Prostatic Intraepithelial Neoplasia

Recent Advances
Alberto G. Ayala, MD; Jae Y. Ro, MD, PhD

Context.There have been 2 putative prostatic cancer precursors, prostatic intraepithelial neoplasia (PIN) and atypical adenomatous hyperplasia (adenosis), but PIN remains as a well-known precancerous condition. Objective.To describe recent advances in knowledge of PIN and to better dene the diagnostic criteria and differential diagnosis of PIN. Data Sources.Review of the pertinent literature and our experience. Conclusions.The presence of ductal/acinar epithelial changes including nuclear enlargement, prominent nucleoli, chromatin alterations, and luminal complexity is an easy way to identify the disorder. Four main patterns of or many years, atypical epithelial lesions of the prostate have been known to occur, but much rening of this knowledge has evolved during the last 2 decades. Initially 2 lesions, dysplasia of the prostate now known as prostatic intraepithelial neoplasia (PIN) and atypical adenomatous hyperplasia, were assumed to be precursors of carcinoma.16 Of these, PIN has remained as the only well-proven preneoplastic condition with clinical signicance. Atypical adenomatous hyperplasia or adenosis is no longer considered a premalignant lesion but rather a benign small glandular process of the transition zone that simulates acinar adenocarcinoma and as such is not discussed here. PROSTATIC INTRAEPITHIAL NEOPLASIA John McNeal introduced the term intraductal dysplasia of the prostate in the early 1960s, postulating that carcinoma of the prostate arose from active ductal/acinar epithelium and not from atrophic acini.79 His concept was not widely accepted until 1986 after an article he coauthored with David Bostwick clearly gave an account of its morphologic criteria and established a grading system that closely predicted the association of invasive carcinoma.1 Numerous articles proposing different terms for this
Accepted for publication April 16, 2007. From the Department of Pathology, The Methodist Hospital, Weill Cornell University School of Medicine, Houston, Tex. The authors have no relevant nancial interest in the products or companies described in this article. Reprints: Alberto G. Ayala, MD, Department of Pathology, The Methodist Hospital, Weill Cornell University School of Medicine, 6565 Fannin St, Room 227 (Main Building), Houston, TX 77030 (e-mail: aayala@tmh.tmc.edu). Arch Pathol Lab MedVol 131, August 2007

high-grade PIN (HGPIN) have been described: tufting, micropapillary, cribriform, and at. In addition, variants of HGPIN have also been described. Both HGPIN and prostatic carcinoma share an increased incidence and severity with advancing age and with high rates of occurrence in the peripheral zone of the prostate. Furthermore, HGPIN and prostate cancer share genetic and molecular markers as well, with PIN representing an intermediate stage between benign epithelium and invasive carcinoma. The clinical signicance of HGPIN is that it identies patients at risk for prostatic carcinoma. With the increased use of extended biopsy protocols, clinicians are more likely to identify HGPIN and less likely to miss concurrent carcinoma. (Arch Pathol Lab Med. 2007;131:12571266) condition have appeared in the literature including large acinar atypical hyperplasia with malignant change2 and ductacinar dysplasia.9 None of these have gained popularity. The term PIN was rst proposed by Bostwick and Brawer in 1987,10 and this term was accepted at the 1989 Workshop on Prostatic Dysplasia (Bethesda, Md; March 1989) as the preferred nomenclature for this preneoplastic change.11,12 The 3-tier grading system proposed by McNeal and Bostwick1 was dropped and PIN was considered to be either low or high grade.11,12 Since then, this term has gained widespread acceptance, and it is the term used in this discussion. HISTOLOGIC CHARACTERISTICS OF PIN The normal prostate is primarily constituted by ductal and acinar structures, but these formations are difcult to discern from each other on routine slides because both have a dual lining with basal and secretory cells. On whole-organ sections of the prostate, the morphology is clear. For clarication, in this article we refer to these structures as ducts, ductal, acinus, acinar, gland, or glandular structures interchangeably. Prostatic intraepithelial neoplasia can be simply dened as a cellular enhancement of the normal glandular architecture with cytologically atypical individual cells. It is readily identied at low magnication by 3 important ndings: (1) the lining of the ductal structures is darker, (2) it is also thicker than the surrounding normal ducts, and (3) there may be a complex intraluminal pattern of growth (Figure 1). At high magnication, there is a cytologic triad including (1) varying degrees of nuclear enProstatic Intraepithelial NeoplasiaAyala & Ro 1257

Figure 1. In this low-power view of prostatic intraepithelial neoplasia there is a cluster of glandular structures with hyperchromatic cells contrasting with adjacent normal glands (hematoxylin-eosin, original magnication 40). Figure 2. On high-power view there is nuclear stratication, nuclear enlargement, and the presence of prominent nucleoli in the majority of the cells (hematoxylin-eosin, original magnication 400). Figure 3. This core biopsy shows partial involvement of a gland by prostatic intraepithelial neoplasia (hematoxylin-eosin, original magnication 100). 1258 Arch Pathol Lab MedVol 131, August 2007

