Precancerous lesions of the prostate: Pathology and clinical implications

INTRODUCTION — The study of precancerous lesions of the prostate is important for understanding prostatic carcinogenesis and for developing potential chemopreventive measures for prostate cancer.

Four major pathologic entities will be discussed in this topic review: prostatic intraepithelial neoplasia (PIN), atypical adenomatous hyperplasia (AAH, also termed adenosis), atrophic lesions, and atypical small acinar proliferation (ASAP). High-grade PIN is the most likely precursor of the majority of prostatic adenocarcinomas. In contrast, AAH and atrophic lesions are possible, although uncertain, precancerous lesions. ASAP is not a true biologic entity but is a diagnostic term in pathology when a lesion suspicious for but not diagnostic of carcinoma is identified. The pathologic characteristics, prevalence, relationship to prostate cancer, and clinical significance of these lesions are discussed in this topic, with a particular emphasis on PIN.

PROSTATIC INTRAEPITHELIAL NEOPLASIA — Prostatic intraepithelial neoplasia (PIN), first described in 1969 [1], is a neoplastic proliferation of prostatic epithelial cells that is confined to preexisting prostatic ducts or acini (glands). PIN was further characterized and initially termed intraductal dysplasia in 1986 [2]; the currently used term "prostatic intraepithelial neoplasia" was introduced in 1987 and endorsed by consensus at a 1989 conference [3,4].

Histology — The histologic characteristics of PIN have been well described [5,6]. The neoplastic prostatic epithelial cells are within prostatic ducts or acini, which are typically large and branched, with a convoluted inner contour similar to benign glands (picture 1). Epithelial cell proliferation produces a layer of crowded, pseudostratified, neoplastic cells with cytologic atypia, characterized by nuclear irregularity, nucleomegaly, hyperchromasia, and prominent nucleoli (picture 1). These findings are similar to those of invasive prostate cancer. (See "Interpretation of prostate biopsy".)

In contrast with adenocarcinoma, the architecture is normal and the PIN glands characteristically contain basal cells around their periphery, seen as a thin and occasionally discontinuous layer on hematoxylin and eosin (H&E) stained sections. Immunohistochemical staining for high molecular weight cytokeratins (34bE12 antibody) easily demonstrates the basal cells (picture 2). This is an important diagnostic feature because the presence of basal cells can help to differentiate PIN from prostatic adenocarcinoma, in which basal cells are absent [3,7-10]. (See "Interpretation of prostate biopsy".)

PIN is commonly divided into low-grade (PIN I) and high-grade (PIN II and PIN III) lesions [4]. High-grade PIN differs from low-grade PIN in that cytologic atypia is more apparent, particularly the presence of prominent nucleoli, as observed using a 20x-power lens (200-fold magnification). Several histologic patterns of high-grade PIN have been described: tufting, micropapillary, flat, and cribriform [11]. Other uncommon patterns (ie, mucinous, signet ring cell, and foamy gland) have also been reported [12,13]. The clinical significance of these different patterns is largely unknown, although cribriform PIN and other unusual patterns are almost exclusively seen in patients with invasive cancer, raising the possibility that they may represent intraductal spread of cancer cells [14].

Diagnosis — PIN is a histologic finding, and its diagnosis can be made only by microscopic examination of prostate tissue (core needle biopsy, transurethral resection [TURP], radical prostatectomy specimens). Digital examination, transrectal ultrasonography, or other imaging studies are not useful for detecting PIN. Furthermore, fine needle aspiration (FNA), which is a popular method for diagnosis of prostate cancer in some countries, cannot distinguish PIN from cancer based on cytologic features alone. (See "Interpretation of prostate biopsy".)

No other clinical or laboratory tests are useful in detecting PIN. Although newer studies using DNA microarray analysis and transgenic mouse models are promising [15,16], no gene or protein that is specific for PIN has been identified to date. The genetic changes that accompany PIN are discussed elsewhere. (See "Molecular biology of prostate cancer".)

