Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Precancerous lesions of the prostate: Pathology and clinical implications

Ximing J Yang, MD, PhD
E David Crawford, MD
Section Editors
Nicholas Vogelzang, MD
W Robert Lee, MD, MS, MEd
Jerome P Richie, MD, FACS
Deputy Editor
Michael E Ross, MD


The study of precancerous lesions of the prostate is important for understanding prostatic carcinogenesis, and more importantly, for developing potential chemopreventive measures for prostate cancer.

Four major pathologic entities will be discussed in this topic review: prostatic intraepithelial neoplasia (PIN), atypical adenomatous hyperplasia (AAH, also termed adenosis), atrophic lesions, and atypical small acinar proliferation (ASAP). High-grade PIN and ASAP are most likely precursors of the majority of prostatic adenocarcinomas. In contrast, AAH and atrophic lesions are possible, although uncertain, precancerous lesions. The pathologic characteristics, prevalence, relationship to prostate cancer, and clinical significance of these lesions are discussed in this topic, with a particular emphasis on PIN.


Prostatic intraepithelial neoplasia (PIN), first described in 1969 [1], is a neoplastic proliferation of prostatic epithelial cells that is confined to preexisting prostatic ducts or acini (glands). PIN was further characterized and initially termed intraductal dysplasia in 1986 [2]; the currently used term "prostatic intraepithelial neoplasia" was introduced in 1987 and endorsed by consensus at a 1989 conference [3,4].

Histology — The histologic characteristics of PIN have been well described [5,6]. The neoplastic prostatic epithelial cells are within prostatic ducts or acini, which are typically large and branched, with a convoluted inner contour similar to benign glands (picture 1). Epithelial cell proliferation produces a layer of crowded, pseudostratified, neoplastic cells with cytologic atypia, characterized by nuclear irregularity, nucleomegaly, hyperchromasia, and prominent nucleoli (picture 1). These findings are similar to those of invasive prostate cancer. (See "Interpretation of prostate biopsy".)

In contrast to adenocarcinoma, the architecture is normal, and the PIN glands characteristically contain basal cells around their periphery, seen as a thin and occasionally discontinuous layer on hematoxylin and eosin (H&E) stained sections. Immunohistochemical staining for high molecular weight cytokeratins (34bE12 antibody) easily demonstrates the basal cells (picture 2). This is an important diagnostic feature because the presence of basal cells can help to differentiate PIN from prostatic adenocarcinoma, in which basal cells are absent [3,7-10]. (See "Interpretation of prostate biopsy".)


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Apr 13, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. McNeal JE. Origin and development of carcinoma in the prostate. Cancer 1969; 23:24.
  2. McNeal JE, Bostwick DG. Intraductal dysplasia: a premalignant lesion of the prostate. Hum Pathol 1986; 17:64.
  3. Bostwick DG, Brawer MK. Prostatic intra-epithelial neoplasia and early invasion in prostate cancer. Cancer 1987; 59:788.
  4. Drago JR, Mostofi FK, Lee F. Introductory remarks and workshop summary. Urology 1992; 39:2.
  5. Bostwick DG, Srigley J. Premalignant lesions. In: Pathology of the prostate, Bostwick DG (Ed), Churchill-Livingston, New York 1990. p.37.
  6. Kovi J, Mostofi FK, Heshmat MY, Enterline JP. Large acinar atypical hyperplasia and carcinoma of the prostate. Cancer 1988; 61:555.
  7. Brawer MK, Peehl DM, Stamey TA, Bostwick DG. Keratin immunoreactivity in the benign and neoplastic human prostate. Cancer Res 1985; 45:3663.
  8. O'Malley FP, Grignon DJ, Shum DT. Usefulness of immunoperoxidase staining with high-molecular-weight cytokeratin in the differential diagnosis of small-acinar lesions of the prostate gland. Virchows Arch A Pathol Anat Histopathol 1990; 417:191.
  9. Hedrick L, Epstein JI. Use of keratin 903 as an adjunct in the diagnosis of prostate carcinoma. Am J Surg Pathol 1989; 13:389.