largement with nuclear stratication, (2) hyperchromasia, and (3) nucleolar prominence (Figure 2). Prostatic intraepithelial neoplasia is usually multifocal and involves clusters of glandular structures or may involve a single gland either partially or completely (Figure 3). In core biopsies of the prostate, the latter is more likely to be seen. At the 1989 Workshop on Prostatic Dysplasia,11,12 it was agreed to designate ductal dysplasia grade 1 as low-grade PIN and to combine ductal dysplasia grades 2 and 3 together as high-grade PIN (HGPIN).12 However, histologic criteria to distinguish between low- and high-grade dysplasia was not given. For the purpose of better understanding the histomorphology of PIN, it is here described as was originally graded by McNeal and Bostwick.1 Low-grade PIN 1 is characterized by epithelial proliferation with nuclear stratication, cellular crowding, variable nuclear enlargement (anisonucleosis), and irregular cell spacing. Nucleoli may be seen but are rare and small (Figure 4, A and B). Grade 2 PIN is a subtle transition from PIN 1 and consists of cells with larger nuclei and nucleoli that are more obvious and larger than in PIN 1 (Figure 5, A and B). In PIN 2, prominent nucleoli are observed only in some cells, but these are more numerous than in PIN 1. In essence, separation of low-grade PIN (PIN 1) versus grade 2 PIN becomes highly subjective to the experience of the examiner. The high-grade type (grade 3 PIN) is easy to identify in as much as the epithelial cells do exhibit nuclear enlargement, hyperchromasia, and presence of 1 or more nucleoli that are usually large, often with clear halos, but may be small especially when there are more than 1, and are characteristically prominent (Figure 6, A and B). These cells resemble those of a microacinar carcinoma of Gleason pattern 3. Mitotic gures are rare in HGPIN and are not included in the grading criteria of PIN.1 In a study of HGPIN in radical prostatectomy specimens,13 the authors reported mitotic gures in only 3% of the cases. In general, there is good distinction between low-grade PIN (PIN 1) and HGPIN (PIN 3) but not with intermediate PIN (grade 2) especially its distinction from low-grade PIN (Table). Furthermore, among the lesions showing HGPIN, there is signicant interobserver variability as to whether the lesion represents PIN 2 or PIN 3. Because of this variability of PIN 2 and PIN 3, the consensus opinion at the Bethesda meeting fused PIN 2 and 3 under the term of high-grade PIN.12 Prostatic intraepithelial neoplasia may display a spectrum of architectural patterns, from a simple at epithelium to a complex cribriform pattern that may be difcult to distinguish from cribriform carcinoma. The 4 most common patterns of HGPIN are the tufting pattern (Figure 4, A) (87%), the micropapillary pattern (Figure 7, A and B) (85%), the cribriform pattern (32%), and the at pattern (Figure 7, C) (28%).13 All of these patterns are frequently observed in the same radical prostatectomy specimen.13 Although it is important for diagnostic purposes to recognize these different patterns, it has been shown that there is no signicant relationship between the pattern of HGPIN and the Gleason grade of carcinomas arising in the same specimen. Several studies have also been done attempting to correlate PIN patterns found in core needle biopsies with invasive carcinoma on rebiopsy. Some have stated that the higher the number of cores involved, the higher the inciProstatic Intraepithelial NeoplasiaAyala & Ro

dence of invasive carcinoma on rebiopsy. Also papillary and cribriform patterns have been cited to have a higher association with invasive carcinoma on rebiopsy. However, other studies have not proven the validity of these studies.14,15 HISTOLOGIC VARIANTS OF PIN Several histologic variants of PIN have been reported in the literature. These include (1) signet ring cell variant,16 (2) mucinous variant (Figure 8, A and B),16 (3) small cell neuroendocrine variant,16 (4) foamy variant,17 (5) inverted variant,18 and (6) PIN with squamous differentiation.19 Reyes et al16 reported several unusual histologic types of HGPIN. One of these, the signet ring cell variant (Figure 8, A and B), is exceedingly rare, and all reported cases have been associated with adjacent invasive signet ring cell carcinoma. The signet ring cells are produced by cytoplasmic vacuoles with indented nuclei. Typically, the signet ring cells seen in the PIN as well as invasive signet ring cell carcinoma are negative for mucin. Another variant reported by Reyes et al16 is mucinous PIN. This type is characterized by intraluminal amorphous bluish mucin distending PIN glands. Because of glandular distention, the lining PIN may show a at pattern of growth. All reported cases of mucinous PIN were associated with adjacent invasive ordinary microacinar carcinoma and none was associated with mucinous adenocarcinoma. The third type of PIN variant reported by Reyes et al16 is small cell neuroendocrine variant. The small cells, which are positive for neuroendocrine markers, contain dense core neurosecretory granules by electron microscopy and form rosettelike structures in the center of PIN glands. At the periphery of the PIN glands, typical glandular-type PIN cells are observed. In this type of variant, a case with invasive mixed small cell/adenocarcinoma has been reported. Two cases of foamy gland HGPIN have been reported by Berman et al.17 The morphologic features of the foamy gland PIN cells are characterized by voluminous xanthomatous cytoplasm with bland nuclei. One of the reported cases was associated with an adjacent invasive microacinar carcinoma without foamy gland carcinoma. Inverted variant (hobnail variant)18 is characterized by polarization of enlarged secretory cell nuclei toward the glandular lumen. Argani and Epstein18 reported 15 cases of this variant of PIN. In all cases, inverted HGPIN was identied on needle biopsies where it merged with typical micropapillary-tufted HGPIN. Inverted secretory cell nuclei frequently demonstrated less prominent nucleoli than adjacent noninverted secretory cell nuclei. Inverted HGPIN was associated with concurrent prostatic adenocarcinoma in 7 cases and with atypical glands suspicious for carcinoma in 1 other case, whereas in 6 other cases inverted HGPIN was the only lesion identied. In 1 case, radical prostatectomy was performed following these biopsies. Inverted HGPIN was localized to the peripheral zone of the prostate where it merged with usual forms of HGPIN and carcinoma. Recently Melissari et al19 reported an unusual variant of PIN with prominent and extensive squamous differentiation. The lesion was identied in the transition zone of a 79-year-old man with a 3-year history of increasing urinary obstructive symptoms and a clinical diagnosis of benign prostatic hyperplasia who underwent simple prostatectomy.
Arch Pathol Lab MedVol 131, August 2007