While some reports suggesting that PIN might result in an elevation of serum total prostate-specific antigen (PSA) [17,18] or higher values of free serum PSA than prostate cancer [18,19], no correlation between the presence of PIN and either total or free serum PSA has been found by others [19-23]. Therefore, if a man with an elevated serum PSA has isolated high-grade PIN on core needle biopsy, a repeat prostate core needle biopsy may be necessary to rule out other conditions causing PSA elevation, particularly prostate cancer. (See "Measurement of prostate-specific antigen".)

Relationship to cancer — PIN is often diagnosed in a specimen that is removed as treatment for other prostatic pathology (eg, in TURP specimens for benign prostatic hyperplasia [BPH]). PIN is a noninvasive neoplastic process, which does not form a tumor mass or cause clinical symptoms.

Despite its histologic similarity to carcinoma in situ (CIS), a precursor to invasive cancer that arises in other organs (eg, breast), the term CIS should not be used to describe high-grade PIN because of the variability in its natural history and biologic behavior. PIN may evolve into an invasive cancer, a process that may take more than 10 years to develop [24], it may remain unchanged, or it may even regress. Because PIN is not considered a malignant process and is not symptomatic, aggressive treatment (eg, surgery or radiation) is not warranted.

The relationship between PIN and invasive cancer was first elucidated in 1986 [2,25]. In a series of prostate glands obtained at autopsy, PIN was more likely to be found in men with prostate cancer than in those without cancer. Later studies have confirmed the strong association between PIN and invasive prostate cancer. The evidence linking PIN and invasive cancer is as follows:

●Like prostate carcinoma, high-grade PIN tends to be multifocal, occurs in the peripheral zone of the prostate, and is more prevalent in prostates that harbor carcinomas than in those that do not [26,27]. High-grade PIN can be identified in 80 to 90 percent of radical prostatectomy specimens, often in close proximity to coexisting prostatic adenocarcinoma; sometimes, a direct transition from high-grade PIN to invasive adenocarcinoma can be seen [26,28-30].

●In autopsy series, the prevalence of high-grade PIN (7, 12, 36, 38, 45, and 48 percent in the third, fourth, fifth, sixth, seventh, and eighth decades in one series) closely follow the prevalence rates of prostate cancer (4, 9, 14, 24, 32, and 33 percent, respectively) [31].

●Histologic, biochemical, and molecular similarities have been identified between PIN and prostatic adenocarcinoma [32-35]. Most prostate cancer markers can also be detected in high-grade PIN, although to a lower extent and lower frequency. For example, increased alpha-methylacyl-CoA racemase (AMACR) can be detected in nearly one-half of high-grade PIN cases [36]. The rearrangement of ERG, another prostate cancer marker, can be detected by immunostaining or fluorescence in situ hybridization (FISH) in a small subset of high-grade PIN, ranging from 7 to 20 percent of high-grade PIN, although its positive rate is much higher in prostatic adenocarcinoma (40 to 50 percent) [37,38]. Therefore, these similarities could make the distinction between these two conditions sometimes difficult, even using molecular testing. (See "Molecular biology of prostate cancer".)

●The precursor status of PIN has been shown in a transgenic mouse model [39].

Prevalence — Because prostate cancer is the most common visceral malignancy in men, the prevalence of PIN, the major premalignant lesion of the prostate, is also high. However, PIN can only be diagnosed microscopically; as a result, its prevalence in the general population may be underreported.

The incidence of PIN varies in different reports, which may be related to the population of men under study, types of specimens, or the diagnostic criteria that are applied. Based upon pathologic examination of prostate glands in autopsy series [2,24,26,28] and from cystoprostatectomy specimens from men who have undergone surgery for bladder cancer [20,40,41], the prevalence of isolated PIN is 40 to 50 percent in men without prostate cancer. Furthermore, both the rate and volume of PIN increase with age [24,31].

