Joseph C. Klink, MD
Eric A. Klein, MD, FACS
BASICS
DESCRIPTION
• Prostatic intraepithelial neoplasia (PIN) describes cytologically atypical cells confined within architecturally benign prostatic glands and acini
• Historically subclassified
– Low-grade PIN (LGPIN) and high-grade PIN (HGPIN)
– PIN 1, 2, or 3
• LGPIN no longer reported because
– Not reliably distinguished from benign prostate by pathologists
– LGPIN carries no increased risk of prostate cancer (PCa) on future biopsies
• HGPIN, and atypical small acinar proliferation (ASAP) are both considered by most to be premalignant and the terms should not be used interchangeably.
• Antiquated names for PIN include intraductal hyperplasia, hyperplasia with malignant change, large acinar atypical hyperplasia, marked atypia, ductal-acinar dysplasia
• Remainder of this chapter will focus on HGPIN
EPIDEMIOLOGY
Incidence
• Parallels PCa incidence
• Increases with age
• In PSA screened men, incidence ranges 0–25%
– Mean incidence 7.7%
Prevalence
• Parallels PCa prevalence
• 7% of men in their 30s
• 91% of elderly African American men
• 67% of elderly Caucasian men
• 21% of Korean men undergoing cystoprostatectomy
RISK FACTORS
• Age
• PCa
– HGPIN often found close to PCa, but does not carry independent prognostic significance once PCa is diagnosed
Genetics
• Many genetic abnormalities shared by HGPIN and PCa
– Leads to conclusion that HGPIN is a precursor of PCa
• TMPRSS2-ERG gene fusion in 16–19% of HGPIN lesions in patients with PCa
• Overexpression of PTOV1 in HGPIN is an independent predictor of PCa on repeat biopsy
• mTOR pathway upregulation
• Chromosomal anomalies in >50% of HGPIN
• Gains of chromosomes (decreasing order of frequency) 8, 10, 7, 12, and Y
• Loss of heterozygosity on 8p12–21
• Telomerase activation
• Epigenetic changes including hypermethylation
PATHOPHYSIOLOGY
• HGPIN may be precursor of PCa (1)
– PCa can develop without HGPIN
• HGPIN extent and frequency greater when PCa present
• Usually in peripheral zone
• Often multifocal
ASSOCIATED CONDITIONS
ALERT
Multifocal HGPIN Predicts Increased Risk of PCa on subsequent biopsy.
• Historically, HGPIN on prostate biopsy often represented failure to sample a nearby PCa (2)
– As the number of cores routinely sampled at prostate biopsy increased, the predictive value of HGPIN for PCa decreased
• With modern 12-core biopsies, a single focus of HGPIN does NOT increase the risk of PCa diagnosis on subsequent biopsies
– Decision for repeat prostate biopsy should be made on other clinical factors (elevated PSA, high PSA velocity, new nodule on DRE), not influenced by the presence of 1 focus of HGPIN
• Multifocal HGPIN indicates higher risk of PCa on repeat biopsy (3)
– Multivariate odds ratio 3.2 for increased cancer detection with multifocal HGPIN
– 16–75% (usually around 30%) PCa rate on repeat biopsy for multifocal HGPIN
• Repeat biopsy usually done 1 yr after initial biopsy
GENERAL PREVENTION
• 5α-reductase inhibitors can reduce the incidence of PIN but are not FDA approved for this use
– Finasteride daily for 7 yr decreased the incidence of HGPIN from 7.1–6% in the Prostate Cancer Prevention Trial
– Dutasteride reduced the incidence of HGPIN from 6–3.7% in the REDUCE trial
• The risk posed by unifocal HGPIN to a patient’s health and life in the absence of PCa is so low that prevention is not indicated
DIAGNOSIS
HISTORY
HGPIN produces no symptoms
PHYSICAL EXAM
• Digital rectal exam (DRE) is usually normal, but may reveal a prostate nodule or induration
• No other physical exam findings
DIAGNOSTIC TESTS & INTERPRETATION
Lab
Elevated PSA may be present but not caused by the HGPIN
Imaging
Not reliably seen on any imaging
Diagnostic Procedures/Surgery
• Transrectal ultrasound-guided biopsy of the prostate taking at least 12 cores
– Indicated to look for PCa. HGPIN is an incidental finding
Pathologic Findings
• Characterized by proliferation of secretory cells with significant cytologic atypia within prostate glands and acini
• Secretory cells are enlarged with increased nuclear/cytoplasmic ratio and prominent nucleoli
• Cytoplasm of the HGPIN cells tends to stain positively for α-methylacyl-CoA
• Most of these features are shared by PCa
• In PCa, basal cells are absent. In HGPIN the basal cell layer is retained although is often discontinuous on H&E stain (Figure 2)
– Basal cells can be demonstrated by immunohistochemical staining with antibodies to high–molecular-weight cytokeratins or nuclear p63
