—  LONG COURSE #02  —

The Pathology of Prostate Cancer: From Population Studies to the Molecule
Moderators: Dr. John R. Srigley and Dr. Rodolfo Montironi

Section 4 - High-Grade Prostatic Intraepithelial
Neoplasia: 2006

David G. Bostwick, M.D., M.B.A., F.C.A.P.
Medical Director, Bostwick Laboratories
Richmond , Virginia


High-grade prostatic intraepithelial neoplasia (PIN ) is the earliest accepted stage in carcinogenesis, possessing most of the phenotypic, biochemical, and genetic changes of cancer without invasion into the fibromuscular stroma. [1, 2, 3, 4, 5, 6, 7, 8, 9, 10] PIN is defined as an abnormal epithelial proliferation within pre-existing ducts and ductules, with nucleomegaly and nucleolomegaly involving at least 10% of the cells. [11, 12, 13] The term "PIN " is usually used today as a synonym for high grade PIN (formerly PIN 2 and 3 on a 1-3 scale). The high level of interobserver variability and apparent lack of predictive value with low grade PIN limits its clinical utility, [14] and most pathologists do not routinely report this finding except in research studies. Thus, PIN is now used interchangeably with high-grade PIN by most investigators. Interobserver agreement for high grade PIN is "good to excellent". [14, 15, 16] Terms such as dysplasia, malignant transformation, carcinoma in situ, and intraductal carcinoma are discouraged. [17]

Epidemiology of PIN
In the United States, an estimated 1,300,000 prostate biopsies are performed annually and in 2006, 27,350 Americans will die of prostate cancer, and 234,460 new cases will be diagnosed. [18] The mean incidence of isolated high-grade PIN is 9% (range 4–16%) of prostate biopsies, similar to our personal experience in Richmond, Virginia in 2005, representing 115,000 annual new cases of high-grade PIN without cancer diagnosed (Table 1, 2) . [19, 20]

The incidence and extent of PIN increase with patient age (Table 1) . [21, 22, 23, 24] An autopsy study of step-sectioned whole mount prostates from older men showed that the prevalence of PIN in prostates with cancer increased with age, predating the onset of carcinoma by more than five years. [23] A similar study of young men revealed that PIN is first seen in men in their twenties and thirties (9% and 22% frequency, respectively}, and preceded the onset of carcinoma by more than ten years. [23, 25] Most foci of PIN in young men were low grade, with increasing frequency of high grade PIN with advancing age. The volume of high grade PIN also increased with patient age. [21]

Table 1: Prevalence of High-Grade PIN in the United States

 High-grade US population* Number of
Age % PIN (Thousands) PIN
40-49 15.2 20,550 3,123,600
50-59 24.0 14,187 3,404,880
60-69 47.3 9,312 4,404,576
70-79 58.4 6,926 4,044,784
80-89 70.0 2,664 1,864,800
Total 53,639,000 16,842,640