In contrast, incidence rates, as determined by prostate core needle biopsies in men participating in PSA screening studies, range from 0.7 to 20 percent, while among those undergoing TURP, the incidence varies from 3 to 33 percent [42-47]. The reasons for this disparity appear related to sampling issues. Prostate tissues from TURP specimens are usually sampled from the transition zone (image 1) where PIN is known to be less prevalent.

The frequency of concurrent or subsequent diagnosis of invasive cancer may also be higher when more than one biopsy specimen contains high-grade PIN [48,49]. The relationship between the number of involved tissue cores and eventual diagnosis of invasive prostate cancer was illustrated in one series of 245 men with isolated PIN who underwent subsequent biopsies [48]. The only independent histologic predictor of the risk of later invasive cancer was the number of cores involved with PIN: 30, 40, and 75 percent with involvement of one to two, three, or more than three cores. However, these data were obtained when routine six core (sextant) prostate biopsies were the norm. In a more recent series that used an extended biopsy scheme, the number of cores involved with PIN did not reliably predict the risk of finding invasive prostate cancer on rebiopsy [50]. (See "Prostate biopsy", section on 'Systematic biopsy'.)

Detection rates of PIN on core needle biopsy specimens also vary based upon the diverse diagnostic standards that are applied by different pathologists and the extent of the biopsy. When samples from 87,713 men in 15 different studies were analyzed using strict diagnostic criteria, the average prevalence of high-grade PIN was 4.26 percent [42], which closely resembles the prevalence of PIN found in our practice.

More and more institutions have adopted extended biopsy schema for prostate core needle biopsies. Compared with the traditional sextant biopsy, these schema recommend 10 to 12 tissue cores be obtained during each prostate biopsy session. As a result, detection rate of high-grade PIN on core needle biopsy may increase simply because more tissue cores are obtained [51]. (See "Prostate biopsy", section on 'Systematic biopsy'.)

Clinical significance

High-grade PIN — Men with isolated high-grade PIN on initial core biopsy are thought to have a higher risk of prostate cancer on a subsequent biopsy as compared with those without high-grade PIN. However, this remains a controversial area, and the magnitude of risk is uncertain. In early studies, the risk of finding cancer on rebiopsy ranged from 51 to 100 percent; however, cancer detection rates on repeat biopsy have declined since 1990 and range from 13 to 27 percent in more recent large series (table 1) [48,52-58].

Perhaps the major reason for the declining rate of cancer detection on repeat biopsies for high-grade PIN is that current extended prostate biopsy schema include a higher number of cores (12 cores) than the previously standard sextant of six-biopsy scheme [59]. This leads to the detection of more prostate cancers on the initial biopsies and reduces the predictive value of finding high-grade PIN on core needle biopsy for detecting cancer in rebiopsy.

The relationship between the number of cores on initial biopsy, the number of cores on rebiopsy, and the risk of finding cancer in the rebiopsy specimen was illustrated in a series of 791 men with high-grade PIN on initial biopsy who underwent rebiopsy within one year of the diagnosis [57]. Cancer detection rates on rebiopsy varied based upon the biopsy schema; they were highest in men who underwent initial sextant biopsy and who then underwent an extended number of cores for rebiopsy (table 2). The authors concluded that for patients diagnosed with high-grade PIN on extended initial core sampling, a repeat biopsy within the first year was unnecessary in the absence of other clinical indicators of cancer. Others concur [59,60].

Extended biopsy will detect more prostate cancer than sextant biopsy. This is one of the reasons that the predictive value of high-grade PIN is decreasing since many cancer cases have been detected on the initial extended biopsy. Nevertheless, more studies are necessary in order to rationally adjust the rebiopsy strategy in men who are found to have high-grade PIN after undergoing extended core biopsy. Whether such men require rebiopsy is still under investigation. The most important aspect is close clinical follow-up with serum PSA measurement. If there are clinical signs suspicious for prostate cancer, these patients should be rebiopsied.