  10. Yang XJ, Lecksell K, Gaudin P, Epstein JI. Rare expression of high-molecular-weight cytokeratin in adenocarcinoma of the prostate gland: a study of 100 cases of metastatic and locally advanced prostate cancer. Am J Surg Pathol 1999; 23:147.
  11. Bostwick DG, Amin MB, Dundore P, et al. Architectural patterns of high-grade prostatic intraepithelial neoplasia. Hum Pathol 1993; 24:298.
  12. Reyes AO, Swanson PE, Carbone JM, Humphrey PA. Unusual histologic types of high-grade prostatic intraepithelial neoplasia. Am J Surg Pathol 1997; 21:1215.
  13. Berman DM, Yang J, Epstein JI. Foamy gland high-grade prostatic intraepithelial neoplasia. Am J Surg Pathol 2000; 24:140.
  14. Kovi J, Jackson MA, Heshmat MY. Ductal spread in prostatic carcinoma. Cancer 1985; 56:1566.
  15. Bull JH, Ellison G, Patel A, et al. Identification of potential diagnostic markers of prostate cancer and prostatic intraepithelial neoplasia using cDNA microarray. Br J Cancer 2001; 84:1512.
  16. Abdulkadir SA, Qu Z, Garabedian E, et al. Impaired prostate tumorigenesis in Egr1-deficient mice. Nat Med 2001; 7:101.
  17. Brawer MK, Lange PH. Prostate-specific antigen and premalignant change: implications for early detection. CA Cancer J Clin 1989; 39:361.
  18. Horninger W, Volgger H, Rogatsch H, et al. Predictive value of total and percent free prostate specific antigen in high grade prostatic intraepithelial neoplasia lesions: results of the Tyrol Prostate Specific Antigen Screening Project. J Urol 2001; 165:1143.
  19. Ramos CG, Carvahal GF, Mager DE, et al. The effect of high grade prostatic intraepithelial neoplasia on serum total and percentage of free prostate specific antigen levels. J Urol 1999; 162:1587.
  20. Yang, XY, Kim, HL. High grade prostatic intraepithelial neoplasia does not cause significant elevation of prostate specific antigen (abstract). Mod Pathol 2001; 14:99A.
  21. Ronnett BM, Carmichael MJ, Carter HB, Epstein JI. Does high grade prostatic intraepithelial neoplasia result in elevated serum prostate specific antigen levels? J Urol 1993; 150:386.
  22. Alexander EE, Qian J, Wollan PC, et al. Prostatic intraepithelial neoplasia does not appear to raise serum prostate-specific antigen concentration. Urology 1996; 47:693.
  23. Morote J, Raventós CX, Encabo G, et al. Effect of high-grade prostatic intraepithelial neoplasia on total and percent free serum prostatic-specific antigen. Eur Urol 2000; 37:456.
  24. Sakr WA, Haas GP, Cassin BF, et al. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 1993; 150:379.
  25. McNeal JE. Significance of duct-acinar dysplasia in prostatic carcinogenesis. Urology 1989; 34:9.
  26. Qian J, Wollan P, Bostwick DG. The extent and multicentricity of high-grade prostatic intraepithelial neoplasia in clinically localized prostatic adenocarcinoma. Hum Pathol 1997; 28:143.
  27. Bostwick DG, Qian J. High-grade prostatic intraepithelial neoplasia. Mod Pathol 2004; 17:360.
  28. Epstein JI, Cho KR, Quinn BD. Relationship of severe dysplasia to stage A (incidental) adenocarcinoma of the prostate. Cancer 1990; 65:2321.
  29. Quinn BD, Cho KR, Epstein JI. Relationship of severe dysplasia to stage B adenocarcinoma of the prostate. Cancer 1990; 65:2328.
  30. Shin M, Takayama H, Nonomura N, et al. Extent and zonal distribution of prostatic intraepithelial neoplasia in patients with prostatic carcinoma in Japan: analysis of whole-mounted prostatectomy specimens. Prostate 2000; 42:81.
  31. Sánchez-Chapado M, Olmedilla G, Cabeza M, et al. Prevalence of prostate cancer and prostatic intraepithelial neoplasia in Caucasian Mediterranean males: an autopsy study. Prostate 2003; 54:238.
  32. Bostwick DG, Pacelli A, Lopez-Beltran A. Molecular biology of prostatic intraepithelial neoplasia. Prostate 1996; 29:117.