PIN DISTRIBUTION Prostatic intraepithelial neoplasia is found predominantly in the peripheral zone of the prostate (75%80%), rarely in the transition zone (10%15%), and extremely rarely in the central zone ( 5%). This distribution parallels the frequency of the zonal predilection for prostatic carcinoma.2022 The frequency of HGPIN in needle biopsy series ranges from 5% to 16% and in transurethral resection of the prostate specimens between 2.3% and 4.2%.19,20,22 McNeal in 1969 mentioned the multifocality of this process9,23; this observation has since been corroborated by others.10,21,22 IMMUNOHISTOCHEMISTRY IN PIN Numerous studies to highlight the basal cells and the secretory cells have been done.2430 The basal cells and luminal cells of the prostatic glands display different keratin immunoreactivity. The high-molecular-weight cytokeratin monoclonal antibody (clone 34 E12, also referred to as CK903) recognizes keratin proteins of 49, 51, 57, and 66 kd and labels the basal cells but not the luminal/secretory cells of the prostatic glands that stain with prostate-specic antigen and prostatic acid phosphatase. -Methylacyl CoA-racemase (AMACR) stains the cells of adenocarcinoma but usually does not stain benign prostate glands.2430 Other antibodies that also mark basal cells include p6323 and CK5/6.25 p6324,25 is a nuclear stain, whereas CK5/6 stains the cytoplasm. The basal cell layer is present in benign epithelial proliferations, may be disrupted in HGPIN, and is absent in invasive carcinoma.10 Bostwick and Brawer10 have shown that the frequency and extent of basal cell disruption in PIN is related to the PIN grade and is greatest in HGPIN (grade 3). A whole body of immunohistochemistry studies27,28,3133 has been done to correlate the relationship between HGPIN and invasive carcinoma, that is, monoclonal antikeratin antibody, KA4, Ulex europaeus lectin (UEA-l), lectin binding pattern, and vimentin. A recent study30 demonstrated that a signicantly higher P504S (AMACR) positive rate (56.0%) was found in isolated HGPIN glands adjacent to cancer (distance less than 5 mm) compared with those away from cancer (distance more than 5 mm; 14%, P .001). High-grade PIN glands adjacent to cancer also showed a higher (P .001) P504S intensity than did those away from cancer. Other studies including argyrophilic nucleolar organizer regions and static DNA ow cytometry suggest that HGPIN and carcinoma have similar proliferative activity and DNA content, and hence HGPIN is the most likely precursor of cancer.3335 Cytogenetic abnormalities (involving 7q, 8q, 10q, 16q) and numerical chromosomal changes are noted in HGPIN and carcinoma.3639 High-grade PIN and prostate cancer share genetic and molecular markers as well, with PIN representing an intermediate stage between benign epithelium and invasive carcinoma.40 DIFFERENTIAL DIAGNOSIS OF PIN Normal prostatic structures, metaplasias, benign epithelial proliferations, and malignant tumors may be confused with PIN. The differential diagnosis of HGPIN is very important when evaluating needle biopsy specimens in which PIN may be very focal. It has been recommended
Prostatic Intraepithelial NeoplasiaAyala & Ro 1259

Figure 4. Low-grade prostatic intraepithelial neoplasia (PIN 1). A, Low-power view shows a focal tufting pattern with stratication of nuclei (hematoxylin-eosin, original magnication 200). B, High-power view may show nucleoli, but they are rare and small (hematoxylin-eosin, original magnication 400). Figure 5. Prostatic intraepithelial neoplasia (PIN) 2. A, In this illustration, there is a relatively normal duct except for the left third in which the cells display nuclear enlargement with ne nuclear chromatin and some prominent nucleoli (hematoxylin-eosin, original magnication 400). B, In this illustration, nuclear enlargement and prominent nucleoli begin to appear for a grade 2 PIN (and consequently high-grade PIN) (hematoxylineosin, original magnication 400). 1260 Arch Pathol Lab MedVol 131, August 2007 Prostatic Intraepithelial NeoplasiaAyala & Ro

Diagnostic Criteria of Prostatic Intraepithelial Neoplasia (PIN)

Features Low-Grade PIN (PIN 1) High-Grade PIN (PIN 2, 3)

Architecture Crowding, stratication, irregular spacing Nuclei Slight enlargement, size variation Chromatin Normal Nucleoli Rarely prominent * T indicates tufting; MP, micropapillary.

