholar · View at Scopus
  78. J. L. Gregg, K. E. Brown, E. M. Mintz, H. Piontkivska, and G. C. Fraizer, “Analysis of gene expression in prostate cancer epithelial and interstitial stromal cells using laser capture microdissection,” BMC Cancer, vol. 10, article 165, 2010. View at Publisher · View at Google Scholar · View at Scopus
  79. D. Huang, G. P. Casale, J. Tian et al., “UDP-glucose dehydrogenase as a novel field-specific candidate biomarker of prostate cancer,” International Journal of Cancer, vol. 126, no. 2, pp. 315–327, 2010. View at Publisher · View at Google Scholar · View at Scopus
  80. R. Mazzucchelli, F. Barbisan, A. Santinelli et al., “Immunohistochemical expression of prostate tumor overexpressed 1 in cystoprostatectomies with incidental and insignificant prostate cancer. Further evidence for field effect in prostatic carcinogenesis,” Human Pathology, vol. 42, no. 12, pp. 1931–1936, 2011. View at Publisher · View at Google Scholar · View at Scopus
  81. A. C. Jones, K. A. Trujillo, and G. K. Phillips, “Early growth response 1 and fatty acid synthase expression is altered in tumor adjacent prostate tissue and indicates field cancerization,” Prostate. In press.
  82. L. L. Cheng, M. A. Burns, J. L. Taylor et al., “Metabolic characterization of human prostate cancer with tissue magnetic resonance spectroscopy,” Cancer Research, vol. 65, no. 8, pp. 3030–3034, 2005. View at Scopus
  83. R. Montironi, L. Diamanti, R. Pomante, D. Thompson, and P. H. Bartels, “Subtle changes in benign tissue adjacent to prostate neoplasia detected with a Bayesian belief network,” The Journal of Pathology, vol. 182, no. 4, pp. 442–449, 1997.
  84. A. Johansson, S. Rudolfsson, P. Hammarsten et al., “Mast cells are novel independent prognostic markers in prostate cancer and represent a target for therapy,” American Journal of Pathology, vol. 177, no. 2, pp. 1031–1041, 2010. View at Publisher · View at Google Scholar · View at Scopus
  85. N. Nonomura, H. Takayama, A. Kawashima et al., “Decreased infiltration of macrophage scavenger receptor-positive cells in initial negative biopsy specimens is correlated with positive repeat biopsies of the prostate,” Cancer Science, vol. 101, no. 6, pp. 1570–1573, 2010. View at Publisher · View at Google Scholar · View at Scopus
  86. N. Nonomura, H. Takayama, K. Nishimura et al., “Decreased number of mast cells infiltrating into needle biopsy specimens leads to a better prognosis of prostate cancer,” British Journal of Cancer, vol. 97, no. 7, pp. 952–956, 2007. View at Publisher · View at Google Scholar · View at Scopus
  87. R. Montironi, L. Diamanti, D. Thompson, H. G. Bartels, and P. H. Bartels, “Analysis of the capillary architecture in the precursors of prostate cancer: recent findings and new concepts,” European Urology, vol. 30, no. 2, pp. 191–200, 1996. View at Scopus
  88. J. A. Siegal, E. Yu, and M. K. Brawer, “Topography of neovascularity in human prostate carcinoma,” Cancer, vol. 75, no. 10, pp. 2545–2551, 1995.
  89. R. M. Hoffman, “Clinical practice. Screening for prostate cancer,” The New England Journal of Medicine, vol. 365, no. 21, pp. 2013–2019, 2011.
  90. R. M. Hoffman and A. Y. Smith, “What we have learned from randomized trials of prostate cancer screening,” Asian Journal of Andrology, vol. 13, no. 3, pp. 369–373, 2011. View at Publisher · View at Google Scholar · View at Scopus
  91. A. Slomski, “Expert panel advocates surveillance for men with low-risk prostate cancer,” JAMA, vol. 307, no. 2, article 133, 2012.
  92. P. Friedl and S. Alexander, “Cancer invasion and the microenvironment: plasticity and reciprocity,” Cell, vol. 147, no. 5, pp. 992–1009, 2011.