  33. McNeal JE, Alroy J, Leav I, et al. Immunohistochemical evidence for impaired cell differentiation in the premalignant phase of prostate carcinogenesis. Am J Clin Pathol 1988; 90:23.
  34. Alcaraz A, Barranco MA, Corral JM, et al. High-grade prostate intraepithelial neoplasia shares cytogenetic alterations with invasive prostate cancer. Prostate 2001; 47:29.
  35. Zitzelsberger H, Engert D, Walch A, et al. Chromosomal changes during development and progression of prostate adenocarcinomas. Br J Cancer 2001; 84:202.
  36. Garabedian EM, Humphrey PA, Gordon JI. A transgenic mouse model of metastatic prostate cancer originating from neuroendocrine cells. Proc Natl Acad Sci U S A 1998; 95:15382.
  37. Abbas F, Hochberg D, Civantos F, Soloway M. Incidental prostatic adenocarcinoma in patients undergoing radical cystoprostatectomy for bladder cancer. Eur Urol 1996; 30:322.
  38. Troncoso P, Babaian RJ, Ro JY, et al. Prostatic intraepithelial neoplasia and invasive prostatic adenocarcinoma in cystoprostatectomy specimens. Urology 1989; 34:52.
  39. Alsikafi NF, Brendler CB, Gerber GS, Yang XJ. High-grade prostatic intraepithelial neoplasia with adjacent atypia is associated with a higher incidence of cancer on subsequent needle biopsy than high-grade prostatic intraepithelial neoplasia alone. Urology 2001; 57:296.
  40. Gaudin PB, Sesterhenn IA, Wojno KJ, et al. Incidence and clinical significance of high-grade prostatic intraepithelial neoplasia in TURP specimens. Urology 1997; 49:558.
  41. Pacelli A, Bostwick DG. Clinical significance of high-grade prostatic intraepithelial neoplasia in transurethral resection specimens. Urology 1997; 50:355.
  42. Hoedemaeker RF, Kranse R, Rietbergen JB, et al. Evaluation of prostate needle biopsies in a population-based screening study: the impact of borderline lesions. Cancer 1999; 85:145.
  43. Mettlin C, Lee F, Drago J, Murphy GP. The American Cancer Society National Prostate Cancer Detection Project. Findings on the detection of early prostate cancer in 2425 men. Cancer 1991; 67:2949.
  44. Skjørten FJ, Berner A, Harvei S, et al. Prostatic intraepithelial neoplasia in surgical resections: relationship to coexistent adenocarcinoma and atypical adenomatous hyperplasia of the prostate. Cancer 1997; 79:1172.
  45. Kronz JD, Allan CH, Shaikh AA, Epstein JI. Predicting cancer following a diagnosis of high-grade prostatic intraepithelial neoplasia on needle biopsy: data on men with more than one follow-up biopsy. Am J Surg Pathol 2001; 25:1079.
  46. Prange W, Erbersdobler A, Hammerer P, et al. Significance of high-grade prostatic intraepithelial neoplasia in needle biopsy specimens. Urology 2001; 57:486.
  47. Naya Y, Ayala AG, Tamboli P, Babaian RJ. Can the number of cores with high-grade prostate intraepithelial neoplasia predict cancer in men who undergo repeat biopsy? Urology 2004; 63:503.
  48. Humilier M, Yang XJ. Increased detection of high grade prostatic intraepithelial neoplasia (PIN) by using additional lateral prostate needle biopsy (abstract). Modern Pathol 2002; 15:165a.
  49. Vis AN, Hoedemaeker RF, Roobol M, et al. The predictive value for prostate cancer of lesions that raise suspicion of concomitant carcinoma: an evaluation from a randomized, population-based study of screening for prostate cancer. Cancer 2001; 92:524.
  50. Kamoi K, Troncoso P, Babaian RJ. Strategy for repeat biopsy in patients with high grade prostatic intraepithelial neoplasia. J Urol 2000; 163:819.
  51. Lefkowitz GK, Taneja SS, Brown J, et al. Followup interval prostate biopsy 3 years after diagnosis of high grade prostatic intraepithelial neoplasia is associated with high likelihood of prostate cancer, independent of change in prostate specific antigen levels. J Urol 2002; 168:1415.