More changes, 4 patterns (T, MP, cribriform, at)* Denite enlargement, less size variation Increased Frequently prominent

that only HGPIN (PIN 2 and PIN 3) be reported in these specimens.11 The 2 normal prostatic structures that are frequently misinterpreted as PIN are normal central zone glands and ejaculatory duct/seminal vesicle epithelium. The central zone glands are architecturally more complex than the peripheral and transition zone glands and exhibit a certain degree of nuclear stratication that may be interpreted as PIN (Figure 9). In addition, bridging, papillary formation, and focal tubular or cribriform pattern may be present; however, papillations contain a central vascular core.41,42 The central zone is frequently encountered in core biopsies from the base of the prostate. The site of the biopsy as well as the presence of the other histologic features of the central zone, including the presence of abundant compact muscular stroma, should aid in the recognition that the epithelial atypia is a normal nding in this location (Figure 9). Nevertheless, HGPIN may occur in the central zone. Thus, PIN in the central zone was found in 13% of cystoprostatectomy specimens in 1 study.43 If a diagnosis of HGPIN is made in the central zone, current information indicates that it has no clinical signicance.43,44 Further work is needed to conrm this nding. Seminal vesicle or ejaculatory duct epithelium may be encountered in transurethral resection of the prostate specimens or needle biopsies. Helpful features in distinguishing these normal structures from HGPIN include the presence of variably sized nuclei (round to oval), often with large monstrous cells containing intranuclear inclusions, and the presence of cytoplasmic pigment (lipofuscin) (Figure 10, A and B).45,46 It should be noted that lipofuscin is also present in prostatic cells.47 In case of doubt, the ejaculatory duct/seminal vesicle epithelium is not immunoreactive to prostate-specic antigen or prostatic acid phosphatase. Normal prostate structures have been reported to be negative for MUC6 (MUC6 belongs to the family of human mucin genes). In contrast, all seminal vesicles and ejaculatory ducts are diffusely immunostained with MUC6 antibody, and therefore this marker can be potentially valuable for the differential diagnosis between PIN and seminal vesicle or ejaculatory duct.48 Low-grade PIN (PIN 1) can be very subtle, and sometimes other epithelial proliferations frequently encountered in the prostate may be initially misinterpreted as PIN 1. Furthermore, normal tissue may be confused with PIN 1. When sections of tissue cores are in the

order of 4 m or less in thickness, it is not unusual to nd a small nucleolus in normal or hyperplastic glandular epithelium. Other lesions that may be confused with low-grade PIN include epithelial hyperplasia of the usual type and transitional metaplasia.49 The usual hyperplasia does not show nuclear enlargement but shows uniform nuclei that are evenly spaced without marked nuclear overlap. Transitional metaplasia is characterized by elongated, oval-shaped nuclei that often contain longitudinal nuclear grooves (Figure 11, A through C). When transitional metaplasia is more immature than usual, some nucleoli may be present; so, it may also be confused with PIN of a higher grade. In general, there is no nuclear enlargement. It must be remembered that there are no clear-cut histologic criteria to differentiate low-grade PIN versus highgrade PIN (Figure 5, A). One must remember that PIN 1 may have prominent nucleoli and some degree of nuclear enlargement, but the number of cells with large nucleoli is minimal. Similarly, only a few cells should have nuclear enlargement. Hyperchromasia alone is not a feature of HGPIN. In case of doubt, one should probably err in the low-grade side of PIN and make a comment in regard to the difculty in arriving at a diagnosis. McNeal and Bostick1 stated that PIN grade 1 and 2 are seldom associated with invasive carcinoma. Other benign epithelial proliferations that should be included in the differential diagnosis of HGPIN include basal cell hyperplasia and clear cell cribriform hyperplasia, which are usually not difcult to differentiate from HGPIN. The carcinomas most likely to be confused with HGPIN include carcinoma in situ (cribriform, solid, or comedo patterns),50 ductal (endometrioid) adenocarcinoma (especially retrograde lling of ductal structures), and transitional cell carcinoma (TCC) involving ducts/acini.5053 Intraductal carcinoma of the prostate in needle biopsies without inltrating carcinoma is extremely rare. Guo and Epstein54 found 27 cases of this disease among 45 000 prostate needle biopsies during a 5-year period. It is characterized by a proliferation of malignant epithelial cells lling large acini/ducts with complete or incomplete retention of basal cells. Marked pleomorphism is present with large hyperchromatic nuclei that are 6 times larger than those of normal ductal epithelium. Intraductal carcinoma of the prostate may show solid, dense cribriform, loose cribriform, and micropapillary patterns. McNeal and Yemoto50 considered intraductal carcinomas with solid, crib-

Figure 6. Prostatic intraepithelial neoplasia 3. A, Medium-power view discloses nuclear enlargement, hyperchromasia, and prominent nucleoli (hematoxylin-eosin, original magnication 200). B, On high-power view, the cells of high-grade prostatic intraepithelial neoplasia look anaplastic. Note retention of the basal cell layer (hematoxylin-eosin, original magnication 400). Arch Pathol Lab MedVol 131, August 2007 Prostatic Intraepithelial NeoplasiaAyala & Ro 1261

Figure 7. Prostatic intraepithelial neoplasia patterns. A, The papillary cribriform type consists of a papillary architecture with complete or incomplete bridging of the lumina (hematoxylin-eosin, original magnication 100). B, On higher power view the cells toward the center of the lumen become darker and smaller (arrows) than those at the periphery, a phenomenon that has been called maturation (hematoxylin-eosin, original magnication 200). C, The at pattern consists of 1 or 2 cells lining the ductal structure demonstrating large nuclei and prominent nucleoli as it is depicted in this illustration (hematoxylin-eosin, original magnication 400).