Table 2. Incidence Of Isolated High-Grade Pin In Prostatic Needle Biopsies

Reference Patient Population No. men Incidence of PIN (%)
SCREENING PROGRAMS
Mettlin et al., 1991 [212] American Cancer Society National Prostate Cancer Detection Project 327 5.2
Feneley et al., 1997 [213] Screening population in Gwent, England, 1991-1993 212 19.8
Hoedemaeker et al., 1999 [42] PSA screening study in Rotterdam , Netherlands 1824 0.7
Postma et al., 2004 [170]Screening population in Rotterdam , Netherlands (1st round} 4,117 0.8
Postma et al., 2004 [170] Screening population in Rotterdam , Netherlands (2nd round, performed at a 4-year interval from the 1st round} 1,840 2.5
UROLOGY PRACTICE
Lee et al., 1989 [22] Consecutive biopsies of hypoechoic lesions at St. Joseph Mercy Hospital 256 11
Bostwick et al., 1995 [214] Consecutive biopsies at Mayo Clinic 200 16.5
Bostwick et al., 1995 [214] Consecutive biopsies at Glendale Hospital (CA.} 200 10.5
Langer et al., 1996 [43] Consecutive biopsies at University of Pennsylvania Med. Ctr. 1275 4.4
Wills et al., 1997 [44] Consecutive biopsies at Johns Hopkins Hospital 439 2.7
Feneley et al., 1997 [213] Consecutive biopsies at University College London Hospitals, 1988-1994 1,205 10.9
Feneley et al., 1997 [213] Consecutive biopsies of symptomatic men at St. Bartholomew's Hospital, London, 1993-1994 118 24.6
Skjorten et al., 1997 [45]Consecutive biopsies from 1974-1975 at Ullevaal and Lovisenberg Hospitals, Oslo, Norway 79 7.6
Perachino et al., 1997 [46] Consecutive biopsies 148 14.1
O'dowd et al., 2000 [53] Consecutive biopsies at UroCor Inc., Oklahoma City, 1994-1998. 132,426 3.7
Borboroglu et al., 2001 [164] Consecutive biopsies 1,391 5.5
Lefkowitz et al., 2001 [168] Consecutive biopsies at the Manhattan Veterans Administration Medical Center 619 16.6
San Francisco et al., 2003 [163] Consecutive biopsies 1996-1997 387 12.6
Roscigno et al., 2004 [162]Consecutive biopsies at San Raffaele Hospital, Milan, Italy. 2,314 3.9
Abdel-Khalek et al., 2004 [177] Consecutive biopsies at Urology and Nephrology Ctr, Mansoura University, Mansoura, Egypt, 1997-2002 3,081 2.7
Alsikafi et al., 2001 [175] Consecutive biopsies at Section of Urology, University of Chicago, 1998-1999 485 4.3
Gupta et al., 2004 [215] Consecutive biopsies at St. John Hospital and Medical Ctr, Detroit, 2001-2002 933 12.3
Gupta et al., 2004 [215] Consecutive biopsies at St. John Hospital and Medical Ctr, Detroit, 1998-2000 515 13.5
Kobayashi et al., 2004 [216] Consecutive biopsies at Hamamatsu Rosai Hospital, Hamamatsu, Japan 104 20.2
Naya et al., 2004 [165] Consecutive biopsies at University of Texas M. D. Anderson Cancer Ctr, Houston, 1997-2003 1,086 8.7
Moore et al., 2005 [169] Consecutive biopsies at Albany Medical College and Stratton Veterans Administration Med. Ctr 1998-2003 1,188 2.5
Tunc et al., 2005 [217] Consecutive biopsies at University of Istanbul, Turkey 505 12.8
Girasole et al., 2006 [173] Consecutive biopsies at OUR LabTM 1998 to 2004 40,966 3



Race and geographic location also appear to influence the incidence of high-grade PIN. [6] When specific age groups were compared between races, there were notable differences in the frequency of high-grade PIN. For example, African-American men had a greater prevalence of high-grade PIN than Caucasians in the 50–60 year-old age group, the decade preceding the manifestation of most clinically detected prostate cancers. [26, 27, 28, 29] African-American men also had the highest incidence of prostate cancer (about 50% more than Caucasians). [26, 27, 28, 30, 31] In contrast, Japanese men living in Osaka, Japan, had a significantly lower incidence of high-grade PIN compared to men residing in the United States, and Asians have the lowest clinically detected rate of prostate cancer. [32, 33] Interestingly, Japanese men diagnosed with high-grade PIN also had an increased likelihood of developing prostate cancer, indicating that high-grade PIN is also a precursor of clinical prostate cancer in Asian men. , [34] The differences in the frequency of high-grade PIN in the 50–60 age group across races essentially mirror the rates of clinical prostate cancer observed in the 60–70-year-old age group. [27], [32]

The likely causal association of high-grade PIN with prostatic adenocarcinoma is supported by the observation that the prevalence of both high-grade PIN and cancer increase with patient age and that high-grade PIN precedes the onset of prostate cancer by less than one decade (Table 1). (23,27), [28, 35] The severity and frequency of high-grade PIN in prostates with cancer are greatly increased (73% of 731 specimens) when compared to prostates without cancer (32% of 876 specimens). (21,36,37,38) When high-grade PIN is found on sextant needle biopsy, there is a 50% risk of finding carcinoma on subsequent biopsies within 3 years, [39] although this risk is lower when more than six cores are obtained; this decline in predictive value is expected given the increased sampling for cancer with a greater number of core biopsies.