  52. Borboroglu PG, Sur RL, Roberts JL, Amling CL. Repeat biopsy strategy in patients with atypical small acinar proliferation or high grade prostatic intraepithelial neoplasia on initial prostate needle biopsy. J Urol 2001; 166:866.
  53. Davidson D, Bostwick DG, Qian J, et al. Prostatic intraepithelial neoplasia is a risk factor for adenocarcinoma: predictive accuracy in needle biopsies. J Urol 1995; 154:1295.
  54. Herawi M, Kahane H, Cavallo C, Epstein JI. Risk of prostate cancer on first re-biopsy within 1 year following a diagnosis of high grade prostatic intraepithelial neoplasia is related to the number of cores sampled. J Urol 2006; 175:121.
  55. Godoy G, Huang GJ, Patel T, Taneja SS. Long-term follow-up of men with isolated high-grade prostatic intra-epithelial neoplasia followed by serial delayed interval biopsy. Urology 2011; 77:669.
  56. Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol 2006; 175:820.
  57. Abdel-Khalek M, El-Baz M, Ibrahiem el-H. Predictors of prostate cancer on extended biopsy in patients with high-grade prostatic intraepithelial neoplasia: a multivariate analysis model. BJU Int 2004; 94:528.
  58. Kronz JD, Shaikh AA, Epstein JI. High-grade prostatic intraepithelial neoplasia with adjacent small atypical glands on prostate biopsy. Hum Pathol 2001; 32:389.
  59. Scattoni V, Roscigno M, Freschi M, et al. Predictors of prostate cancer after initial diagnosis of atypical small acinar proliferation at 10 to 12 core biopsies. Urology 2005; 66:1043.
  60. Ingels A, Ploussard G, Allory Y, et al. Concomitant high-grade prostatic intraepithelial neoplasia is associated with good prognosis factors and oncologic outcome after radical prostatectomy. Urol Int 2014; 92:264.
  61. Langer JE, Rovner ES, Coleman BG, et al. Strategy for repeat biopsy of patients with prostatic intraepithelial neoplasia detected by prostate needle biopsy. J Urol 1996; 155:228.
  62. Merrimen JL, Jones G, Walker D, et al. Multifocal high grade prostatic intraepithelial neoplasia is a significant risk factor for prostatic adenocarcinoma. J Urol 2009; 182:485.
  63. Lee MC, Moussa AS, Zaytoun O, et al. Using a saturation biopsy scheme increases cancer detection during repeat biopsy in men with high-grade prostatic intra-epithelial neoplasia. Urology 2011; 78:1115.
  64. Iczkowski KA, Bostwick DG. Criteria for biopsy diagnosis of minimal volume prostatic adenocarcinoma: analytic comparison with nondiagnostic but suspicious atypical small acinar proliferation. Arch Pathol Lab Med 2000; 124:98.
  65. Balaji KC, Rabbani F, Tsai H, et al. Effect of neoadjuvant hormonal therapy on prostatic intraepithelial neoplasia and its prognostic significance. J Urol 1999; 162:753.
  66. Ferguson J, Zincke H, Ellison E, et al. Decrease of prostatic intraepithelial neoplasia following androgen deprivation therapy in patients with stage T3 carcinoma treated by radical prostatectomy. Urology 1994; 44:91.
  67. Vailancourt L, Ttu B, Fradet Y, et al. Effect of neoadjuvant endocrine therapy (combined androgen blockade) on normal prostate and prostatic carcinoma. A randomized study. Am J Surg Pathol 1996; 20:86.
  68. Thompson IM, Lucia MS, Redman MW, et al. Finasteride decreases the risk of prostatic intraepithelial neoplasia. J Urol 2007; 178:107.
  69. Yang XJ, Lecksell K, Short K, et al. Does long-term finasteride therapy affect the histologic features of benign prostatic tissue and prostate cancer on needle biopsy? PLESS Study Group. Proscar Long-Term Efficacy and Safety Study. Urology 1999; 53:696.
  70. Bostwick DG, Qian J. Effect of androgen deprivation therapy on prostatic intraepithelial neoplasia. Urology 2001; 58:91.