1262 Arch Pathol Lab MedVol 131, August 2007

Prostatic Intraepithelial NeoplasiaAyala & Ro

riform, and comedo patterns as variants of carcinoma in situ. Thus, intraductal carcinoma of the prostate with any of these patterns has overlapping features with HGPIN. Intraductal carcinoma of the prostate generally occurs in conjunction with invasive cribriform or ductal-endometrioid adenocarcinoma of the prostate. Distinguishing features in favor of intraductal carcinoma of the prostate with cribriform pattern include large size of the ductal structures with irregular borders, the presence of cribriform glands with prominent cytologic atypia, and central necrosis (Figure 12, A and B). The nuclear features of cribriform carcinoma are uniform throughout the duct. In contrast, in HGPIN with a cribriform/papillary pattern, the nuclei present at the top of the papillae or in the cribriform areas toward the center of the duct are smaller, rounder, and more hyperchromatic than the nuclei present toward the periphery of the gland (Figure 7, B). This feature is sometimes referred to as maturation. Although this distinction rarely poses a problem in the evaluation of radical prostatectomy specimens, it does pose a problem in the interpretation of core needle biopsies. Intraductal carcinoma of the prostate with micropapillary pattern as seen in ductal-endometrioid carcinoma usually displays highgrade morphology, with cribriform pattern and/or true papillary fronds. The presence of comedonecrosis is a feature that strongly indicates an invasive adenocarcinoma of the prostate. High-grade PIN may have apoptosis, but extensive central necrosis is no part of HGPIN. Recognizing that some cases are borderline between HGPIN and intraductal carcinoma of the prostate, the surgical pathology report should convey uncertainty as to the differential diagnosis and a strong recommendation for repeat biopsy should be made to uncover an invasive component. Features helpful in distinguishing TCC from HGPIN include the occasional presence of a residual luminal cell layer and cytologic characteristics. The cells of TCC usually vary signicantly in size and shape and have a very coarse chromatin pattern, signicant mitotic activity, and frequent tumor necrosis. In lower grade TCC, the cells may show longitudinal nuclear grooves. Because TCC in situ of the bladder frequently shows pagetoid spread, prostatic ducts involved by TCC frequently demonstrate a basal cell layer, as in HGPIN. Mitotic gures are frequently present in high-grade TCC and in prostate carcinoma of ductal origin and are rare in cribriform carcinoma and in HGPIN. Although the presence of mitoses in glands considered to be HGPIN should call to mind other diagnostic considerations, it should be noted that mitoses are not infrequent in PIN in needle biopsies that have been subjected to rapid xation. CLINICAL SIGNIFICANCE OF PIN As HGPIN is strongly predictive of the presence of carcinoma (about one third of cases),1 the identication of HGPIN in biopsy specimens has important clinical impli

cations. It has been recommended that only HGPIN diagnosis be included in the pathology report.11 The pathologist should also indicate its extent in single or multiple core biopsy specimens. It is also important to specify the number of foci of HGPIN and the number of cores involved. Kronz et al15 reported that when 3 cores are involved with HGPIN, there is a 40% chance of nding invasive carcinoma on rebiopsy, but when 4 or more cores are involved, the percentage increases to 75%.15 Furthermore, in another retrospective study the authors found a 39% likelihood of nding invasive carcinoma of the prostate in patients with an initial diagnosis of widespread HGPIN (dened as the presence of HGPIN in 4 or more core biopsies).55 When HGPIN, found in core needle biopsies, is present without carcinoma, the clinical signicance of this diagnosis has to be evaluated in conjunction with other clinical parameters, that is, sextant biopsies (6 cores, 3 on each side of the prostate) versus extended biopsies (more than 10 cores from different sites) to determine whether immediate rebiopsy is indicated or whether interval followup with serum prostate-specic antigen, digital rectal examination, and ultrasound should be recommended. Although HGPIN is associated with invasive carcinoma in about one third of the patients, the tendency to rebiopsy patients with diagnosis of HGPIN has resulted in consistently negative rebiopsies year after year in many of the patients.55 Extended biopsies also called saturation biopsies consisting of sampling more than 10 sites of the prostate is now another strategy for the diagnosis of invasive prostate carcinoma.56,57 These biopsies sample far more areas of the prostate that the sextant biopsy procedure does. Thus, the lateral-anterior aspects of the peripheral zone, the so-called horns, and the anterior transition zone area between the urethra and the pubis margin are included in addition to the usual areas sampled by the routine sextant biopsy procedure. These areas may harbor hidden microscopic foci of carcinoma that would not have been detected with the sextant biopsy procedure. The traditional management for a patient with a HGPIN diagnosed by sextant biopsies was to do a repeat set of biopsies. Because extended biopsies literally map out the major portion of the prostate, the predictive value for invasive carcinoma on rebiopsy is far less than the predictive values of HGPIN found on sextant biopsies. If there were to be a focus of invasive carcinoma in this situation, it is probably too small and of no clinical signicance, allowing for clinical follow-up.57 Eskicorapci et al58 concluded that the yield of extended 14-core biopsy protocol was higher in patients with previous negative sextant biopsies compared with previous negative 10-core biopsy. High-grade PIN found on previous sextant biopsy was a strong predictor for carcinoma on repeat biopsy; however, this nding was not true for patients with previous 10core biopsy.58 Some investigators have proposed that the nding of

