AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Background

Prostate cancer is one of the most common malignancies diagnosed in men and is the most common cancer found in men older than 60 years. One third or more of all men older than 50 years have a latent form of prostate cancer that may progress to life-threatening prostate cancer. The prevalence of latent prostate cancer is similar among men of all cultures, races, and ethnic groups, but the frequency of clinically active cancer is markedly different.

Environmental factors have been implicated in activating latent prostate cancer. If cancer can be identified in an early or latent stage, the neoplastic process may be reversed.

Prostatic intraepithelial neoplasia (PIN), particularly high-grade PIN (HGPIN), and atypical small acinar proliferation (ASAP) have been identified as precursor lesions to prostatic carcinoma. PIN refers to the precancerous end of a morphologic spectrum involving cellular proliferation within prostatic ducts, ductules, and acini. 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, those at the consensus conference agreed that only the terms low-grade PIN (LGPIN) and high-grade PIN (HGPIN) would be used. Many pathologists no longer report the presence of LGPIN and note only the histologic findings associated with HGPIN.

High-grade prostatic intraepithelial neoplasia

HGPIN is characterized by architecturally benign prostatic acini and ducts lined by atypical cells whose morphologic, histochemical, immunohistochemical, and genetic changes are similar to those of prostate cancer. HGPIN does not invade the basement membrane of the prostatic glands. LGPIN may also be a precursor lesion but is no longer considered to be important enough to be included in the pathologic description.

When HGPIN is identified, the pathologist carefully searches tissue specimens for evidence of cancer. Patients in whom HGPIN is found are usually advised by a urologist to begin continued follow-up care with serum prostate-specific antigen (PSA) testing, physical examination, and, possibly, repeat biopsies. An estimated 30% of men with HGPIN develop clinical evidence of prostate cancer within one year.

HGPIN itself is not considered to be a disease that produces symptoms, nor does it require therapy. Although the general agreement is that HGPIN is a potential harbinger for the development of clinical prostatic adenocarcinoma, most experts agree that observation alone is safe for these patients.

Atypical small acinar proliferation

ASAP is another histologic entity that denotes a focus of atypical glands that are suspicious for cancer. ASAP differs from HGPIN; thus, the two categories should not be used interchangeably. The implication is that this is a specific lesion that is analogous to HGPIN, but ASAP includes a group of lesions (eg, adenosis, atypical adenomatous hyperplasia, intraductal hyperplasia, acinar atypical hyperplasia) that have varying clinical significance. Some ASAP lesions mimic cancer, and, in many instances, focal carcinoma may be present, but cytological, histochemical, and architectural atypia are insufficient to establish a definitive diagnosis.

The histologic findings of ASAP are characterized by the presence of abnormal or atypical glands that have insufficient cytological or architectural atypia for a definitive diagnosis of cancer. ASAP lesions have been identified in 0.5-23% (mean, 5.5%) of patients undergoing needle biopsies of the prostate. In patients with ASAP, the likelihood of finding cancer in a subsequent biopsy sample is 40-50%.

This article reviews the current approach for managing patients with HGPIN and ASAP and discusses their relevance.

Pathophysiology

Bostwick et al have described 4 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.

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 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.

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 cytological or architectural atypia are present to diagnose cancer. In this scenario, the pathologist usually suggests that another biopsy be performed.

Clinically, the specific pattern and morphologic features 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 or number of biopsy cores that contain these lesions. In patients diagnosed with prostate cancer, the finding of an associated HGPIN or ASAP becomes irrelevant.  

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.³ 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.

Frequency

United States

The frequency of PIN in men with prostate cancer is significantly higher than in those without cancer. The reported frequency of HGPIN alone varies from 0.7-20%, which seems to depend on 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%) had HGPIN. The largest contributors to this total were Orozco et al,⁴ with 62,537 patients (of whom 4.1% had HGPIN), and Novis et al,⁵ with 15,753 patients (of whom 3.9% had HGPIN).