Two factors that may be particularly important in predicting the development of prostate cancer in the setting of high-grade PIN are elevated serum PSA and the presence of adjacent atypical small glands (acini) that are suspicious, but not diagnostic, for prostate cancer (termed atypical small acinar proliferation [ASAP]). (See "Interpretation of prostate biopsy", section on 'Cases with diagnostic uncertainty'.)

As noted above, elevated serum PSA concentrations cannot be attributed solely to the presence of high-grade PIN; rebiopsy in such men is particularly important to rule out the presence of prostate cancer. If histologic evaluation reveals the presence of high-grade PIN with adjacent ASAP suspicious for cancer, the risk of documenting cancer on repeat biopsy is 50 percent or more compared with patients with high-grade PIN alone [42,55,61,62].

Concomitant high-grade PIN has been associated with good prognosis factors and a favorable oncologic outcome after radical prostatectomy in prostate cancer [63]. However, the reported incidence of high-grade PIN in radical prostatectomy specimens was 54 percent, which is significantly lower than our experience of more than 95 percent of radical prostatectomy cases with prostatic adenocarcinoma. Therefore, it is possible that under-sampling and under-reporting of high-grade PIN in prostatectomy specimens account for this observation. However, high-grade, high-volume prostate cancers are more destructive, which may destroy the major portion of benign prostatic tissue and the tissue harboring high-grade PIN.

Low-grade PIN — Low-grade PIN has no clinical significance, and men with low-grade PIN do not require a repeat biopsy unless other clinical indicators are present. In fact, it is unnecessary to even include low-grade PIN in the pathologic diagnosis because its presence is not an indication for more aggressive follow-up or treatment.

In contrast with high-grade PIN, the presence of low-grade PIN is distinctly different. Histologically, low-grade PIN is characterized by abnormally proliferating secretory cells within acini or ducts, but these cells lack significant cytological atypia. (See "Interpretation of prostate biopsy".)

Management of high-grade PIN — The presence of high-grade PIN on a prostate biopsy is not an indication for aggressive treatment, but instead, the need for close monitoring and possibly for repeat biopsy because of its association with invasive prostate cancer. (See 'Clinical significance' above.)

Rebiopsy — The optimal rebiopsy strategy is unclear [64]. Although rebiopsy should focus on the original site of PIN, cancer detection rates increase with sampling of adjacent sites and the contralateral lobe in the standard sextant locations. Others recommend the addition of transition zone sampling [55]. Given the decreased predictive value of high-grade PIN in patients with 12 or more core biopsies, rebiopsy is generally not recommended. However, patients with persistently rising serum PSA levels or reasons for clinical suspicion should undergo rebiopsy [65].

The management of men with no evidence of invasive prostate cancer on repeat biopsy after an initial biopsy showing isolated high-grade PIN is unclear. Some investigators have found a slightly higher risk of subsequent cancer (24 percent) if high-grade PIN is documented as compared with a totally benign repeat biopsy [48].

On the other hand, a 24 percent rate of finding invasive cancer is not insignificant and may be considered high enough that it indicates the need for rebiopsy. One study found that the number of foci of high-grade PIN may be associated with risk of finding prostate cancer in repeat biopsy, which led to a recommendation that an earlier repeat biopsy be carried out in men with more than one core involved by high-grade PIN [66]. Other studies have found that a saturation biopsy scheme increases cancer detection in men with high-grade PIN [67]. Although these biopsy methods and recommendations have not been widely accepted, they can be considered as options. The ideal timing and frequency for rebiopsy following the diagnosis of high-grade PIN remain unclear. Additional studies are needed to address this question.

