Precancerous Lesions of the Prostate

Updated: Feb 07, 2017
  • Author: Stanley A Brosman, MD; Chief Editor: Edward David Kim, MD, FACS  more...
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Prostatic intraepithelial neoplasia (PIN), particularly high-grade PIN (HGPIN), and atypical small acinar proliferation (ASAP) have been identified as precancerous lesions of the prostate; that is, precursor lesions to prostatic carcinoma. PIN refers to the precancerous end of a morphologic spectrum involving cellular proliferation within prostatic ducts, ductules, and acini.

ASAP differs from HGPIN; thus, the two categories should not be used interchangeably. Neither HGPIN nor ASAP can metastasize. These lesions are located only in the prostate gland.


Bostwick and Brawer introduced the term PIN in 1987. [1] At an international conference in 1989, the term PIN was accepted as a replacement for various other terms (eg, intraductal hyperplasia, hyperplasia with malignant change, large acinar atypical hyperplasia, marked atypia, ductal-acinar dysplasia).

Three grades of PIN were initially described; however, the consensus conference participants agreed that only the terms low-grade PIN (LGPIN) and high-grade PIN (HGPIN) would be used.


HGPIN is characterized by architecturally benign prostatic acini and ducts lined with atypical cells whose morphologic, histochemical, immunohistochemical, and genetic changes are similar to those of prostate cancer. However, HGPIN does not invade the basement membrane of the prostatic glands.

Bostwick et al have described four architectural patterns of HGPIN: tufting, micropapillary, cribriform, and flat. [2] Tufting is the most common and is present in 97% of all HGPINs. Most histologic samples contain multiple patterns, and the various HGPIN patterns carry equivalent prognoses.


LGPIN is believed to have different clinical outcomes than does HGPIN. Most cases of LGPIN do not progress, and follow-up care in patients with LGPIN is the same as in patients in whom PIN has not been identified. Most pathologists no longer report the presence of LGPIN.


The category ASAP includes a group of lesions (eg, lesions of adenosis, atypical adenomatous hyperplasia, intraductal hyperplasia, and acinar atypical hyperplasia) that have varying clinical significance. Some ASAP lesions mimic cancer, and in many instances, focal carcinoma may be present, but cytologic, histochemical, and architectural atypia are insufficient to establish a definitive diagnosis of cancer.


PIN and ASAP Rates

The reported frequency of HGPIN varies from 0.7-20%; the frequency seems to vary with the pathologist and the number of biopsies obtained.

In an analysis of 17 studies, in which a total of 87,713 patients underwent biopsy, 3735 (4.26%) patients had HGPIN. The largest contributors to this total were Orozco et al, [3] with 62,537 patients (of whom 4.1% had HGPIN), and Novis et al, [4] with 15,753 patients (of whom 3.9% had HGPIN).

ASAP lesions have been identified in 0.5-23% of patients undergoing needle biopsies of the prostate.

Prevalence of cancer in patients with HGPIN or ASAP

Borboroglu et al reported cancer detection rates on repeat biopsy ranging from 25-79% for HGPIN and 21-51% for ASAP. [5] (However, the figures for ASAP have also been put at 40-50%.)

In another study, by O'Dowd et al, out of 3030 patients with HGPIN, about 23% were diagnosed with cancer on subsequent biopsy. [6] Davidson et al found cancer in 35% of subsequent biopsy samples in men who had HGPIN and in 13% of subsequent biopsy samples in men without PIN. [7]

Historical studies have been criticized, however, for evaluating samples obtained using sextant needle biopsy, which is no longer the standard technique. Current, extended biopsy schemes obtain 12 or more biopsy cores, depending on the size of the prostate. In some situations, saturation biopsies consisting of more than 20 cores are performed.