Borboroglu et al reported cancer detection rates on repeat biopsy ranging from 25-79% for HGPIN and 21-51% for ASAP.⁶

Eight additional publications have reported the results of repeat biopsy. As many as 3446 patients were diagnosed, with cancer in 23% (range, 23-100%). Of this number, O'Dowd et al contributed 3030 patients, with 23% diagnosed with cancer.⁷

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%.

One of the criticisms of these historical studies is that they evaluated data obtained using sextant needle biopsies, which is no longer the standard technique. Current extended biopsy schemes obtain more than 10 biopsy cores (usually 10-12) 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.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. The results in the ASAP group were much different. The first repeat biopsy revealed cancer in 19 (36%) of 53 men and 13 (16%) of 19 on a second repeat biopsy.

McNeal and Bostwick identified PIN in 82% of prostates studied at autopsy in men with cancer, but they also identified HGPIN in only 43% of men of similar age who had benign prostatic hyperplasia (BPH).⁹ Qian et al found that 86% of 195 whole-mount radical prostatectomy specimens contained HGPIN, which was usually located within 2 mm of the cancer.¹⁰ The severity and extent of HGPIN was increased compared with cancer-free prostates.

International

No racial or societal differences in the prevalence of HGPIN or in its association with prostate cancer have been found.

Mortality/Morbidity

Mortality and morbidity are not directly associated with the presence of PIN or ASAP. Prostate cancer, which may require therapy, develops in a significant number of men with HGPIN and in perhaps even more men with ASAP. Many experts believe that neither HGPIN nor ASAP requires any specific therapy. Others believe that therapy should be considered, particularly in men with multiple foci of HGPIN or ASAP. Some evidence indicates that the use of selective estrogen receptor modulators (SERMs), 5-alpha reductase inhibitors, and antiandrogens may decrease the risk of cancer.

Race

No racial differences in the frequency of HGPIN or ASAP have been identified, but racial differences related to the presence of clinically active prostate cancer have been reported. The highest rate of prostate cancer is in black males.

Age

• Most studies indicate that the risk and extent of HGPIN and ASAP increase with patient age. However, McNeal and Bostwick reported that this correlation was not evident in patients with prostate cancer who were older than 50 years.⁹
• Lee et al studied 256 patients who underwent ultrasonography-guided prostate biopsies and identified 103 patients with cancer and an additional 27 who had PIN and cancer. The mean age of those with PIN was 65 years; the mean age of those with cancer was 70 years.
• Qian et al studied 195 radical prostatectomy specimens and observed that the volume of HGPIN increased with age.¹⁰ In order to determine if HGPIN alone had the same prognostic significance as HGPIN associated with adjacent atypical glands, Alsikafi et al studied 485 consecutive patients who underwent prostate biopsies.¹¹ The overall rate of HGPIN with or without 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 identify the presence of prostate cancer in 3 (14%) of the patients in whom only HGPIN was found on the initial biopsy, while 9 (75%) patients with adjacent atypical glands were subsequently found to have cancer.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

History

Neither high-grade prostatic intraepithelial neoplasia (HGPIN) nor atypical small acinar proliferation (ASAP) alone causes symptoms; however, they may be precursors to prostate cancer and are therefore important. Ordinarily, in patients in whom only a single focus of disease is identified (particularly with HGPIN), therapy may not be necessary. In patients with multiple areas of HGPIN or ASAP on the initial or subsequent biopsies, therapy may be considered, as the risk of cancer in these patients is greatly increased. Prostate cancer–prevention studies indicate that 5-alpha reductase inhibitors, antiandrogens, and SERMs may be effective in eliminating these histologic entities, thus decreasing the risk of prostate cancer.

Neither HGPIN nor ASAP seems to affect PSA production, meaning that PSA evaluation cannot be used to monitor the progression of these entities. In addition, they are not readily detectable with any imaging technology. Only prostate biopsy can be used to identify these lesions.

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. Treatment consisting of testosterone and estradiol in Noble rats recapitulates the progression from normal histology to cancer. Both low-grade PIN (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.

Physical

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. Pathologists can identify this lesion only by microscopically examining prostatic tissue.

