eMedicine Specialties > Urology > Cancer, Prostate
Precancerous Lesions of the Prostate
Updated: Apr 24, 2009
Introduction
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
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.
More on Precancerous Lesions of the Prostate |
 Overview: Precancerous Lesions of the Prostate |
| Differential Diagnoses & Workup: Precancerous Lesions of the Prostate |
| Treatment & Medication: Precancerous Lesions of the Prostate |
| Follow-up: Precancerous Lesions of the Prostate |
| References |
| Further Reading |
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Keywords
prostatic intraepithelial neoplasia, prostate cancer, prostatic adenocarcinoma, prostate adenocarcinoma, PIN, high-grade prostatic intraepithelial neoplasia, low-grade prostatic intraepithelial neoplasia, high-grade PIN, HGPIN, low-grade PIN, LGPIN, atypical small acinar proliferation, ASAP, intraductal hyperplasia, prostatic hyperplasia with malignant change, precursor lesions, large acinar atypical hyperplasia, marked atypia, ductal-acinar dysplasia, benign prostatic hyperplasia, BPH, atypical adenomatous hyperplasia (AAH), adenosis, prostate-specific antigen, PSA, digital rectal examination, DRE, proliferative inflammatory atrophy, lobular atrophy, postatrophic hyperplasia, atypical basal cell hyperplasia, cribriform hyperplasia, radiation-induced metaplasia, prostatitis