Moore et al evaluated the biopsy results of 105 men in whom repeat extended biopsies were performed to further evaluate a finding of HGPIN or ASAP and found that repeat biopsy revealed cancer more often in patients with ASAP than in those with HGPIN. [8] In the HGPIN group, cancer was diagnosed in 1 (4.5%) of 22 men based on first repeat biopsy results and in 0 of 11 based on a second repeat biopsy result. In the ASAP group, in contrast, the first repeat biopsy revealed cancer in 19 (36%) of 53 men and 13 (16%) of 19 on a second repeat biopsy.

In a retrospective study by Leone et al of 264 men who had ASAP identified on prostate biopsy, 34% had prostate cancer identified on repeat biopsy. However, only 22% (8% of the total cohort)  had high-grade disease: 78% had Gleason scores of 3+3 or lower, while 17% had Gleason 7 and 6% had Gleason scores of 8-10 or higher. These authors concluded that most men found to have ASAP do not require immediate repeat biopsy. [9]

McNeal and Bostwick identified PIN in 82% of prostates studied at autopsy in men with cancer, but they identified HGPIN in only 43% of men of similar age who had benign prostatic hyperplasia (BPH). [10] Qian et al found that 86% of 195 whole-mount radical prostatectomy specimens contained HGPIN, which was usually located within 2mm of the cancer. [11] The severity and extent of HGPIN was increased compared with cancer-free prostates.

Although most pathologists recognize the association between HGPIN and prostate cancer, they do not all agree that every HGPIN lesion is necessarily premalignant. A study suggests that on initial biopsy, when HGPIN is stratified into multifocal and bilateral disease, the risk of prostate cancer is significantly increased. [12]

Race-related demographics

No racial differences in the frequency of HGPIN or ASAP have been identified, but racial differences in rates of clinically active prostate cancer have been reported, with the highest rate in the black population.

Age-related demographics

HGPIN appears to precede cancer by more than 10 years, with a parallel age-related increase in the frequency of HGPIN and cancer. HGPIN has been found in 9% of men in the second decade of life, 22% of men in the third decade, and 40% of men in the fourth decade. The prevalence of HGPIN in men aged 80 years is 70%.

In a study of 256 patients, Lee et al found that the mean age of patients with PIN was 65 years, and the mean age of patients with cancer was 70 years. In the investigation, patients underwent ultrasonography-guided prostate biopsies. Cancer was found in 103 patients, and a combination of PIN and cancer was found in an additional 27 patients.

In a study of 195 radical prostatectomy specimens, Qian et al observed that the volume of HGPIN increased with age. [11]

However, although most studies indicate that the risk and extent of HGPIN and ASAP increase with patient age, McNeal and Bostwick reported that this correlation was not evident in patients with prostate cancer who were older than age 50 years. [10]


Diagnostic Significance

When HGPIN or ASAP is identified, the pathologist carefully searches tissue specimens for evidence of cancer, since these entities are frequently found in prostates in which prostate cancer cells are present. Indeed, it was because of this association that these lesions came to be considered noncancerous precursors to the development of actual prostate cancer.

If no cancer cells are identified in the patient, a follow-up protocol is usually initiated, since there is a higher risk of prostate cancer in these individuals. The follow-up protocol consists of serum prostate-specific antigen (PSA) testing, physical examination, and, possibly, repeat biopsies. However, the presence of a small amount of HGPIN in only 1-2 cores is considered to be inconsequential, and these patients require no special follow-up.

PIN itself is not thought to produce symptoms, and some urologists believe that observation alone is a safe way to manage PIN lesions. Others employ a course of medication, such as finasteride, dutasteride, or toremifene, which may eliminate PIN cells.

Prognoses associated with HGPIN and ASAP

Prostate cancer develops within 1-2 years in an estimated 30% of men with multiple cores containing HGPIN and in perhaps even more men with ASAP. Indeed, the presence of HGPIN or ASAP cells in multiple areas has such a high predictive value for prostate adenocarcinoma that the existence of these cells alerts the pathologist to search for any areas in the biopsy sample that might harbor carcinoma.

However, the presence of HGPIN or ASAP does not necessarily imply that prostate cancer is inevitable; although these conditions may progress to invasive cancer, HGPIN and ASAP remain stable for years in many patients and regress in some individuals.