Incidence of PIN
The incidence of PIN varies according to the population of men under study (Table 2). [40, 41, 42, 43, 44, 45, 46] The lowest likelihood is in men participating in PSA screening and early detection studies, with an incidence of PIN in biopsies ranging from 0.7 to 20%. [40, 41, 42, 43, 44, 45, 46]

Men seen by urologists in practice have PIN in 4.4– 25% of contemporary needle biopsies. Those undergoing transurethral resection have the highest likelihood of PIN, varying from 2.8 to 33% (Table 3). [45, 47, 48] In such cases, all tissue should be examined, but serial sections of suspicious foci are usually not necessary. Unfortunately, needle biopsy specimens fail to show the suspicious focus on deeper levels in about half of cases, often precluding assessment by immunohistochemistry and compounding the diagnostic dilemma.

Table 3. Incidence Of Isolated High Grade Pin In Prostatic Turps

Reference Specimen Patient Population Number of men Incidence of PIN (%)
Gaudin et al., 1997 [47] TURP Consecutive TURPs without cancer at Johns Hopkins Hospital 158 3.2
Pacelli and Bostwick, 1997 [186] TURP Consecutive TURPs without cancer at Mayo Clinic 570 2.8
Skjorten et al., 1997 [45] TURP Consecutive TURPs from 1974-1975 at Ullevaal and Lovisenberg Hospitals, Oslo, Norway 731 33



Diagnostic Criteria of PIN
There are four main patterns of high grade PIN : tufting, micropapillary, cribiform, and flat. (Figures 1-4). [49] The tufting pattern is the most common, present in 97% of cases, although most cases have multiple patterns. There are no known clinically important differences between the architectural patterns, and their recognition appears to be only of diagnostic utility. Sporadic retorspective reports have suggested that the cribriform or micropapillary patterns may indicate higher risk of coexistent cancer, but this has been repeatedly refuted. Other unusual patterns of PIN include the signet ring-cell pattern, small cell neuroendocrine (oat-cell) pattern, mucinous pattern, microvacuolated (foamy-gland) pattern, and inverted (hobnail) pattern (Figures 5-8). [50] The presence of extensive PIN appears to be more predictive of cancer than the more common isolated single acinus with PIN .

There is inversion of the normal orientation of epithelial proliferation with PIN; proliferation in the benign epithelium normally occurs in the basal cell compartment, whereas, in PIN , the greatest proliferation occurs on the luminal surface, similar to pre-invasive lesions in the colon (tubular adenoma) and other sites.

PIN spreads through prostatic ducts in multiple different patterns, similar to prostatic carcinoma. In the first pattern, neoplastic cells replace the normal luminal secretory epithelium, with preservation of the basal cell layer and basement membrane. This pattern often has a cribriform or near-solid appearance. Foci of high grade PIN are usually indistinguishable from intra-ductal/intra-acinar spread of carcinoma by routine light microscopy. [51] In the second pattern, there is direct invasion through the ductal or acinar wall, with disruption of the basement


Section 4 - Figure 1 - Tufting
Section 4 - Figure 2 - Micropapillary

Section 4 - Figure 3 - Cribriform
Section 4 - Figure 4 - Flat

membrane and basal cell layer. In the third pattern, neoplastic cells invaginate between the basal cell layer and columnar secretory cell layer ("pagetoid spread"), a very rare finding.

Early stromal invasion, the earliest evidence of carcinoma, occurs at sites of acinar outpouching and basal cell disruption in acini with high grade PIN. Such microinvasion is present in about 2% of high power microscopic fields of PIN, and is seen with equal frequency in all architectural patterns. [49]

The mean volume of PIN in prostates with cancer is 1.2–1.32 cc, and the volume increases with increasing pathologic stage, Gleason grade, positive surgical margins, and perineural invasion. [21, 52] These findings underscore the close spatial and biologic relationship of PIN and cancer, and may result from an increase in PIN with increasing cancer volume.


Section 4 - Figure 5 - Foamy Cell Pattern
Section 4 - Figure 6 - Small Cell Pattern

Section 4 - Figure 7 - Neuroendocrine Pattern
Section 4 - Figure 8 - Signet Ring-Cell Pattern

PIN and cancer are usually multicentric. [10, 21, 49] PIN is multicentric in 72% of radical prostatectomies with cancer, including 63% of those involving the non-transition zone and 7% of those involving the transition zone; 2% of cases have concomitant single foci in all zones. [21] The peripheral zone of the prostate, the area in which the majority of prostatic carcinomas occur (70% or more), is also the most common location for PIN. [21, 22, 23, 25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 53] Cancer and PIN are frequently multicentric in the peripheral zone, indicating a "field" effect similar to the multicentricity of urothelial carcinoma of the bladder.