Figure 8. A, The mucinous type prostatic intraepithelial neoplasia displays intraluminal mucin (hematoxylin-eosin, original magnication 100). B, Cytologically, the cellular lining is similar to any other high-grade prostatic intraepithelial neoplasia (hematoxylin-eosin, original magnication 400). Figure 9. This core biopsy of the central zone is characterized by abundant stroma between the glands. In the lower half, there is nuclear stratication simulating prostatic intraepithelial neoplasia and the gland above shows acinar formation that is commonly seen in this zone (hematoxylin-eosin, original magnication 100). Arch Pathol Lab MedVol 131, August 2007 Prostatic Intraepithelial NeoplasiaAyala & Ro 1263

Figure 10. Ejaculatory duct and seminal vesicle may simulate prostatic intraepithelial neoplasia. A, In this illustration of an ejaculatory duct, there is a focal collection of cells with hyperchromatic nuclei and a few nucleoli simulating prostatic intraepithelial neoplasia. Keys to diagnose ejaculatory duct include large abnormal nuclei, occasionally including small nucleoli (see left lower aspect of the gland), and the presence of lipofuscin (hematoxylin-eosin, original magnication 200). B, In this illustration there are rare large nuclei and lipofuscin pigment (hematoxylineosin, original magnication 100).

1264 Arch Pathol Lab MedVol 131, August 2007

Prostatic Intraepithelial NeoplasiaAyala & Ro

drug therapy remains a decision that should be arrived at by both the urologist and the patient.
References
1. McNeal JE, Bostwick DG. Intraductal dysplasia: a premalignant lesion of the prostate. Hum Pathol. 1986;17:6471. 2. Allam CK, Bostwick DG, Hayes JA, et al. Interobserver variability in the diagnosis of high grade prostatic intraepithelial neoplasia and adenocarcinoma. Mod Pathol. 1996;9:742751. 3. Kovi J, Mosto FK, Heshmat MY, Enterline JP. Large acinar atypical hyperplasia and carcinoma of the prostate. Cancer. 1988;61:555561. 4. Amin MB, Ro JY, Ayala AG. Prostatic intraepithelial neoplasia: relationship to adenocarcinoma of the prostate. Path Annu. 1994;29:130. 5. Kastendieck H, Altenahr E, Husselmann H. Carcinoma and dysplastic lesions of the prostate. Z Krebsforsch. 1976;88:3354. 6. Helpap B. The biological signicance of atypical hyperplasia of the prostate. Virchows Arch A. 1980;387:307317. 7. Amin MB, Ro JY, Ayala AG. Ideas in pathology: putative precursor lesions of prostatic adenocarcinoma: fact or ction? Mod Pathol. 1993;6:476483. 8. McNeal JE. Morphogenesis of prostate carcinoma. Cancer. 1965;18:1659 1666. 9. McNeal JE. Signicance of duct-acinar dysplasia in prostatic carcinogenesis. Prostate. 1988;13:91102. 10. Bostwick DG, Brawer MK. Prostatic intra-epithelial neoplasia and early invasion in prostate cancer. Cancer. 1987;59:788794. 11. Prostatic intraepithelial neoplasia: signicance and correlation with prostate-specic antigen and transrectal ultrasound. Proceedings of a workshop of the National Prostate Cancer Detection Project; March 13, 1989; Bethesda, Md. Urology. 1989;34:269. 12. Drago JR, Mosto FK, Lee F. Introductory remarks and workshop summary. Urology. 1989;34:23. 13. Bostwick DG, Amin MB, Dundore P, Marsh W, Schultz DS. Architectural patterns of high-grade prostatic intraepithelial neoplasia. Hum Pathol. 1993;24: 298310. 14. Bishara T, Ramnani DM, Epstein JI. High-grade prostatic intraepithelial neoplasia on needle biopsy: risk of cancer on repeat biopsy related to number of involved cores and morphologic pattern. Am J Surg Pathol. 2004;28:629633. 15. Kronz JD, Allan CH, Shaikh AA, Epstein JI. Predicting cancer following a diagnosis of high-grade prostatic intraepithelial neoplasia on needle biopsy: data on men with more than one follow-up biopsy. Am J Surg Pathol. 2001;25:1079 1085. 16. Reyes AO, Swanson PE, Carbone JM, Humphrey PA. Unusual histologic types of high-grade prostatic intraepithelial neoplasia. Am J Surg Pathol. 1997; 21:12151222. 17. Berman DM, Yang J, Epstein JI. Foamy gland high-grade prostatic intraepithelial neoplasia. Am J Surg Pathol. 2000;24:140144. 18. Argani P, Epstein JI. Inverted (Hobnail) high-grade prostatic intraepithelial neoplasia (PIN): report of 15 cases of a previously undescribed pattern of highgrade PIN. Am J Surg Pathol. 2001;25:15341539. 19. Melissari M, Lopez-Beltran A, Mazzucchelli R, Froio E, Bostwick DG, Montironi R. High grade prostatic intraepithelial neoplasia with squamous differentiation. J Clin Pathol. 2006;59:437439. 20. Gaudin PB, Sesterhenn IA, Wojno K, Mosto FK, Epstein JI. Incidence and clinical signicance of high grade prostatic intraepithelial neoplasia in TURP specimens. Urology. 1997;49:558563. 21. Pacelli A, Bostwick DG. Clinical signicance of high-grade prostatic intraepithelial neoplasia in transurethral resection specimens. Urology. 1997;50:355 359. 22. Bostwick DG, Qian J, Frankel K. The incidence of high-grade prostatic intraepithelial neoplasia in needle biopsies. J Urol. 1995;154:17911794. 23. McNeal JE. Origin and development of carcinoma in the prostate. Cancer. 1969;23:2434. 24. Zhou M, Shah R, Shen R, Rubin MA. Basal cell cocktail (34betaE12 p63) improves the detection of prostate basal cells. Am J Surg Pathol. 2003;27: 365371. 25. Abrahams NA, Ormsby AH, Brainard J. Validation of cytokeratin 5/6 as an effective substitute for keratin 903 in the differentiation of benign from malignant glands in prostate needle biopsies. Histopathology. 2002;41:3541. 26. Brawer MK, Peehl DM, Stamey TA, Bostwick DG. Keratin immunoreactivity in the benign and neoplastic human prostate. Cancer Res. 1985;45:3663 3667. 27. Perlman EJ, Epstein JI. Blood group antigen expression in dysplasia and adenocarcinoma of the prostate. Am J Surg Pathol. 1990;14:810818. 28. McNeal JE, Leav I, Alroy J. Differential lectin staining of central and pe-