When biopsy reveals prostate cancer, the prognosis is determined by the grade and stage of the cancer. The presence of HGPIN or ASAP in such cases does not alter the prognosis. The mean volume of HGPIN or ASAP in prostates with cancer is 1.2-1.32 mL. The volume of HGPIN correlates directly with increasing pathologic stage, Gleason grade, positive surgical margins, and perineural invasion.

Patients with HGPIN or ASAP not associated with existing prostate cancer should be informed about the need for surveillance. Patients should also be told that neither HGPIN nor ASAP seems to affect PSA levels.

In a study of 485 consecutive patients who underwent prostate biopsies, Alsikafi et al determined that the incidence of cancer in patients with HGPIN associated with adjacent atypical glands was significantly higher than in patients with HGPIN alone. The overall rate of HGPIN with or without the presence of associated atypical glands was 6.8% (33 patients). Of these patients, 21 (64%) had HGPIN alone, and 12 (36%) had HGPIN with adjacent atypical glands. Subsequent biopsies helped to identify prostate cancer in 3 (14%) patients in whom only HGPIN was found on the initial biopsy, and in 9 (75%) patients with adjacent atypical glands. [13]

A study by Epstein et al revealed that among patients in whom a prostate biopsy performed prior to radical prostatectomy for cancer revealed glands that were suspicious (but not diagnostic) for carcinoma, the tumor grade and pathologic stage of their carcinoma were significantly lower than in men who had received no such biopsy results. The investigators analyzed 169 radical prostatectomy specimens from men initially diagnosed with suspicious glands and found that organ-confined disease was predicted by the atypical biopsy. [14]

Cicione et al reported that men with metabolic syndrome who are found to have widespread HGPIN are at higher risk of having prostate cancer on repeat biopsy. In their review of 283 patients with widespread HGPIN, prostate cancer was subsequently detected in 52.3% of those with metabolic syndrome. versus 29.5% of those with a normal metabolic profile (P = 0.002). [15]

Pathologists have developed criteria for distinguishing HGPIN and ASAP from benign and malignant conditions, and they report the presence and extent of these lesions. The presence of PIN or ASAP may influence therapeutic choices and management decisions.

Clinically, the specific pattern and morphologic features of HGPIN and ASAP are not as important as the mere presence of either of these entities. The clinical importance and the follow-up strategy depend on the amount of lesions found or the number of biopsy cores that contain these lesions. In patients diagnosed with prostate cancer, the finding of an associated HGPIN or ASAP becomes irrelevant.

No data demonstrate a correlation between the amount of PIN and the timing of tumor progression or length of survival.

Additional prognostic markers

Fusion of the TMPRSS2 and ERG gene fusions is the most common gene fusion seen in prostate cancer. TMPRSS2-ERG fusion is not seen benign prostate tissue but is observed in approximately 15% of HGPIN and in some prostate cancers, and may represent a distinct molecular subclass of prostate cancer. [16]

In a study that included 3 years of follow-up prostate biopsies in patients with HGPIN, Park et al found that those patients whose biopsy demonstrated ERG expression were more likely to develop prostate carcinoma. Progression to prostate cancer occurred in 27 (53%) of 51 ERG-positive patients and 143 (35%) of 410 ERG-negative patients (P = 0.014). [16]  

Morais et al suggest that immunostaining of needle biopsy specimens for PTEN and ERG proteins may help in distinguishing intraductal carcinoma from HGPIN, which can otherwise be difficult. Of biopsies demonstrating morphologically identified intraductal carcinoma with concurrent invasive tumor, 76% (38/50) lacked PTEN and 58% (29/50) expressed ERG. In contrast, none of the 19 PIN cases showed PTEN loss or ERG expression.. [17]