Causes

• 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 prostatic cancer, as do genetic and many other unknown factors.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Other Problems to be Considered

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

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Lab Studies

• No laboratory studies can be used to confirm a diagnosis of high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP).
• Serum PSA levels are not affected by HGPIN or ASAP but may be elevated in the presence of an associated cancer or an inflammatory process.

Imaging Studies

• Imaging studies, including standard and color Doppler ultrasonography, CT scanning, and 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.
• Neither HGPIN nor ASAP can metastasize. These lesions are located only in the prostate gland.

Other Tests

• No routine laboratory tests are used to evaluate for the presence of HGPIN or ASAP. Once identified, phenotypic biomarkers can be obtained for experimental purposes. 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.

Procedures

• Prostate biopsy
• • Biopsy is the definitive method for detecting PIN and early invasive prostate cancer. Attempts at using imaging studies (eg, ultrasonography, MRI) have failed to detect PIN or to distinguish it from areas suggestive of cancer. Transrectal ultrasonography-guided biopsies using the 12-core (or more) biopsy schemes described in Treatment are most likely to reveal clinically significant cancers and areas of PIN.
  • Pathologists have developed criteria for distinguishing HGPIN and ASAP from benign and malignant conditions and report the presence and extent of these lesions. The presence of PIN or ASAP may influence therapeutic choices and management decisions.
  • Multicentricity and location of HGPIN, ASAP, and prostate cancer
  • • HGPIN, ASAP, and prostate cancer are usually multicentric. Bostwick and Brawer reported that HGPIN was multicentric in 72% of radical prostatectomy specimens, which included 63% of those involving a non–transition zone and 7% of those occurring within the transition zone.¹ Only 2% of the specimens had concomitant single foci in all zones.
    • The peripheral zone accounts for 75-80% of all prostate cancers and is the most common location for HGPIN and ASAP. In a report by Qian et al, 63% of documented PIN was in the peripheral zone, 36% was found in the peripheral and transition zones, and only 1% was found solely in the transition zone.¹⁰
    • The transition zone, which is periurethral and the area where BPH develops, accounts for 20-25% of prostate cancers, and up to 37% of these patients have HGPIN. Most transition zones that contain PIN and cancer are found in radical prostatectomy specimens.
    • This implies that HGPIN and ASAP, as possible precursor lesions to cancer, may account for most cancers that arise in the transition zone. Pathologists usually diagnose these cancers based on tissue specimens obtained during transurethral resection of the prostate or from an adenoma surgically removed as a result of suspected BPH.
  • Volume of PIN in prostates
  • • 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.
    • No data demonstrate a correlation between the amount of PIN and the timing of tumor progression or length of survival.
  • Continuum from normal to neoplastic prostatic epithelium
  • • A morphologic continuum has been identified that demonstrates the histologic changes that occur during the transition from normal prostatic epithelium to early invasive carcinoma. Low-grade PIN (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.
    • Although most pathologists recognize the association between HGPIN and prostate cancer and the higher rate of cancer in patients who harbor HGPIN, they do not all agree that every lesion is necessarily premalignant.
    • Basal cell–specific monoclonal antibodies directed against high molecular weight keratin are used to identify these 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.
  • Cell proliferation and apoptosis
  • • Cancer cell growth represents a balance between cell proliferation and apoptosis, which depends on various factors, including patient age, nutritional status, hormonal status, and growth factors in the microenvironment.
    • Prostate cancer has a relatively slow doubling time compared with 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.
    • 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 found in the basal cells, with a diminishing number 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 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 increase, 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, 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 instability in 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.¹² The first is identified in hyperplastic epithelium and LGPIN and is characterized by DNA duplication without nuclear division, which results in euploidy. The second is found only in HGPIN and cancer in which an emergence of aneuploid cells occurs.
    • 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.¹³ Amin et al found a frequency of 32% aneuploidy in HGPIN and 55% in cancer.¹⁴ 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.

Histologic Findings

The description of PIN comes largely through the work of Bostwick and O'Neil. They have defined this entity and provided the most comprehensive elucidation of its appearance.