Figure 12. Cribriform carcinoma simulates prostatic intraepithelial neoplasia and often is difcult to differentiate from high-grade prostatic intraepithelial neoplasia. A, In this illustration, there are several enlarged ductal structures showing a cribriform pattern (hematoxylin-eosin, original magnication 40). B, On higher magnication, the cells are uniform with large nucleoli. Marked expansion and irregularities of the borders of these structures should help to arrive at a diagnosis of cribriform carcinoma. In some cases, this diagnosis cannot be made and often the patients have to undergo another set of biopsies (hematoxylin-eosin, original magnication 100).

HGPIN on saturation biopsies should not mandate an immediate rebiopsy, but rather than that, the patient should be closely followed with serum prostate-specic antigen, digital rectal, and ultrasound examinations.5961 Furthermore, there are currently experimental drug protocols geared to eradicate HGPIN.6264 For now the situation as to which management strategy for a patient with diagnosis of HGPIN should be done, immediate or delayed rebiopsy, close clinical follow-up, or

Figure 11. Transitional cell metaplasia. A, In this low-power view, there is focal tufting arrangement of the cells simulating prostatic intraepithelial neoplasia (hematoxylin-eosin, original magnication 100). B, On high power, the individual cells exhibit oblong-elongated nuclei with characteristic nuclear grooves (hematoxylin-eosin, original magnication 400). C, Transitional cell metaplasia may also be cellular with hyperchromasia, but the elongation of the cells and the grooves are clues for the diagnosis (hematoxylin-eosin, original magnication 200). Arch Pathol Lab MedVol 131, August 2007 Prostatic Intraepithelial NeoplasiaAyala & Ro 1265

ripheral zones of the prostate and alterations in dysplasia. Am J Clin Pathol. 1988; 89:4148. 29. McNeal JE, Alroy J, Leav I, Redwine EA, Freiha FS, Stamey TA. Immunohistochemical evidence for impaired cell differentiation in the premalignant phase of prostate carcinogenesis. Am J Clin Pathol. 1988;90:2332. 30. Wu CL, Yang XJ, Tretiakova M, et al. Analysis of alpha-methylacyl-CoA racemase (P504S) expression in high-grade prostatic intraepithelial neoplasia. Hum Pathol. 2004;35:10081101. 31. Nagle RB, Brawer MK, Kittelson J. Phenotypic relationships of prostatic intraepithelial neoplasia to invasive prostatic carcinoma. Am J Pathol. 1991;138: 119128. 32. Deschenes J, Weidner N. Nucleolar organizer regions (NOR) in hyperplastic and neoplastic prostate disease. Am J Surg Pathol. 1990;14:11481155. 33. Sesterhenn IA, Becker RL, Avallone FA. Image analysis of nucleoli and nucleolar organizer regions in prostatic hyperplasia, intraepithelial neoplasia, and prostatic carcinoma. J Urogenital Pathol. 1991;1:6174. 34. Amin MB, Schultz DS, Zarbo RJ. Computerized static DNA ploidy analysis of prostatic intraepithelial neoplasia. Arch Pathol Lab Med. 1994;118:260264. 35. Weinberg DS, Weidner N. Concordance of DNA content between prostatic intraepithelial neoplasia and concomitant invasive carcinoma: evidence that prostatic intraepithelial neoplasia is a precursor of invasive prostatic carcinoma. Arch Pathol Lab Med. 1993;117:11321137. 36. Emmert-Buck MR, Vocke CD, Pozzatt RO, et al. Allelic loss of chromosome 8p12-21 in microdissected prostatic intraepithelial neoplasia. Cancer Res. 1995; 55:29592962. 37. Macoska JA, Trybus TM, Benson PD, et al. Evidence for three tumor suppressor gene loci on chromosome 8p in human prostate cancer. Cancer Res. 1995;55:53905395. 38. Qian J, Jenkins RB, Bostwick DG. Genetic and chromosomal alterations in prostatic intraepithelial neoplasia and carcinoma detected by uorescence in situ hybridization. Eur Urol. 1999;35:479483. 39. Al-Maghrabi J, Vorobyova L, Toi A, et al. Identication of numerical chromosomal changes detected by interphase uorescence in situ hybridization in high-grade prostate intraepithelial neoplasia as a predictor of carcinoma. Arch Pathol Lab Med. 2002;126:165169. 40. Brawer MK. Prostatic intraepithelial neoplasia: an overview. Rev Urol. 2005;7(suppl 3):S11S18. 41. Epstein JI. Central zone histology. In: Epstein JI, Yang XJ, eds. Prostate Biopsy Interpretation. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002:39. 42. Young RH, Srigley JR, Amin MB, Ulbright TM, Cubilla AL. Histology and zonal variations in histology: the normal prostate gland: classication of tumors and tumors-like lesions. In: Rosai J, Sobin LH, eds. Tumors of the Prostate Gland, Seminal Vesicles, Male Urethra, and Penis. Washington, DC: Armed Forces Institute of Pathology; 2000:914. Atlas of Tumor Pathology; 3rd series, fascicle 28. 43. Troncoso P, Babaian RJ, Ro JY, et al. Prostatic intraepithelial neoplasia and invasive prostatic adenocarcinoma in cystoprostatectomy specimens. Urology. 1989;34:5256. 44. Harvei S, Skjorten FJ, Robsahm TE, Berner A, Tretli S. Is prostatic intraepithelial neoplasia in the transition/central zone a true precursor of cancer? A longterm retrospective study in Norway. Br J Cancer. 1998;78:4649. 45. Kuo T, Gomez LG. Monstrous epithelial cells in human epididymis and seminal vesicles: a pseudomalignant change. Am J Surg Pathol. 1981;5:483490.