Glybochko et al found that in patients with PIN, the presence of active telomerase in prostate biopsy specimens identifies patients at increased risk for development of prostate cancer. In their study of 92 patients, active telomerase was detected in 98% of prostate biopsy specimens from patients with prostate cancer, in 33% of patients with HGPIN, and in 20% of patients with LGPIN. Of patients with both active telomerase and PIN in initial prostate biopsy specimens, 50-56% developed prostate cancer in the following 6 months to 4 years; no patients with PIN but without telomerase activity in initial biopsy specimens developed prostate cancer. [18]


Neoplastic Progression and Continuum


HGPIN spreads through the prostatic ducts in 3 patterns that resemble prostate cancer. In the first pattern, neoplastic cells replace the normal luminal secretory epithelium, but the basal layer and basement membrane are preserved. Foci of HGPIN may be indistinguishable from the ductal spread of carcinoma when viewed with light microscopy.

The second pattern is characterized by direct invasion through the ductal or acinar wall, with disruption of the basal cell layer. In the third pattern, neoplastic cells invaginate between the basal cell layers. This rare pattern is sometimes described as pagetoid spread.

Prostate cancer has a relatively slow doubling time compared with that of other epithelial cancers. Depending on the tumor grade, doubling times range from 0.5-5 years. PSA measurements can be used as a surrogate to evaluate tumor growth. Log-linear growth rates tend to be constant, with a mean doubling time of 2.4 years in localized cancers and 1.8 years in metastatic prostate cancer. High Gleason grades (4-5) are associated with even shorter doubling times.

Immunohistochemical analysis using antibodies against proliferating cell nuclear antigen and Ki-67 show a mean growth fraction of 8.7-16.3%, with the most rapid growth located at the advancing edge of the cancer. The growth fraction is 0.6% in atrophic prostatic glands, 3.2-4% in BPH, 6-9.5% in LGPIN, and 7.9-13% in HGPIN.


A morphologic continuum has been identified that demonstrates the histologic changes that occur during the transition from normal prostatic epithelium to early invasive carcinoma. LGPIN is a minimal to mild dysplasia, whereas HGPIN corresponds with moderate to severe dysplasia and carcinoma in situ. This cancer precursor state ends when the cells begin to penetrate the basement membrane and invade the stroma. This invasion is associated with a disruption of the basal cell layer, which is considered to be evidence for adenocarcinoma.


Features of PIN Cells

Basal cell–specific monoclonal antibodies directed against high–molecular weight keratin are used to identify HGPIN cells. Normal prostatic epithelial cells are consistently stained with these antibodies, showing a continuous, intact, circumferential basal cell layer. Cancer cells have lost their receptors for these antibodies.

Basal cell disruption affects 56% of patients with HGPIN and is usually found in glands adjacent to invasive cancer. The degree of disruption correlates with HGPIN. More than one third of the basal cell layer is lost in 52% of foci that contain HGPIN.

In persons with HGPIN and in many with low-grade cancer, the basement membrane that surrounds the prostatic glands remains intact. The expression of collagenase type 4 in PIN and associated cancer cells is abnormally high. The presence of collagenase type 4 and other enzymes is associated with a degradation of the basement membrane, allowing cell invasion into the stroma. Concurrently, the basal cell layer is diminished. This seems to occur primarily at sites of glandular outpouching.

Increased angiogenesis with an increased number of microvessels is associated with the progression of HGPIN to cancer. The microvessels in HGPIN are shorter than those in benign epithelium and have irregular contours and open lumens, an increased number of endothelial cells, and a greater distance from the basement membrane.

Mitotic figures

Mitotic figures are rare in the epithelium of benign and neoplastic prostate cells, but mitosis progressively increases during the transition from benign to PIN to malignancy. Mitotic figures in BPH are found in the basal cell, with a mean value of 0.002%. In PIN, most of the mitotic figures are located in the basal cells, with a diminishing number of such figures found as the layers reach the luminal surface. In HGPIN, the mean value of mitotic figures is 0.19% in the basal layer, 0.08% in the intermediate layers, and 0.05% in the superficial layer.