Atypical small acinar proliferation — ASAP is not a biologic entity or a premalignant lesion but a diagnostic term used by some pathologists and understood by clinical colleagues. ASAP is a condition when a pathologist finds a small focus of atypical glands (typically two to three glands, sometimes a few more) suspicious for adenocarcinoma, but there is not sufficient histologic evidence to make a definitive diagnosis of prostatic adenocarcinoma [68]. The diagnosis of ASAP is typically made on a core needle biopsy, occasionally on a TURP specimen, but it is not found in prostatectomy specimens. (See "Interpretation of prostate biopsy", section on 'Cases with diagnostic uncertainty'.)

There is a 40 to 50 percent risk of prostate adenocarcinoma with repeat biopsies in a man with ASAP. Generally speaking, the recommendation for ASAP is rebiopsy, if clinically indicated.

Although some pathologists may not use the term ASAP, the high risk for prostate cancer and the need for a repeat biopsy in men with a suspicious prostate diagnosis have to be communicated to clinical colleagues. The suspicious area of the prostate may be sampled more extensively but not exclusively; other areas of the prostate with benign diagnosis should also be sampled in a repeat biopsy.

The most important issue is that high-grade PIN is totally different from atypical foci suspicious for cancer on prostate core needle biopsy, which carries a much higher risk (40 to 50 percent) of finding cancer at the time of rebiopsy. As a result, men with atypical foci suspicious for adenocarcinoma should be rebiopsied within three to six months, while rebiopsy within one year for men with high-grade PIN alone could be considered optional. (See "Interpretation of prostate biopsy", section on 'Cases with diagnostic uncertainty'.)

Specific treatment — Treatment that is designed for men with invasive prostate cancer (ie, radical prostatectomy, radiation therapy, androgen ablation) is not suitable for those with PIN. Although theoretically such treatments could reduce the incidence of PIN and potentially prevent prostate cancer, no medication has been shown to prevent the development of prostate cancer from high-grade PIN.

Because of the known influence of neoadjuvant hormone therapy in reducing the incidence of PIN [69-71], it has been suggested that finasteride, an oral agent with no impact on serum testosterone levels, may be a useful agent for treating high-grade PIN. The Prostate Cancer Prevention Trial (PCPT) randomly assigned 18,882 men to finasteride (5 mg daily) or placebo, and followed men for seven years with annual digital rectal examination and PSA [72]. The number of men evaluable for high-grade PIN in the finasteride and placebo groups was 4568 and 4866, respectively. Men were evaluable for high-grade PIN if they had a diagnosis of high-grade PIN or invasive cancer on an interim or end of study biopsy, or if they had a completely negative biopsy at the end of study endpoint (seven years). When men diagnosed with high-grade PIN alone or high-grade PIN concurrently with invasive prostate cancer were examined jointly, those receiving finasteride had a significant 21 percent lower risk of high-grade PIN (9.2 versus 11.7 percent, hazard ratio [HR] 0.79, p = 0.001). (See "Chemoprevention strategies in prostate cancer".)

Based upon our experience, blockade of 5-alpha reductase (5-AR) with finasteride does not cause obvious change in the morphology of prostate cancer on histologic evaluation [73]. Unlike other forms of androgen deprivation therapy, the effects of finasteride on morphology of high-grade PIN and Gleason score are unknown [74].

In randomized trials, 5-AR inhibitors have been shown to significantly decrease the incidence of prostate cancer. However, no trials have demonstrated an impact of prostate cancer mortality, and the possibility that these agents increase the incidence of high-grade lesions cannot be excluded. (See "Chemoprevention strategies in prostate cancer", section on 'Finasteride: PCPT'.)

Another clinical trial, using toremifene, an estrogen agonist/antagonist, was conducted in men with high-grade PIN, but toremifene also failed to prevent the development of prostate cancer [75]. (See "Interpretation of prostate biopsy".)