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. 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 attempt to report LGPIN.

HGPIN is considered a precursor of prostate cancer. This microscopic entity 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 mentioned above, 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.

HGPIN and prostate cancer are almost always multifocal within the prostate. PIN spreads through prostatic ducts in several different methods similar to 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.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Medical Care

The association of high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical small acinar proliferation (ASAP) with prostate cancer makes these histologic findings clinically significant. HGPIN has been identified in up to 0.7-20% (average, 4.26%) of patients undergoing needle biopsies of the prostate, but the frequency is difficult to determine in the clinical setting because many pathologists do not report its presence.

In a series of 330 biopsies in men older than 50 years, HGPIN and cancer were identified in 17 (5.2%) and 58 (15.8%), respectively. Again, pathologists usually report only HGPIN or cancer.

The presence of HGPIN or ASAP in multiple areas has such a high predictive value for prostate adenocarcinoma that its presence alerts the pathologist to search for any areas in the biopsy sample that might harbor carcinoma. The clinician is also alerted because these patients must be carefully monitored, and additional biopsies must be collected, if clinically indicated.

Davidson et al found cancer in 35% of subsequent biopsy samples in men who had HGPIN and 13% of subsequent biopsy samples in men without PIN.¹⁵ 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 induced a review of this protocol, and the minimum number of biopsy cores is currently 12, with additional cores taken depending on the size of the prostate. Additional cores are obtained from the lateral edges and anterior portion of the prostate and have raised the finding of cancer from 20% to 40%. This technique change has also increased the number of patients in whom HGPIN is found and in whom prostate cancer is subsequently found.

HGPIN, patient age, and serum PSA levels are significant predictors of cancer. The risk of cancer in patients with PIN or ASAP is 15 times that in patients without these entities. The predictive value for cancer reportedly ranges from 38-100%. Although PIN and ASAP are not considered to be cancer and do not require therapy, careful follow-up care by a urologist is necessary. Additional prostate biopsies at 6-month intervals for 2 years (using the new biopsy protocol) should reveal the presence of any significant cancer. A patient with a solitary focus of HGPIN who has undergone adequate biopsy with 12 or more cores does not require further biopsies. The PSA level and rectal prostate examination findings can dictate the need for additional biopsies.

Prostate biopsy is the only method for identifying the presence of HGPIN or ASAP and for diagnosing coexisting cancer. HGPIN and ASAP have a minimal influence on 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.

• The extent and prevalence of HGPIN in patients treated with androgen ablation therapy is markedly decreased compared with that in untreated patients. This decrease is associated with epithelial hyperplasia, cytoplasmic clearing, and glandular atrophy with a decreased glands-to-stroma ratio. This suggests that the dysplastic prostate epithelium is hormone-sensitive. In normal prostate epithelium, luminal secretory cells are more sensitive to the effects of androgen deprivation than basal cells. HGPIN exhibits this same sensitivity. The loss of normal, hyperplastic, dysplastic, and cancer cells in the absence of androgens is mediated by the induction of apoptosis.
• In the absence of carcinoma, a finding of HGPIN or ASAP in a biopsy specimen does not necessarily require further investigation or therapy. The presence of HGPIN or ASAP alerts a urologist that cancer may be present, which could be missed in a biopsy sample. Patients with HGPIN or ASAP are at higher risk for developing a malignancy, although they are not treated until cancer is diagnosed. Even under this circumstance, therapy may be withheld in some patients if the cancer is low grade and apparently low volume.
• HGPIN and ASAP represent unstable epithelia that may progress to prostate cancer, although other precursor abnormalities are also likely to be present. PIN is associated with progressive abnormalities of phenotype and genotype that represent a continuum between normal prostatic epithelium and cancer. De Marzo et al used the term proliferative inflammatory atrophy to describe a group of lesions induced by environmental carcinogens.³ The presence of HGPIN indicates that abnormalities of cell differentiation and regulatory control have already started, but they may be reversible at this stage.
• 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.
• HGPIN and ASAP are important because of their association with prostatic carcinoma. HGPIN and ASAP may remain stable for years in many patients, regress in some, or progress to invasive cancer in a significant number. Urologists depend on pathologists to recognize these entities and to distinguish them from other lesions that may appear similar. Low-grade PIN (LGPIN) is believed to have clinical outcomes that are different from those of 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.