Apoptotic bodies

Apoptotic bodies can be found throughout the normal prostatic epithelium and in the gland lumens. In the transition from BPH to PIN to cancer, the number of apoptotic bodies progressively increases, with the greatest number found in the basal cell layer or at the periphery of malignant glands adjacent to the stroma. The percentage of apoptotic bodies is 0.26% in BPH, 0.68% in LGPIN, 0.75% in HGPIN, and 0.92-2.1% in cancer. Mitotic figures do not correlate with apoptotic bodies.

Cytoplasmic expression of BCL2, the oncogene that suppresses apoptosis, is greater in PIN (100% of cells) and cancer (62% of cells) than in benign and hyperplastic epithelium. Enhanced expression of BCL2 seems to play an early role in the progression of normal cells to cancer cells by allowing cells with genetic abnormalities to escape the natural apoptotic mechanism.

Morphologic similarities of HGPIN and cancer

Many studies have demonstrated a remarkable similarity between the nuclear characteristics of prostate cancer cells and HGPIN compared with those of normal and hyperplastic epithelium. These include nuclear area, deoxyribonucleic acid (DNA) content, chromatin content, chromatin distribution, nuclear perimeter, nuclear diameter, and nuclear roundness.

Cancer cells and PIN also share nucleolar abnormalities. The results of these studies further support the concept that a morphologic continuum from normal to PIN to cancer exists.


Genetic Features of PIN

Studies of nuclear DNA content demonstrate a progressive genetic instability in the progression from normalcy to PIN and then to cancer. Montironi et al postulated that 2 successive phases of intraepithelial neoplasia occur. [19] The first is identified in hyperplastic epithelium and LGPIN and is characterized by DNA duplication without nuclear division, which results in euploidy. The second, found only in HGPIN and cancer, is characterized by the emergence of aneuploid cells.

Petein et al observed that the mean proliferative index and proportion of aneuploid cell nuclei in HGPIN were similar to those in cancer but significantly differed from those found in hyperplastic epithelial cells and LGPIN. [20] Amin et al found an aneuploidy frequency of 32% in HGPIN and 55% in cancer. [21] Others have noted similar findings and have found that up to 70% of aneuploid cases were associated with aneuploid invasive cancer, whereas 29% of aneuploid cancer was associated with aneuploid HGPIN.

HGPIN and cancer share some molecular alterations, including the loss of heterozygosity at 8p, 10q, and 16q.

Studies in animal models have helped to solidify the association of HGPIN with prostate cancer. In Noble rats, administration of testosterone and estradiol recapitulates the progression from normal histology to cancer. LGPIN and HGPIN can be identified. The transgenic adenocarcinoma of mouse prostate (TRAMP) model reproduces the natural history of human prostate cancer. By expressing an SV40 early gene under prostate-specific control of the probasin promoter, TRAMP mice display PIN by 6-12 weeks, well-differentiated cancer by 10-16 weeks, and metastatic disease by 18-24 weeks.

If the genetic alterations associated with HGPIN continue, a progressive loss of some markers of secretory differentiation occurs, which may include PSA production, secretory proteins, cytoskeletal proteins, glycoproteins, and neuroendocrine cells. In contrast, the levels of c-erb -b2 oncoprotein, BCL2, epidermal growth factor, epidermal growth factor receptor, type 4 collagenase, Lewis Y antigen, transforming growth factor–alpha, apoptotic bodies, proliferating cell nuclear antigen expression, aneuploidy and various genetic abnormalities, and microvessel density progressively increase.


Possible Risk Factors

No known specific risk factors are associated with the development of HGPIN or ASAP. Environmental and dietary factors have been implicated in the development of prostate cancer, but whether these factors are associated with PIN or ASAP formation is unknown.

Epidemiologic studies suggest that the major dietary factor associated with prostate cancer is fat intake. An additional component is total energy (caloric) intake (regardless of source). Obesity and a high-fat diet have been shown to correlate with the development of prostate cancer, as do genetic and many other, unknown factors.

De Marzo and associates have suggested that proliferative inflammatory atrophy, which may represent regenerative epithelium in response to environmental insults, may precede the development of PIN and early carcinoma. [22] These lesions may arise in the setting of inflammation and exposure to dietary toxins, such as the carcinogens that have been identified in charred meat.


