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 [2–7]. 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.” H？ckel and Dornh？fer 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,
References
[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.
[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.
[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.
[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.
[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.
[8]
M. H？ckel and N. Dornh？fer, “The hydra phenomenon of cancer: why tumors recur locally after microscopically complete resection,” Cancer Research, vol. 65, no. 8, pp. 2997–3002, 2005.
[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.
[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.
[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.
[12]
M. Andreoiu and L. Cheng, “Multifocal prostate cancer: biologic, prognostic, and therapeutic implications,” Human Pathology, vol. 41, no. 6, pp. 781–793, 2010.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[23]
J. H. Pinthus, D. Pacik, and J. Ramon, “Diagnosis of prostate cancer,” Recent Results in Cancer Research, vol. 175, pp. 83–99, 2007.
[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.
[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.
[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.
[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.
[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.
[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.
[30]
J. C. Presti, “Prostate biopsy strategies,” Nature Clinical Practice Urology, vol. 4, no. 9, pp. 505–511, 2007.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[74]
P. Wikstr？m, 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.
[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.
[76]
C. H？ggl？f, 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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[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.
[106]
C. L. Sawyers, “The cancer biomarker problem,” Nature, vol. 452, no. 7187, pp. 548–552, 2008.