ATYPICAL ADENOMATOUS HYPERPLASIA (ADENOSIS) — In contrast with high-grade prostatic intraepithelial neoplasia (PIN), the evidence for premalignant potential of atypical adenomatous hyperplasia (AAH) is inconclusive. AAH was first described in 1941 [76] and further characterized as a distinct entity in 1965 [77]. Another synonym, "adenosis," was introduced in 1986 [78]. Although the term AAH was advocated in a consensus meeting [79], some experts consider the term "atypical" inappropriate for this condition, leading to confusion with prostate cancer or a lesion that is suspicious for prostate cancer (eg, atypical small acinar proliferation [ASAP]). (See 'Clinical significance' above.)

AAH is defined as a well-circumscribed lobule of closely packed crowded small glands (acini) [80]. Similar to low-grade prostatic adenocarcinoma, AAH typically lacks significant cytologic atypia despite its abnormal architecture (picture 3). However, in contrast with invasive cancer, the presence of basal cells, although patchy in distribution, is characteristic of AAH and demonstrable by immunostaining for high molecular weight cytokeratins (34bE12) (picture 3). (See "Interpretation of prostate biopsy".)

The reported prevalence of AAH is between 1.6 to 19.6 percent of transurethral resection (TURP) specimens and from 5 to 23 percent of radical prostatectomy specimens [81-83]. This wide range is likely due to variable diagnostic criteria employed by different pathologists. In our practice, AAH is found in less than 5 percent of TURP or radical prostatectomy specimens when relatively strict diagnostic criteria are applied. In addition to its low prevalence, AAH is often present without coexisting adenocarcinoma, and direct transition from AAH to invasive cancer has been seen only rarely.

There is controversy as to whether AAH is a premalignant lesion. Because most AAH is located in the transition zone (image 1), where low-grade prostatic adenocarcinoma is often situated, it has been hypothesized that AAH is a precursor for low-grade prostate cancer [84]. Furthermore, the histologic and cytological features are intermediate between benign prostatic hyperplasia (BPH) and low-grade carcinoma [85]. Because of its low prevalence, AAH is unlikely to be responsible for the majority of prostatic adenocarcinoma. In fact, AAH is often present without coexisting adenocarcinoma. Direct transition from AAH to cancer has been seen only rarely. There is no convincing clinical follow-up information available to link AAH and prostate cancer.

Evidence from clinical, biochemical, and molecular analyses of AAH have generated inconclusive results to substantiate the notion that AAH is a premalignant lesion [86-89]. However, our study demonstrated that 17.5 percent of AAH overexpressed alpha-methylacyl-CoA racemase (AMACR), which is considered a molecular marker for prostate cancer [87] (see "Interpretation of prostate biopsy", section on 'Immunohistochemistry'). This finding strongly suggested that at least a small subset of AAH might be a precursor for low-grade adenocarcinoma in the prostatic transition zone.

If some cases of AAH do have malignant potential, it is likely to represent the minority of cases. In general, the majority of AAH can be considered benign, and immediate rebiopsy is not indicated in men with isolated AAH unless other clinical indicators or pathologic warnings are present. It is possible that AAH will be eventually divided histologically and biochemically into benign conditions (the majority), which do not require rebiopsy, and atypical lesions (the minority), which warrant rebiopsy and close follow-up. Further studies are needed to clarify the role of AAH in the pathogenesis of low-grade prostate cancer and to determine its clinical significance. A comparison between prostatic adenocarcinoma, high-grade PIN, and AAH is listed in the table (table 2).

INTRADUCTAL CARCINOMA OF THE PROSTATE — Intraductal carcinoma of the prostate (IDCP) is a newly defined entity that has been described in detail [90,91]. IDCP is important because it may be confused with high-grade prostatic intraepithelial neoplasia (PIN). This entity is discussed separately. (See "Interpretation of prostate biopsy", section on 'Intraductal carcinoma of the prostate'.)