Differential Diagnosis

The presence of inflammatory atypia of the benign epithelium is the most frequently encountered cellular change mimicking HGPIN. In the presence of acute or chronic inflammation, the diagnosis of HGPIN or ASAP can be very difficult to confirm.

Moreover, non-PIN lesions can show architectural and cytologic alterations, including cytologic abnormalities, that can be confused with HGPIN.

ASAP is characterized by localized proliferation of small acini that may be confused with cancer. These lesions are usually found in intimate association with nodular hyperplasia in the transition zone, often at the periphery of a nodule. Cytologic and histologic features distinguish ASAP from PIN, but differentiating ASAP from cancer may be very difficult.

HGPIN and ASAP are difficult, if not impossible, to recognize following radiation therapy. The cytologic changes caused by radiation therapy have many similarities to those associated with HGPIN. Nevertheless, Arakawa et al found that the frequency of HGPIN in radical prostatectomy specimens obtained following radiation therapy was similar to the rate found in nonradiated prostatectomy specimens. [23]

Cribriform adenocarcinoma, ductal carcinoma, and urothelial carcinoma involving prostatic ducts and acini are malignant lesions that may also be confused with HGPIN.

A summary of the differentials for precancerous prostatic neoplasms is as follows:

  • Lobular atrophy
  • Postatrophic hyperplasia
  • Atypical basal cell hyperplasia
  • Cribriform hyperplasia
  • Radiation-induced metaplasia
  • Infarction
  • Prostatitis
  • Inflammatory atypia of the benign epithelium
  • Cribriform adenocarcinoma
  • Ductal carcinoma
  • Urothelial carcinoma involving prostatic ducts and acini

Diagnosis of PIN and ASAP

Only prostate biopsy can be used to identify HGPIN or ASAP. [24] Neither type of lesion alone causes symptoms, and therefore, no physical examination findings reveal the presence of PIN or ASAP.

The prostate may be enlarged secondary to BPH, but this is unrelated to HGPIN. Areas in the prostate may have palpable nodules, or other areas may indicate cancer. None of these physical findings suggests the presence of HGPIN or ASAP.

Some pathologists may note that a small focus of atypical glands has been identified in a biopsy specimen but that, although the finding is suspicious for cancer, not enough cytologic or architectural atypia are present to diagnose cancer. In this scenario, the pathologist usually suggests that another biopsy be performed.

Neither HGPIN nor ASAP seems to affect PSA production, meaning that PSA evaluation cannot be used to detect or to monitor the progression of these entities. In addition, neither HGPIN nor ASAP are readily detectable with any imaging technology.

Prostate biopsy

Transrectal ultrasonography-guided biopsy is the definitive method for detecting PIN and early invasive prostate cancer. HGPIN and ASAP tend to arise in the peripheral zone of the prostate, which is located on the posterior surface of the prostate, arching anteriorly on each side. Ultrasonographic studies help the physician to understand the anatomy and to develop a reasonable biopsy strategy for each patient.

Current biopsy techniques include administering local anesthesia by injecting lidocaine around the base of the prostate and/or instilling lidocaine gel into the rectum. Prophylactic antibiotics are prescribed on the day of a prostate biopsy and often for the following day.

When much of the data on PIN were collected, the standard biopsy protocol involved obtaining 6 sextant biopsies. The large number of false-negative results prompted a review of this protocol, and the minimum number of biopsy cores is currently 12, with additional cores taken from the lateral edges and anterior portion of the prostate, depending on the size of the gland, the number of palpable lesions, and the clinician's level of suspicion. If the prostate volume is approximately 40mL, 16-18 cores may be obtained.

This change in technique has increased the number of patients in whom PIN and, subsequently, prostate cancer have been found. For example, the practice of taking additional lateral and anterior cores has raised the finding of cancer from 20% of 6-core biopsies to 40% of biopsies using the 12-core (or more) biopsy schemes.