• 4 main architectural patterns of HGPIN have been described (tufting, micropapillary, cribriform, and flat), but these do not make a difference clinically
• HGPIN usually found in the peripheral zone
DIFFERENTIAL DIAGNOSIS
• Prostate Cancer (PCa)
• ASAP
– Confers an increased risk of subsequent PCa diagnosis
– Requires repeat prostate biopsy in a few months to rule out PCa
• Normal anatomic structures and embryonic rests
• Atypia induced by inflammation, infarction, or radiation
• Lobular atrophy and postatrophic hyperplasia
• Transitional cell metaplasia
• Typical and atypical basal cell metaplasia
• Cribriform hyperplasia
• Cribriform, ductal endometrioid, and urothelial carcinoma
TREATMENT
GENERAL MEASURES
• If HGPIN was found on initial prostate biopsy of <10 cores, the biopsy should be repeated with an extended scheme
• If multifocal HGPIN is found on initial prostate biopsy, the biopsy should be repeated within 1 yr
• Repeat biopsy should sample the entire prostate, not just the HGPIN area
MEDICATION
First Line
• Not necessary to treat HGPIN
• HGPIN often used to identify patients at “high risk” of developing PCa to enroll them in clinical trials of medications to prevent PCa
Second Line
N/A
SURGERY/OTHER PROCEDURES
Radical prostatectomy not indicated for HGPIN in the absence of PCa
ADDITIONAL TREATMENT
Radiation Therapy
Not indicated for HGPIN in the absence of PCa
Additional Therapies
N/A
Complementary & Alternative Therapies
• Green tea catechins for 1 yr in men with HGPIN reduced the incidence of PCa from 30 to 3%
• Soy, vitamin E, and selenium did not slow the rate of progression of HGPIN to PCa in a randomized double-blind trial (SELECT Trial)
• None of these therapies routinely recommend to men with HGPIN
ONGOING CARE
PROGNOSIS
• Excellent prognosis in the absence of PCa
• Must monitor for the development of PCa as outlined above
COMPLICATIONS
None other than the risks of biopsy
FOLLOW-UP
Patient Monitoring
• In certain situations as noted, HGPIN may indicate an increased risk of PCa and, therefore, may require repeat biopsy at 1 yr
• LGPIN should not be diagnosed on pathology and, therefore, does not require any follow-up
Patient Resources
• American Cancer Society http://www.cancer.org/treatment/understandingyourdiagnosis/understandingyourpathologyreport/prostatepathology/high-grade-prostatic-intraepithelial-neoplasia
• http://prostatecancerinfolink.net/diagnosis/pin/
REFERENCES
1. Klink JC, Miocinovic R, Magi Galluzzi C, et al. High-grade prostatic intraepithelial neoplasia. Korean J Urol. 2012;53(5):297–303.
2. Bostwick DG, Cheng L. Precursors of prostate cancer. Histopathology. 2012;60:4–27.
3. Epstein JI, Grignon DJ, Humphrey PA, et al. Interobserver reproducibility in the diagnosis of prostatic intraepithelial neoplasia. Am J Surg Pathol. 1995;19:873–886.
ADDITIONAL READING
• Antonelli A, Tardanico R, Giovanessi L, et al. Predicting prostate cancer at rebiopsies in patients with high-grade prostatic intraepithelial neoplasia: A study on 546 patients. Prostate Cancer Prostatic Dis. 2011;14:173–176.
• Bostwick DG, Qian J. High-grade prostatic intraepithelial neoplasia. Mod Pathol. 2004;17:360–379.
• Heidenreich A, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part 1: Screening, diagnosis, and treatment of clinically localized disease. Eur Urol. 2011;59:61–71.
• Kawachi MH, Bahnson RR, Barry M, et al. NCCN clinical practice guidelines in oncology: Prostate cancer early detection. J Natl Compr Canc Netw. 2010;8:240–262.
See Also (Topic, Algorithm, Media)
• Atypical Small Acinar Proliferation, Prostate (ASAP)
• Prostate Cancer, General
• Prostate Nodule
• Prostatic Intraepithelial Neoplasia (PIN) Images 
• PSA Elevation, General Considerations
CODES
ICD9
• 233.4 Carcinoma in situ of prostate
• 602.3 Dysplasia of prostate
ICD10
• D07.5 Carcinoma in situ of prostate
• N42.3 Dysplasia of prostate
CLINICAL/SURGICAL PEARLS
• If HGPIN was found on initial prostate biopsy of <10 cores, the biopsy should be repeated with an extended scheme.
• If multifocal HGPIN is found on initial prostate biopsy, the biopsy should be repeated within 1 yr.
• With modern 12-core biopsies, a single focus of HGPIN does NOT increase the risk of PCa diagnosis on subsequent biopsies.
• Decision for repeat prostate biopsy should be made on other clinical factors (elevated PSA, high PSA velocity, new nodule on DRE), not influenced by the presence of 1 focus of HGPIN.