High-grade PIN and prostate cancer are morphometrically and phenotypically similar. High-grade PIN occurs primarily in the peripheral zone and is seen in areas that are in continuity with prostate cancer. [7, 21, 29, 38, 54, 55] High-grade PIN and prostate cancer are multifocal and heterogeneous. [21, 56, 57] Increasing rates of aneuploidy and angiogenesis as the grade of PIN progresses are further evidence that high-grade PIN is precancerous [1, 54, 58, 59, 60, 61] Prostate cancer and high-grade PIN also have similar proliferative and apoptotic indices. [1, 3, 32, 62, 63, 64, 65, 66, 67]

It is often difficult with small foci in needle biopsies to separate cancer from suspicious foci (atypical small acinar proliferation suspicious for but not diagnostic of malignancy (ASAP)) when there is coexistent high-grade PIN; the difficulty is based on the inability to separate tangential cutting of the larger pre-existing acini of PIN (that may appear as small separate adjacent acini) from the smaller discrete acini of cancer. In such cases, we prefer the term PIN + ASAP (referring to the coexistence of the two lesions--high-grade PIN and ASAP-- in the same high-power microscopic field) to avoid over-diagnosis of tangential cutting of PIN and cancer.

Recent renewed efforts to introduce the term "intraductal carcinoma" rely on the abandoned concept that dysplasia (defined here as malignancy arising at that specific site within the epithelium) can be separated reliably from intraductal/intra-acinar spread of cancer (defined here as extension of malignant cells through the pre-existing lumens of the prostate); however, this concept was rejected by consensus on multiple occasions owing to lack of reproducible criteria for making this distinction, and the non-committal term intraepithelial neoplasia was internationally adopted and repeatedly reconfirmed as it begs the question of site of origin of the process. Those who persist with the belief that "intraductal carcinoma" can be diagnosed rely on proximity of the epithelial abnormality to invasive cancer, but this criterion is arbitrary and not based on valid objective confirmatory data. More importantly, there is no clinical utility at present that requires separation of dysplasia and intraductal/intra-acinar spread of cancer—the clinical response is the same. It is conceivable that future studies may allow diagnostic separation of dysplasia and intraductal/ intra-acinar spread of cancer; if so, then these steps in the biologic progression of prostate cancer may be shown to have differential predictive value for prostate cancer. We agree that identification of subsets of high-grade PIN that indicate greater risk of cancer is a clinically important area of investigation, but such attempts to date have been fruitless.

Useful Immunohistochemical Markers for the diagnosis of PIN
Select antibodies such as anti-keratin 34βE12 (high molecular weight keratin) or p63 may be used to stain tissue sections for the presence of basal cells, [68] recognizing that PIN retains an intact or fragmented basal cell layer whereas cancer does not.

Monoclonal basal cell-specific antikeratin 34βE12 stains virtually all the normal basal cells of the prostate, with continuous intact circumferential staining in many instances. There is no staining in the secretory and stromal cells. This marker is the most commonly used immunostain for prostatic basal cells, [69, 70, 71] and methods of use with paraffin-embedded sections have been optimized. [72] Keratin 34βE12 is formalin sensitive and requires pretreatment by enzymes or heat if formalin-based fixatives are used. After pepsin predigestion or microwaving, there is progressive loss of immunoreactivity from one week or longer of formalin fixation. Heat-induced epitope retrieval with a hot plate yielded consistent results with no decrease in immunoreactivity with as long as 1 month of formalin fixation. [72] The staining intensity was consistently stronger at all periods of formalin fixation when the hot plate method was used, compared with pepsin predigestion or microwaving. Weak immunoreactivity was rarely observed in cancer cells after hot plate treatment, but not with pepsin predigestion or microwave antigen retrieval. Steam-EDTA in combination with protease significantly enhanced basal cell immunoreactivity compared with protease treatment alone in benign prostatic epithelium. [73] Nonreactive benign acini were always the most peripheral acini in a lobule, a small cluster of outpouched acini furthest from a large duct, or the terminal end of a large duct. [74] More proximal acini had a discontinuous pattern of immunoreactivity. Electron microscopy showed occasional acini with luminal cells abutting the basement membrane, without the interposition of basal cell cytoplasm, and other acini with extremely attenuated basal cell cytoplasmic processes containing sparse bundles of intermediate filaments.