  93. D. Basanta, D. W. Strand, R. B. Lukner et al., “The role of transforming growth factor-β-mediated tumor-stroma interactions in prostate cancer progression: an integrative approach,” Cancer Research, vol. 69, no. 17, pp. 7111–7120, 2009. View at Publisher · View at Google Scholar · View at Scopus
  94. K. A. Iczkowski and M. S. Lucia, “Frequency of positive surgical margin at prostatectomy and its effect on patient outcome,” Prostate Cancer, vol. 2011, Article ID 673021, 12 pages, 2011. View at Publisher · View at Google Scholar
  95. P. G. Borboroglu and C. L. Amling, “Correlation of positive prostate sextant biopsy locations to sites of positive surgical margins in radical prostatectomy specimens,” European Urology, vol. 39, no. 6, pp. 648–654, 2001. View at Publisher · View at Google Scholar · View at Scopus
  96. B. Malavaud, A. Villers, V. Ravery et al., “Role of preoperative positive apical biopsies in the prediction of specimen-confined prostate cancer after radical retropubic prostatectomy: a multi-institutional study,” European Urology, vol. 37, no. 3, pp. 281–288, 2000. View at Scopus
  97. H. Rogatsch, W. Horninger, H. Volgger, G. Bartsch, G. Mikuz, and T. Mairinger, “Radical prostatectomy: the value of preoperative, individually labeled apical biopsies,” Journal of Urology, vol. 164, no. 3, pp. 754–758, 2000. View at Scopus
  98. N. J. Touma, J. L. Chin, T. Bella, A. Sener, and J. I. Izawa, “Location of a positive biopsy as a predictor of surgical margin status and extraprostatic disease in radical prostatectomy,” BJU International, vol. 97, no. 2, pp. 259–262, 2006. View at Publisher · View at Google Scholar · View at Scopus
  99. S. W. Fine and V. E. Reuter, “Anatomy of the prostate revisited: implications for prostate biopsy and zonal origins of prostate cancer,” Histopathology, vol. 60, no. 1, pp. 142–152, 2012.
  100. J. Pendleton, L. L. Pisters, K. Nakamura, S. Anai, and C. J. Rosser, “Neoadjuvant therapy before radical prostatectomy: where have we been? Where are we going?” Urologic Oncology, vol. 25, no. 1, pp. 11–18, 2007. View at Publisher · View at Google Scholar · View at Scopus
  101. G. Sonpavde, K. N. Chi, T. Powles et al., “Neoadjuvant therapy followed by prostatectomy for clinically localized prostate cancer,” Cancer, vol. 110, no. 12, pp. 2628–2639, 2007. View at Publisher · View at Google Scholar · View at Scopus
  102. D. Mazhar, S. Ngan, and J. Waxman, “Improving outcomes in early prostate cancer: part II—neoadjuvant treatment,” BJU International, vol. 98, no. 4, pp. 731–734, 2006. View at Publisher · View at Google Scholar · View at Scopus
  103. J. L. Dominguez-Escrig, S. R. McCracken, and D. Greene, “Beyond diagnosis: evolving prostate biopsy in the era of focal therapy,” Prostate Cancer, vol. 2011, Article ID 386207, 11 pages, 2011. View at Publisher · View at Google Scholar
  104. U. Lindner, N. Lawrentschuk, O. Schatloff, J. Trachtenberg, and A. Lindner, “Evolution from active surveillance to focal therapy in the management of prostate cancer,” Future Oncology, vol. 7, no. 6, pp. 775–787, 2011. View at Publisher · View at Google Scholar · View at Scopus
  105. S. J. Freedland, “Screening, risk assessment, and the approach to therapy in patients with prostate cancer,” Cancer, vol. 117, no. 6, pp. 1123–1135, 2011. View at Publisher · View at Google Scholar · View at Scopus
  106. C. L. Sawyers, “The cancer biomarker problem,” Nature, vol. 452, no. 7187, pp. 548–552, 2008. View at Publisher · View at Google Scholar · View at Scopus