Monday, April 28, 2014

Non-Cancerous Findings on Prostate Biopsy

Men with an elevated PSA often undergo prostate biopsy to look for prostate cancer.  Many times, the prostate biopsy does not demonstrate cancer but gives another diagnosis including:

  • High-grade prostatic intraepithelial neoplasia (HGPIN)
  • Proliferative Inflammatory Atrophy (PIA)
    • Acute or Chronic Inflammation
  • Atypia, or Atypical small acinar proliferation (ASAP)

None of these diagnoses are cancerous, however valuable information can be gained by each diagnosis, in some cases implications regarding the future risk of cancer.  Here we review the implications of benign diagnoses on prostate biopsy.

High-grade prostatic intraepithelial neoplasia (HGPIN)

HGPIN currently is the only recognized premalignant precursor to prostatic adenocarcinoma.  Under the microscope, HGPIN appears much like prostate cancer with atypical cells containing prominent nucleoli.  However, the main histologic difference between prostate cancer and HGPIN is that HGPIN has a preserved basal cell layer in the glandular architecture.  Morphologic and molecular data also support HGPIN as a precursor to prostatic carcinoma.[1,2]  Morphologically,  prostate cancer is observed budding off areas of HGPIN.[1,2]  Molecularly, HGPIN and prostate cancer share a number of molecular genetic and chromosomal abnormalities that support a common evolution.[3]

HGPIN appears in prostate biopsies in 5-8% of men and concomitantly with prostate cancer at radical prostatectomy in up to 80% of cases.[4,5]  HGPIN can be seen as early as the 3rd decade of life, preceding the age of prostate cancer diagnosis by at least 10 years.  However, the risk of detecting subsequent prostate cancer is the range of 22-24% - which is not clinically or statistically different from the risk of finding prostate cancer after a previous negative biopsy in men with an elevated PSA.[4,6]  The amount of HGPIN found may influence the detection of subsequent prostate cancer.  In men with 3 or greater cores of HGPIN, the risk of prostate cancer is significantly higher.[7-11]  Therefore, men with 1-2 cores of HGPIN should be followed with routine PSA and digital rectal examination with repeat biopsy within 3 years or as indicated sooner; and men with 3 or more cores of HGPIN undergo repeat biopsy within 12-18 months of the initial diagnosis.

Proliferative Inflammatory Atrophy (PIA) and Inflammation

Occasionally prostate biopsies will demonstrate inflammatory cells and PIA.  Atrophy occurs in the setting of inflammation and has been suggested relate to prostate cancer as early as the 1950's.[12,13]  PIA contains atrophic epithelial cells that appear to be regenerating in response to cellular damage.  The cellular damage is mediated by inflammatory cell infiltrates.[14]  PIA will occasionally merge directly with HGPIN and morphological transitions between PIA, HGPIN and prostate cancer have been described.[15,16]  However, other than its relationship to HGPIN and cancer, no association between PIA on biopsy on subsequent prostate cancer is noted.

Atypical small acinar proliferation (ASAP)

ASAP or atypia does not have specific histologic, morphologic or molecular features that align it with prostate cancer like HGPIN.  Rather, ASAP is a diagnosis of exclusion for glands within the prostate that do not meet criteria for prostate cancer but appear suspicious for the diagnosis.  The incidence of ASAP on initial prostate biopsy is 2-3%.  However, different from HGPIN, the risk of subsequent prostate cancer on repeat biopsy is as high as 60%.[17-21]  Therefore men with ASAP should undergo repeat biopsy within 6-12 months due to the high likelihood of harboring undetected prostate cancer.


  • HGPIN is a premalignant prostate cancer lesion.  It is present in 5-8% of biopsies.
    • If 1-2 cores of HGPIN, repeat PSA and DRE annually, consider repeat biopsy within 3 years or sooner if clinically indicated.
    • If 3 or mores cores of HGPIN are found at biopsy, a repeat biopsy should be performed within 12-18 months.
  • PIA is found with inflammation and in the spectrum of HGPIN and prostate cancer.  There is no evidence that inflammation or PIA on biopsy is indicative of prostate cancer on subsequent biopsy.
  • ASAP or atypia is found in 2-3% of prostate biopsies and highly correlated with prostate cancer on subsequent biopsy; men with ASAP should be biopsied within 6-12 months of an initial diagnosis. 