  71. Taneja SS. Re: 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 Urol 2013; 190:536.
  72. Baron E, Angrist A. Incidence of occult adenocarcinoma of the prostate after 50 years of age. Arch Pathol 1941; 32:787.
  73. McNeal JE. Morphogenesis of prostatic carcinoma. Cancer 1965; 18:1659.
  74. Brawn PN. Adenosis of the prostate: a dysplastic lesion that can be confused with prostate adenocarcinoma. Cancer 1982; 49:826.
  75. Bostwick DG, Algaba F, Amin MB, et al. Consensus statement on terminology: recommendation to use atypical adenomatous hyperplasia in place of adenosis of the prostate. Am J Surg Pathol 1994; 18:1069.
  76. Bostwick DG, Srigley J, Grignon D, et al. Atypical adenomatous hyperplasia of the prostate: morphologic criteria for its distinction from well-differentiated carcinoma. Hum Pathol 1993; 24:819.
  77. Gaudin PB, Epstein JI. Adenosis of the prostate. Histologic features in transurethral resection specimens. Am J Surg Pathol 1994; 18:863.
  78. Qian J, Bostwick DG. The extent and zonal location of prostatic intraepithelial neoplasia and atypical adenomatous hyperplasia: relationship with carcinoma in radical prostatectomy specimens. Pathol Res Pract 1995; 191:860.
  79. Gaudin PB, Epstein JI. Adenosis of the prostate. Histologic features in needle biopsy specimens. Am J Surg Pathol 1995; 19:737.
  80. Grignon DJ, Sakr WA. Atypical adenomatous hyperplasia of the prostate: a critical review. Eur Urol 1996; 30:206.
  81. Helpap B, Bonkhoff H, Cockett A, et al. Relationship between atypical adenomatous hyperplasia (AAH), prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma. Pathologica 1997; 89:288.
  82. Cheng L, Shan A, Cheville JC, et al. Atypical adenomatous hyperplasia of the prostate: a premalignant lesion? Cancer Res 1998; 58:389.
  83. Yang XJ, Wu CL, Woda BA, et al. Expression of alpha-Methylacyl-CoA racemase (P504S) in atypical adenomatous hyperplasia of the prostate. Am J Surg Pathol 2002; 26:921.
  84. Häussler O, Epstein JI, Amin MB, et al. Cell proliferation, apoptosis, oncogene, and tumor suppressor gene status in adenosis with comparison to benign prostatic hyperplasia, prostatic intraepithelial neoplasia, and cancer. Hum Pathol 1999; 30:1077.
  85. Doll JA, Zhu X, Furman J, et al. Genetic analysis of prostatic atypical adenomatous hyperplasia (adenosis). Am J Pathol 1999; 155:967.
  86. Guo CC, Epstein JI. Intraductal carcinoma of the prostate on needle biopsy: Histologic features and clinical significance. Mod Pathol 2006; 19:1528.
  87. EpsteinJI, Oxley J, Ro JY, et al.. Intraductal carcinoma. In: WHO classification of tumours of the urinary system and male genital organs, 4th, Moch H, Humphrey PA, Ulbright TM, Reuter VE. (Eds), World Health Organization, Lyon 2016. p.164.
  88. Ruska KM, Sauvageot J, Epstein JI. Histology and cellular kinetics of prostatic atrophy. Am J Surg Pathol 1998; 22:1073.
  89. Gardner WA Jr, Culberson DE. Atrophy and proliferation in the young adult prostate. J Urol 1987; 137:53.
  90. Cheville JC, Bostwick DG. Postatrophic hyperplasia of the prostate. A histologic mimic of prostatic adenocarcinoma. Am J Surg Pathol 1995; 19:1068.
  91. Oppenheimer JR, Wills ML, Epstein JI. Partial atrophy in prostate needle cores: another diagnostic pitfall for the surgical pathologist. Am J Surg Pathol 1998; 22:440.
  92. Putzi MJ, De Marzo AM. Morphologic transitions between proliferative inflammatory atrophy and high-grade prostatic intraepithelial neoplasia. Urology 2000; 56:828.
  93. Amin MB, Tamboli P, Varma M, Srigley JR. Postatrophic hyperplasia of the prostate gland: a detailed analysis of its morphology in needle biopsy specimens. Am J Surg Pathol 1999; 23:925.