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Diagnosis, Management, And Follow-Up Strategies For High Grade Prostatic Intraepithelial Neoplasia

By Bahram Robert Oliai, M.D.


In my pathology practice one issue that seems to come up frequently as a cause of frustration to both my urologist colleagues, and perhaps more so to their patients, is what to do following a diagnosis of high grade prostatic intraepithelial neoplasia (HGPIN) and/or so-called atypical acini, the now infamous “atypical small acinar proliferation,” (A.K.A. ASAP).

How do we as pathologists make these diagnoses? What do they mean for the patient in terms of cancer risk? What is/are the optimal strategies for follow-up so that if cancer does eventually develop it is caught at an early, curable stage? These are some of the questions that I seek to address in this my first series of FOCUS on genitourinary pathology newsletters. Each of this first series of three newsletters will cover a different topic starting with High Grade Prostatic Intraepithelial Neoplasia, continuing with Atypical Acini/ASAP, and concluding with small foci of prostate cancer.

High Grade Prostatic Intraepithelial Neoplasia (HGPIN):

HGPIN refers to architecturally benign acini/ducts lined by atypical cells. These cells show large nuclei and prominent nucleoli (cytologic features of carcinoma). Generally at least 10% of the luminal cells should show these features to make the diagnosis. Additionally, HGPIN cells have been shown to share the histochemical and genetic changes associated with cancer, and as such HGPIN is the putative precursor lesion to prostatic adenocarcinoma (FIGS 1a, 1b, 1c).

As in many so-called “premalignant lesions,” the diagnosis of HGPIN is somewhat subjective. Although not perfect the above mentioned criteria allow for fairly high diagnostic reproducibility among pathologists, especially for those with special training in genitourinary pathology (3). While HGPIN has been shown to be reproducible and as we will see has clinical relevance, low grade prostatic intraepithelial neoplasia has poor reproducibility (even among experts), ill defined diagnostic criteria, and no true clinical relevance. It is for these reasons that I do not personally diagnose LGPIN.

The incidence of HGPIN varies by source, but ranges from 0-24.6% with a mean reported incidence of 7.7%. In a recent review, Epstein and Herawi considered an incidence of 4-8% a reasonable practice benchmark in terms of HGPIN diagnosis (3).

In previous studies the risk of carcinoma on follow-up biopsy for a HGPIN diagnosis has been reported to be as high as 50%, however, when the data is based on series with increased case numbers, this decreases to around 25% (3). Interestingly, when comparing the risk of carcinoma on repeat biopsy for HGPIN versus that for a previous benign diagnosis, there may not be a statistically significant difference. In several studies the only factor which seemed to possibly increase the risk of carcinoma on subsequent biopsy was the amount of HGPIN on the original sampling. Kronz et al. reported an increased risk of carcinoma when 3 or more cores were involved, however this was based on relatively small numbers (4). Although in an excellent paper by Bishara et al. the correlation between multicore HGPIN on initial biopsy and cancer on follow-up just missed statistical significance, the number of cores involved by HGPIN on initial repeat biopsy was predictive of subsequent carcinoma. In addition, morphologic patterns of HGPIN (i.e. flat, tufted, micropapillary, cribriform) and clinical parameters (PSA levels, PSA velocity, PSA ratio, PSA density, DRE, TRUS, family history) have not been shown to be predictive of subsequent carcinoma. There is data suggesting that when initial biopsy sampling is extensive (12 cores or more) the risk of finding carcinoma following a diagnosis of HGPIN is significantly reduced (3). The increased number of cores taken in current biopsy sampling regimens may explain the “drift downward” in cancer rates after the diagnosis of HGPIN.

Although there have been several follow-up strategies for patients with a diagnosis of HGPIN, many recommend re-biopsy within 3-6 months. One protocol includes biopsies at 3-6 months for 2 years, followed by yearly biopsies for life (1). In a comprehensive recent review on this topic (mentioned earlier), a recommendation was made that in the absence of other clinical indicators worrisome for cancer, men do not need a routine repeat biopsy within a year following a HGPIN diagnosis.

One rationale for this recommendation was that men who have undergone the more extensive initial sampling currently in vogue do not have a higher risk of cancer on repeat biopsy than those with an initial benign diagnosis (3). As the natural history of HGPIN in any given patient is not known, the decision to take additional biopsies past 1 year is best made on a patient by patient basis with a frank discussion between the physician and patient.

Although carcinoma will most often be found in the same sextant site as that of the original HGPIN, various studies have shown that cancer is often diagnosed in adjacent sites and even within the contralateral lobe (3). It is for this reason that when re-biopsy is performed for HGPIN sampling should be concentrated in the region of the previous HGPIN with the rest of the gland sampled so as not to miss small foci of cancer. Specimens should be meticulously labeled as to site (in addition to patient identification) and optimally no more than 2 cores should be submitted per container.



Special thanks to Dr. Jonathan Epstein for his permission in using images from Epstein JI, Yang XJ. Prostate biopsy interpretation, Philadelphia: Lippincott, Williams & Wilkins, 2002.



1. Bostwick DG, Qian J. High-grade prostatic intraepithelial neoplasia. Modern Pathology 2004; 17: 360-379.

2. Bishara T, Ramnani DM, Epstein JI. High grade prostatic intraepithelial neoplasia on needle biopsy risk of cancer on repeat biopsy related to number of involved cores and morphologic pattern. The American Journal of Surgical Pathology 2004; 28: 629-633.

3. Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. The Journal of Urology 2006; 175: 820-834.

4. 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. The American Journal of Surgical Pathology 2001; 25(8): 1079-1085.


Date of last revision: January 2007.


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