Increasing grades of PIN are associated with progressive disruption of the basal cell layer, according to studies utilizing anti-keratin 34βE12. Basal cell layer disruption is present in 56% of cases of high grade PIN, and is more frequent in acini adjacent to invasive carcinoma than in distant acini. The amount of disruption increases with increasing grades of PIN. Early invasive carcinoma occurs at sites of glandular outpouching and basal cell discontinuity in association with PIN. [12] The cribriform pattern of PIN may be mistaken for the cribriform pattern of adenocarcinoma, and the use of anti-keratin staining is often useful in making this distinction. [75] Cancer cells consistently fail to react with this antibody, although admixed benign acini may be misinterpreted as cancerous staining. Thus, immunohistochemical stains for antikeratin 34βE12 may show the presence or absence of basal cells in a small focus of atypical glands, helping to establish a benign or malignant diagnosis respectively. We believe that this antibody can be employed successfully if one judiciously interprets the results in combination with the light microscopic findings; relying solely on the absence of immunoreactivity (absence of basal cell staining) to render the diagnosis of cancer is without precedent in diagnostic immunohistochemistry and is discouraged. [76] Nonetheless, some studies have noted that the rate of equivocal cases can be reduced considerably, [77] by 68%, [69] or from 5.1 to 1.0% [78] by addition of this immunohistochemical marker. Evaluation of prostate biopsies following therapy such as radiation therapy may be one of the most useful roles for antikeratin 34βE12 (see below). [79]

In addition to PIN and cancer, basal cell layer disruption or loss also occurs in inflamed acini, atypical adenomatous hyperplasia, and postatrophic hyperplasia, and may be misinterpreted as cancer if one relies exclusively on the immunohistochemical profile of a suspicious focus. Furthermore, basal cells of Cowper's glands may not express keratin 34βE12, [80] although this has been disputed. [81] Rare (0.2%) cases of adenocarcinoma have been reported that express keratin 34βE12, including foci of metastatic high-grade adenocarcinoma; these cases did not appear phenotypically to be basal cell/adenoid cystic carcinoma. [82]

Basal cell hyperplasia is a histologic mimic of cancer, and use of anti-keratin 34βE12 is recommended in any equivocal cases that include this lesion in the differential considerations as it is invariably positive in that lesion. [83, 84, 85]

CK5 and CK14 mRNA and protein are expressed in the basal cells of benign acini and PIN, and CK14 mRNA is present in low levels in the luminal cells of the most of some foci of PIN; thus, if PIN is derived from basal cells, as is currently believed, CK14 translation is depressed and a low level of CK14 mRNA may persist. [86] CK8 mRNA and protein were constitutively expressed in all epithelia of normal and abnormal prostate tissues. CK19 mRNA and protein were expressed in both basal and luminal cells of benign acini. CK16 mRNA was expressed in a similar pattern as CK19, but CK16 protein was not detected. [86]

We routinely generate unstained intervening sections of all prostate biopsies for possible future immunohistochemical staining, recognizing that small foci of concern are often lost when the tissue block is recut; one study reported loss of the suspicious focus in 31 of 52 cases. [87]

Other markers of basal cells include proliferation markers, differentiation markers, and genetic markers. The preferential localization of many of these markers in basal cells but not in secretory cells suggests that they play a role in growth regulation. P63 is a recently introduced nuclear marker that may be useful for separating PIN and cancer from benign mimics. Basal cells display immunoreactivity at least focally for keratins 5, 10, 11, 13, 14, 16, and 19; of these, only keratin 19 is also found in secretory cells. [88, 89, 90, 91]­ ­­­­­­­­ Keratins found exclusively in the secretory cells include 7, 8, and 18. Basal cells usually do not display immunoreactivity for prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), and S-100 protein, and only rare single cells stain with chromogranin and neuron-specific enolase. Conversely, the normal secretory luminal cells invariably stain with PSA and PAP. Prostatic basal cells do not usually display myoepithelial differentiation, [90], [92] in contrast with basal cells in the breast, salivary glands, pancreas, and other sites.