[1] Bostwick DG, Qian J. High-grade prostatic intraepithelial neoplasia.  Mod Pathol. 2004;17(3):360-379.
[2] Joniau S, Goeman L, Pennings J, et al. Prostatic intraepithelial neoplasia  (PIN): importance and clinical management. Eur Urol. 2005;48(3): 379-385.
[3] Dickinson SI.  Premalignant and malignant prostate lesions: pathologic review.Cancer Control. 2010 Oct;17(4):214-22.
[4] Ayala AG, Ro JY. Prostatic intraepithelial neoplasia: recent advances. Arch Pathol Lab Med. 2007;131(8):1257-1266.
[5] Pierorazio PM, Lambert SM, Matsukhani M, Sprenkle PC, McCann TR, Katz AE, Olsson CA, Benson MC, McKiernan JM.High-grade prostatic intraepithelial neoplasia is an independent predictor of outcome after radical prostatectomy.BJU Int. 2007 Nov;100(5):1066-70. Epub 2007 Sep 3.
[6] McNeal JE. Origin and development of carcinoma in the prostate.  Cancer. 1969;23:24-34.
[7] Kronz JD, Allan CH, Shaikh AA, et al. 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(8):1079-1085.
[8] 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(4):528-533.
[9] Netto GJ, Epstein JI. Widespread high-grade prostatic intraepithelial neoplasia on prostatic needle biopsy: a significant likelihood of subsequently diagnosed adenocarcinoma. Am J Surg Pathol. 2006;30(9):1184-1188.
[10] Akhavan A, Keith JD, Bastacky SI, et al. The proportion of cores with high-grade prostatic intraepithelial neoplasia on extended-pattern needle biopsy is significantly associated with prostate cancer on site-directed repeat biopsy. BJU Int. 2007;99(4):765-769.
[11] Godoy G, Taneja SS. Contemporary clinical management of isolated high-grade prostatic intraepithelial neoplasia. Prostate Cancer Prostatic Dis. 2008;11(1):20-31.
[12] De Marzo AM, Platz EA, Epstein JI et al. A working group classification of focal prostate atrophy lesions. Am.J. Surg. Pathol. 2006; 30: 1281–91.
[13] Liavåg I. Atrophy and regeneration in the pathogenesis of prostatic carcinoma. Acta Pathol. Microbiol. Scand. 1968;73: 338–50.
[14] De Marzo AM , Marchi VL , Epstein JI , Nelson WG . Proliferative inflammatory atrophy of the prostate: implications for prostatic carcinogenesis . Am. J. Pathol. 1999 ; 155 ; 1985 – 1992 .
[15] Putzi MJ , De Marzo AM . Morphologic transitions between proliferative inflammatory atrophy and high-grade prostatic intraepithelial neoplasia . Urology 2000 ; 56 ; 828 – 832 .
[16] Wang W , Bergh A , Damber J-E . Morphological transition of proliferative inflammatory atrophy to high-grade intraepithelial neoplasia and cancer in human prostate . Prostate 2009 ; 69 ; 1378 – 1386 .
[17] Bostwick DG, Meiers I. Atypical small acinar proliferation in the prostate: clinical significance in 2006. Arch Pathol Lab Med. 2006;130(7): 952-957.
[18] Leite KR, Camara-Lopes LH, Cury J, et al. Prostate cancer detection at rebiopsy after an initial benign diagnosis: results using sextant extended prostate biopsy. Clinics (Sao Paulo). 2008;63(3):339-342.
[19] Montironi R, Scattoni V, Mazzucchelli R, et al. Atypical foci suspicious but not diagnostic of malignancy in prostate needle biopsies (also referred to as “atypical small acinar proliferation suspicious for but not diagnostic of malignancy”). Eur Urol. 2006;50(4):666-674.
[20] 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(3 pt 1):820-834.
[21] Mallén E, Gil P, Sancho C, Jesús Gil M, et al. Atypical small acinar proliferation: review of a series of 64 patients. Scand J Urol Nephrol. 2006;40(4):272-275


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