Surgical Care

Because PIN does not require therapy, surgical procedures are unnecessary.

Consultations

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.

Diet

Dietary factors have been implicated in the development of prostate cancer. Patients are advised to have 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. Whether dietary factors are associated with the development or management of HGPIN or ASAP is not known.

For more information, See Prostate Cancer: Nutrition.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Drug therapy is ordinarily not recommended for patients with high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP). In patients with multiple lesions with findings that persist on repeat biopsy, therapy can be considered. Treatment of HGPIN and ASAP with 5-alpha reductase inhibitors, antiandrogens, or SERMs has been advocated as a form of cancer prevention, although the effectiveness of this approach is unclear. These therapies can reverse HGPIN and ASAP, possibly reducing the risk of prostate cancer.

For example, toremifene citrate (Acapodene) is a nonsteroidal SERM that is currently used to treat breast cancer in women. In a multicenter, double-blind study, 514 men with HGPIN and no cancer (as determined with prestudy prostatic biopsy results) were randomized to receive either placebo or various doses of toremifene. All patients then underwent subsequent biopsies at 6 and 12 months.

The incidence of prostate cancer development in patients who received toremifene 20 mg for 12 months was 48% less than in the placebo group. Those in whom prostate cancer did develop had tumor grades that were similar to those in the placebo group. The medication was well-tolerated, with similar side-effect profiles between the two groups. Further studies and clinical trials are pending to determine if toremifene is truly safe and effective in reducing the eventual development of prostate cancer in patients with HGPIN or ASAP.

Yamauchi et al used an animal model to investigate the chemopreventive effects of bicalutamide on prostate cancer and PIN.¹⁶ They found that the drug significantly suppressed cancer cells but that it did not suppress HGPIN.

Patients with prostate cancer may be treated with surgery, radiation therapy, cryosurgery, or androgen ablation therapy, depending on the status of the disease. Drugs used for treating prostate cancer include luteinizing hormone-releasing hormone agonists or antagonists and antiandrogens. Patients with metastatic cancer in whom these medications do not elicit a response may benefit from antineoplastic agents.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Further Outpatient Care

• When high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP) has been identified, follow-up care is essential. No clearly established protocol has been established for managing either condition. A part of the problem relates to the amount of HGPIN or ASAP that is present. For example, if HGPIN or ASAP is found in only a 1 of 10 or more biopsy cores, a more limited follow-up protocol would be reasonable. If 6 of 10 cores demonstrate HGPIN or ASAP, a more aggressive program would be appropriate. Repeat prostate biopsies are generally recommended at 6-month intervals for 2 years. If the degree of PIN or ASAP is low, , no additional biopsies would be necessary if the follow-up biopsy finding at 6 months is negative.
• • Prostate cancer has been found in 36% of patients following the second biopsy (ie, the first repeat biopsy), particularly in men with multiple positive cores.
  • Moore et al assert that no additional biopsies are necessary if the first repeat biopsy shows no HGPIN or ASAP, but this is PIN volume–related.⁸ Neither PIN nor ASAP alone changes the PSA level. 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.
• The number of biopsies necessary correlates with the size of the prostate and to the presence of palpable lesions. Current biopsy techniques include applying local anesthesia by injecting lidocaine around the base of the prostate and/or instilling lidocaine gel into the rectum.
• • Most urologists obtain at least 8 cores of tissue; if the prostate volume is approximately 40 mL, 12 cores are obtained. The larger the prostate and the higher the level of suspicion, the more cores obtained.
  • PIN 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 to understand the anatomy and to develop a reasonable biopsy strategy for each patient. Color Doppler and MRI are used to visualize the prostate, but they do not reveal PIN or ASAP and often cannot be used to distinguish cancer from areas of inflammation.