46. Arias-Stella J, Takano-Moron J. Atypical epithelial changes in the seminal vesicles. Arch Pathol. 1958;66:761766. 47. Amin MB, Bostwick DG. Pigment in prostatic epithelium and adenocarcinoma: a potential source of diagnostic confusion with seminal vesicular epithelium. Mod Pathol. 1996;9:791795. 48. Leroy X, Ballereau C, Villers A, et al. MUC6 is a marker of seminal vesicleejaculatory duct epithelium and is useful for the differential diagnosis with prostate adenocarcinoma. Am J Surg Pathol. 2003;27:519521. 49. Yantiss RK, Young RH. Transitional cell metaplasia in the prostate gland: a survey of its frequency and features based on 103 consecutive prostatic biopsy specimens. J Urol Pathol. 1997;7:7180. 50. McNeal JE, Yemoto CE. Spread of adenocarcinoma within prostatic ducts and acini: morphologic and clinical correlations. Am J Surg Pathol. 1996;20:802 814. 51. Randolph T, Amin MB, Ro JY. Histologic variants of the prostatic adenocarcinoma and other carcinomas of the prostate. Mod Pathol. 1997;10:612629. 52. Wilcox G, Soh S, Chakraborty S, et al. Patterns of high-grade prostatic intraepithelial neoplasia associated with clinically aggressive prostate cancer. Hum Pathol. 1998;29:11191123. 53. Kronz JD, Shaikh AA, Epstein JI. Atypical cribriform lesions on prostate biopsy. Am J Surg Pathol. 2001;25:147155. 54. Guo CC, Epstein JI. Intraductal carcinoma of the prostate on needle biopsy: histologic features and clinical signicance. Mod Pathol. 2006;19:15281535. 55. Netto GJ, Epstein JI. Widespread high-grade prostatic intraepithelial neoplasia on prostatic needle biopsy: a signicant likelihood of subsequently diagnosed adenocarcinoma. Am J Surg Pathol. 2006;30:11841188. 56. Eskew LA, Bare RL, McCoullogh DL. Systematic 5-region biopsy prostatic biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol. 1997;157:199203. 57. Chen M, Troncoso P, Johnston DA, Tang K, Babaian JR. Optimization of prostate biopsy strategy using computer based analysis. J Urol. 1997;158:2168 2175. 58. Eskicorapci SY, Guliyev F, Islamoglu E, Ergen A, Ozen H. The effect of prior biopsy schema on prostate cancer detection for repeat biopsy population: results of the 14-core prostate biopsy technique [published online ahead of print June 1, 2006]. Int Urol Nephrol. 59. Babaian RJ, Toi A, Kamoi K, et al. A comparative analysis of sextant and an extended 11-core multisite directed biopsy strategy. J Urol. 2000;163:152 157. 60. Leftkowitz GK, Taneja SS, Brown J, Melamed J, Lepor H. Followup interval prostate biopsy 3 years after diagnosis of high-grade prostatic intraepithelial neoplasia is associated with high likelihood of prostate cancer, independent of change in prostatic specic antigen levels. J Urol. 2002;168:14151418. 61. Scattoni V, Montironi R, Mazzuccheli R, et al. Pathological changes of high-grade prostatic intraepithelial neoplasia and prostate cancer after monotherapy with bicalutamide 150 mg. BJU Int. 2006;98:5458. 62. Bono AV, Mazzucchelli R, Ferrari I, et al. Bicalutamide 50mg monotherapy in patients with isolated high-grade PIN: ndings in repeat biopsies at six months [published online ahead of print July 5, 2006]. J Clin Pathol. 63. Taneja SS. Drug therapies for eradicating high-grade prostatic intraepithelial neoplasia in the prevention of prostate cancer. Rev Urol. 2005;7(suppl 3): S19S29. 64. Marshall JR, Sakr W, Wood D, et al. Design and progress of a trial of selenium to prevent prostate cancer among men with high-grade prostatic intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev. 2006;15:14791484.

1266 Arch Pathol Lab MedVol 131, August 2007

Prostatic Intraepithelial NeoplasiaAyala & Ro