Goenka and colleagues found CT-guided transgluteal prostate biopsy to be a safe and reliable alternative approach for the systematic random sampling of the prostate in patients without a rectal access. [15]

Imaging of prostate lesions

As stated above, imaging studies, including standard and color Doppler ultrasonography, computed tomography (CT) scanning, and magnetic resonance imaging (MRI) of the prostate, have not proven beneficial in identifying the presence of HGPIN or ASAP.

Color Doppler ultrasonography can reveal abnormal areas in the prostate that have increased vascularity. Some prostate cancers can be identified with this technique, but areas of inflammation may have the same visual characteristics. In addition, not all cancers have enough vascularity to permit identification. The vascular changes caused by HGPIN and ASAP are not sufficient for identification.

MRI with spectroscopy may reveal areas with biochemical abnormalities suggestive of cancer, but HGPIN and ASAP are more difficult to find, because they are small and multifocal and are often located at the periphery of a cancer.

Laboratory tests

No routine laboratory tests are used to evaluate for the presence of HGPIN or ASAP. Once these conditions are identified, however, phenotypic biomarkers can be obtained for experimental purposes. [25] Such studies show that HGPIN is more closely related to carcinoma than to benign epithelium. Cytoplasmic expression of p160-erb -b3 and p185-erb -b2 is greater in HGPIN and cancer than in normal or hyperplastic epithelium.

HGPIN and high-grade cancer are associated with the loss of secretory markers (eg, PSA cytoskeletal proteins, glycoproteins). These markers have no specific clinical value in predicting the progression of PIN to cancer but lend further evidence to the concept that HGPIN is a precursor to cancer.

Histologic findings

PIN in biopsy samples usually involves single acini or small clusters of acini. When the entire prostate is available for analysis, multiple areas of PIN can usually be identified. HGPIN and prostate cancer are almost always multifocal within the prostate.

Acini appear hyperchromatic because of proliferation, crowding, and irregular spacing of the inner secretory cells, in contrast to the benign acini. The acini are medium sized or enlarged with rounded contours. Occasionally, a portion of acini shows changes attributed to PIN. Overlapping nuclei are prominent, and cell borders are indistinct. On the luminal surface, most cells display cytoplasmic blebs suggestive of apocrine secretion.

In LGPIN, the epithelium lining ducts and acini are heaped up, crowded, and irregularly spaced. Nuclear size greatly varies. Elongated, hyperchromatic nuclei and small nucleoli may be present. The diagnosis of PIN requires a combination of cytologic and architectural features. Lesions that display some, but not all, features are considered atypical but not neoplastic. Many pathologists do not report the presence of LGPIN.

HGPIN consists of a proliferation of epithelial cells with cytologic changes associated with carcinoma, including nuclear and nucleolar enlargement. HGPIN resembles LGPIN, but nucleomegaly, cell crowding, and stratification are more pronounced. Nuclear size is less variable, because most nuclei are enlarged. The presence of prominent nucleoli, often multiple, is typical of HGPIN.

At the periphery of PIN, the basal cell layer is usually inconspicuous and may be difficult to visualize on routine light microscopy. Discontinuity of the basal cell layer is a distinctive finding in about half of acini with HGPIN and often requires immunohistochemical studies.

As previously mentioned, HGPIN has 4 main architectural patterns: tufting, micropapillary, cribriform, and flat. These patterns often merge with each other. Other than diagnostic utility, these architectural patterns have no known clinical significance.

Also as previously discussed, PIN spreads through prostatic ducts in 3 different patterns, which are similar to those of cancer. Neoplastic cells may replace the normal luminal secretory epithelium without disrupting the basal cell layer and basement membrane. Foci of HGPIN are often indistinguishable from ductal spread of carcinoma on routine light microscopy.

In another pattern, direct invasion through the ductal or acinar wall occurs, with disruption of the basal cell layer. In a third pattern, neoplastic cells invaginate between the basal cell layers, a finding that is quite rare. Early invasive carcinoma occurs at sites of acinar outpouching and basal cell disruption.