In/Out Patient Meds

• Antibiotics are prescribed on the day of a prostate biopsy and, often, for the following day.
• Most authorities do not recommend treating patients with a single focus of HGPIN. ASAP represents a potentially more serious situation; if ASAP is confirmed on subsequent biopsy, therapy should be considered. Most urologists do not treat these conditions, whereas others have advocated the use of 5-alpha reductase inhibitors, anti-inflammatory agents, SERMs, and dietary supplements (eg, selenium, lycopene). Few data have been collected on the use of dietary measures to manage these patients.
• • If HGPIN is present on only a single core, the only course of action that seems reasonable is to observe the patient at 6-month intervals with PSA measurements and digital rectal examination.
  • If multiple biopsy cores demonstrate HGPIN, a repeat biopsy at 6 months is recommended. If multiple cores of HGPIN are still present (without cancer), a biopsy should be repeated in another 6 months. If the findings persist, some type of therapy may be considered.
  • The finding of ASAP in one or more biopsy samples necessitates a follow-up biopsy in 6 months. Repeated findings of ASAP may encourage the urologist to initiate therapy.

Deterrence/Prevention

No known measures that prevent the development of HGPIN or ASAP have been identified. Numerous agents, including finasteride, bicalutamide, selenium, vitamin E, soy isoflavonoids, and toremifene, have been studied to determine their ability to eradicate HGPIN.

Complications

The only potential complication of HGPIN or ASAP is the development of prostate adenocarcinoma.

Prognosis

• The prognostic significance of HGPIN and ASAP is related to possible development of prostate cancer. HGPIN and ASAP are important because they are frequently associated with cancer, although their presence does not necessarily imply that prostate cancer is inevitable. The grade and stage of prostate cancer has prognostic significance, but the presence of HGPIN or ASAP does not alter this prognosis.
• The importance of recognizing HGPIN and ASAP relates to their association with prostatic carcinoma. HGPIN may remain stable for years in many patients, regress in some, or progress to invasive cancer.

Patient Education

• Patients with HGPIN or ASAP not associated with an existing prostate cancer should be informed about the need for surveillance because they are at an increased risk for developing prostate cancer. Patients should be informed that neither HGPIN nor ASAP affects PSA levels.
• Regular PSA measurements and physical examinations should be performed every 6 months. Patients with HGPIN who have only a single biopsy core demonstrating HGPIN do not need additional biopsies. Patients with multiple cores of HGPIN or even one biopsy core positive for ASAP should have repeat biopsies at 6-month intervals for at least 2 years.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Medical/Legal Pitfalls

• Failing to diagnose high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP) is not nearly as important as failing to diagnose prostate cancer. However, a physician who fails to carefully monitor a patient with PIN or ASAP and to inform him that he may be at increased risk for developing prostate cancer is not serving the best interests of the patient.
• The presence of HGPIN or ASAP should alert the physician to the possibility of an existing cancer and to the patient’s heightened risk of developing prostate cancer in the future.

Special Concerns

• HGPIN is generally diagnosed without difficulty. ASAP includes various microscopic entities such as lobular atrophy, postatrophic hyperplasia, atypical basal cell hyperplasia, atypical adenomatous hyperplasia, cribriform hyperplasia, radiation-induced metaplasia, infarction, and prostatitis. Inflammatory atypia of the benign epithelium is the most frequently encountered cellular change that mimics HGPIN. In the presence of acute or chronic inflammation, the diagnosis of HGPIN or ASAP can be very difficult to confirm, and non-PIN lesions show architectural and cytologic alterations, including cytologic abnormalities, that can be confused with HGPIN.
• 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.¹⁷
• Cribriform adenocarcinoma, ductal carcinoma, and urothelial carcinoma involving prostatic ducts and acini are malignant lesions that may also be confused with HGPIN.
• ASAP is considered to be precancerous and has a greater association with prostate cancer than 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.

FURTHER READING

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

For more information, see Medscape’s Prostate Cancer Resource Center.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

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