ATROPHY AND ATROPHIC LESIONS — The relationship between atrophy and atrophic lesions of the prostate and prostate adenocarcinoma is even less clear. Atrophy is histologically recognized by the presence of small acini and ducts with a reduced amount of cytoplasm. In contrast with its name and appearance, atrophy is not a degenerative process, but rather, a proliferative condition [92]. Atrophic prostatic lesions include a spectrum of conditions, namely typical atrophy [93], postatrophic hyperplasia [94], partial atrophy [95], and proliferative inflammatory atrophy [96].

Atrophic lesions are very common in the peripheral zone of the prostate where most prostate adenocarcinomas develop. Atrophic lesions do not correlate with the size of the prostate. Although finding coexistent atrophy and prostate cancer is not uncommon [97], a causal relationship has not been defined. It has been proposed that proliferative inflammatory atrophy is a precursor of high-grade prostatic intraepithelial neoplasia (PIN) or a precursor of prostate adenocarcinoma because of its frequency in the peripheral zone and proliferative nature, though more studies are necessary to substantiate this claim. It is not clear whether proliferative inflammatory atrophy is just a histologic variant of atrophy similar to postatrophic hyperplasia or a distinct pathologic entity linked to the development of high-grade PIN. Furthermore, the diagnosis of proliferative inflammatory atrophy cannot be established on hematoxylin and eosin (H&E) stained slides alone because immunostaining with a proliferative marker, such as Ki-67, is needed to identify its presence. At present, atrophy and its variants are considered benign conditions, and their presence does not warrant a repeat biopsy if other clinical indications are absent.

SUMMARY

●Prostatic intraepithelial neoplasia (PIN) is a neoplastic proliferation of epithelial cells within the benign preexisting ducts or acini. PIN is histologically divided into low-grade and high-grade lesions. High-grade PIN is considered to be a premalignant lesion and a precursor of the majority of prostate cancer cases. PIN is typically not associated with any clinical symptoms or signs, or associated with an elevation of prostate-specific antigen (PSA). Imaging studies have not shown to be useful in identifying PIN either. Therefore, the only preoperative diagnosis of PIN is obtained from prostate core needle biopsy. (See 'Histology' above.)

●Neoplastic cells in high-grade PIN share many features with invasive prostatic adenocarcinoma based upon their morphologic appearance, and biochemical and molecular genetic characteristics. The key difference is that PIN is noninvasive, similar to carcinoma in situ (CIS), and typically associated with the presence of basal cells. The natural history and latent period for PIN to progress to cancer are unclear.

●There is a strong association between the presence of high-grade PIN on prostate biopsy and the presence of prostate adenocarcinoma. The optimal strategy for rebiopsy in men with high-grade PIN but without prostate cancer is unclear. Generally, these patients with isolated high-grade PIN need to be followed, at least with serial PSA levels. In contrast, low-grade PIN does not appear to have clinical significance, and rebiopsy is not indicated. (See 'High-grade PIN' above and 'Low-grade PIN' above and 'Rebiopsy' above.)

●Patients with atypical small acinar proliferation (ASAP) on prostate biopsy should have repeat biopsy, as prostate cancer will be subsequently identified in 40 to 50 percent of cases. (See 'Atypical small acinar proliferation' above.)

●Whether other lesions are precursors of prostate cancer is less certain. Atypical adenomatous hyperplasia (AAH) is characterized by a well-circumscribed lobule of crowded small glands without significant cytologic atypia. Whether AAH is a premalignant lesion is controversial, but it appears to be a benign lesion in most, if not all, cases. Atrophy and atrophic lesions are very common in the prostate and typically are considered benign. Although these lesions can be proliferative in nature, whether there is a relationship between such atrophic lesions and prostatic adenocarcinoma is not conclusive. Therefore, rebiopsy is not indicated for men with benign atrophic lesions of the prostate. (See 'Atypical adenomatous hyperplasia (adenosis)' above and 'Atrophy and atrophic lesions' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges E David Crawford, MD, who contributed to an earlier version of this topic review.

We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.