Diagnostic confirmation

Confirming a diagnosis of HGPIN, ASAP, or prostate cancer may be difficult. Review of the slides by another pathologist is beneficial if the diagnosis is unclear. These lesions may be difficult to diagnose in patients with chronic or acute inflammation or in those who have received radiation therapy.


Monitoring and Pharmacologic Therapy

Ordinarily, in patients in whom only a single focus of PIN, particularly HGPIN, has been identified, therapy may not be necessary. In patients with multiple areas of HGPIN or ASAP on the initial biopsy or on subsequent biopsies, therapy may be considered, as the risk of cancer in these patients is 15 times that in patients without these entities. Prostate cancer–prevention studies indicate that 5-alpha reductase inhibitors, antiandrogens, and selective estrogen receptor modulators (SERMs) may be effective in eliminating HGPIN and ASAP, thus decreasing the risk of prostate cancer.


When HGPIN or ASAP has been identified, follow-up care is essential. Although there is no clearly established protocol for managing either condition, regimens typically take into account the amount of HGPIN or ASAP that is present.

If HGPIN is present in only a single core, a reasonable course of action is to observe the patient at 6-month intervals with PSA measurements and digital rectal examinations. Most authorities do not recommend treating these patients.

If multiple biopsy cores demonstrate HGPIN, repeat prostate biopsies are generally recommended at 6-month intervals for 2 years.

If the degree of HGPIN on the initial biopsy is low and the follow-up biopsy finding at 6 months is negative, no additional biopsies are necessary. If multiple foci of HGPIN persist, some type of therapy may be considered.

ASAP represents a potentially more serious situation. The finding of ASAP in even a single biopsy sample necessitates a follow-up biopsy at 6 months. Repeated findings of ASAP may encourage the urologist to initiate therapy.

The PSA level and rectal prostate examination findings can dictate the need for additional biopsies. HGPIN and ASAP apparently do not influence PSA levels, but patients with an elevated PSA level related to prostate size or those with a rapidly rising PSA level should undergo follow-up biopsies at 3 or 6 months. A continuously rising PSA level that is doubling at 12 months or less would prompt the need for prostate biopsies, regardless of the presence of PIN or ASAP.

Pharmacologic therapy

Drug therapy is ordinarily not recommended for patients with HGPIN or ASAP unless multiple biopsy cores demonstrate HGPIN. In patients with multiple lesions, with findings that persist on repeat biopsy, therapy can be considered. Treatment of HGPIN and ASAP with one of the 5-alpha reductase inhibitors, finasteride or dutasteride, has been shown to be effective. These agents are usually administered for 6-12 months, and a follow-up prostate biopsy is then performed.

A report indicated that toremifene citrate (Fareston)—a nonsteroidal selective estrogen receptor modulator (SERM) that is currently used to treat breast cancer in women—can reduce the incidence of prostate cancer in patients with HGPIN. In the multicenter, double-blind study, 514 men with HGPIN and no cancer were randomized to receive either placebo or various doses of toremifene. The incidence of prostate cancer development in patients who received toremifene 20 mg for 12 months was 48% lower than in the placebo group. [26]

However, no difference in prostate cancer–free survival with toremifene was seen in a 3-year phase III, double-blind, multicenter trial in 1590 men with HGPIN, or HGPIN and atypia. Prostate cancer was detected in 32.3% of men receiving toremifene citrate 20 mg and in 34.7% of the men in the placebo group (P = 0.39). [27]

Dietary considerations

There is no current evidence of an association between diet and HGPIN or ASAP. However, because dietary factors have been implicated in the development of prostate cancer, patients are advised to consume a diet low in fat, particularly animal fat, and high in fruits, vegetables, and fiber. Patients should avoid taking in more calories than they expend, as obesity is associated with an increased risk of developing prostate cancer. No dietary supplements, such as selenium and lycopene, have shown any benefit. (See Prostate Cancer and Nutrition for more information on this topic.)