A new molecular marker, racemase (alpha-methylacyl-CoA racemase, P504S) was introduced for separating benign and neoplastic acini. This marker has proven useful for evaluation of ASAP (atypical small acinar proliferation suspicious for but diagnostic of cancer) and separation of cancer from hormonally-treated benign acini. Its advantage over anti-keratin 34βE12 is its positive granular cytoplasmic staining in cancer cells, with little or no staining in benign acini. In PIN, monoclonal and polyclonal antibodies to alpha-methylacyl-CoA racemase, P504S were positive in 77% and 91%, respectively, [93] consistent with previously published studies. [94, 95, 96, 97, 98] Since racemase is not specific for prostate cancer and is present in high grade PIN (> 90%), this staining must be interpreted with caution and the diagnosis of PIN or prostate cancer should be rendered only with convincing histologic evidence. [99] The gene for alpha-methylacyl-CoA racemase (AMACR) is greatly overexpressed in prostate cancer cells. Racemase is a well-characterized enzyme that catalyzes the conversion of several (2R)-methyl-branched-chain fatty acyl-CoAs to their (S)-stereoisomers. Analysis of mRNA levels of racemase revealed an average upregulation of nine-fold in prostate cancer. Other reports have substantiated the differential expression of this enzyme protein in benign and cancerous prostate tissues by immunohistochemistry.

Genetic and Molecular Changes
High-grade PIN and prostate cancer share similar genetic alterations. [1, 100, 101, 102, 103] For example, the frequent 8p12–21 allelic loss commonly found in prostate cancer was also found in microdissected PIN. [100] Other examples of genetic changes found in carcinoma that already exist in PIN include loss of heterozygosity (LOH) at 8p22, 12pter-p12, 10q11.2, [26, 100] and gain of chromosomes 7, 8, 10, and 12. [104] Loss of heterozygosity frequencies at 13q (one of the most common chromosomal alterations in high-stage prostate cancer) is 0% vs. 49% in PIN and clinical prostate cancer, respectively. [105] Alterations in oncogene bcl2 expression and RER+ phenotype are similar for PIN and prostate cancer. [106, 107] In summary, these clinical and molecular studies taken together provide strong evidence that high-grade PIN alerts both the clinician and the patient that progression to clinically significant prostate cancer is likely.

PIN is associated with progressive abnormalities of phenotype and genotype, which are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. [108] There is progressive loss of some markers of secretory differentiation, including prostate-specific antigen, prostatic acid phosphatase, secretory proteins, [88] cytoskeletal proteins, [88] glycoproteins such as blood group antigens, neuroendocrine cells, p-cadherin, [109] fibroblast growth factor-2, [110] inhibin, [111] prostate-specific transglutaminase, [112] androgen receptor expression, [113] insulin-like growth factor binding protein-3, [114, 115] and telomerase. [116] A member of the CIP/KIP family of cyclin-dependent kinase inhibitory proteins, p27KIP1, also showed significant reduction in expression in PIN, cancer, and metastatic cancer when compared with benign prostatic epithelium. [117, 118] Other markers show progressive increase, including human glandular kallikrein 2 (hK2), [119, 120] c-erbB-2 (Her-2/neu} and c-erbB-3 oncoproteins, [110, 121] c-met proto-oncogene, bcl-2 oncoprotein, [122, 123] mutator (RER (+)) phenotype, [106] epidermal growth factor and epidermal growth factor receptor, [110] type IV Collagenase, Lewis Y antigen, TGF-alpha, apoptotic bodies, [64, 66, 106, 124] mitotic figures, [64] PCNA expression, Ki-67 expression, MIB-1 expression, [113, 118] tenascin-C, [125] aneuploidy and genetic abnormalities, [113, 126, 127, 128, 129, 130] microvessel density, [131] Ep-Cam transmembrane glycoprotein, [132] insulin-like growth factor binding protein IGFBP-rP1, and p53 mutations, [133] although one group found no p53 expression immunohistochemically in PIN. [134] Prostatic-specific membrane antigen, an abundant transmembrane glycoprotein, shows increased expression in PIN and cancer when compared with benign epithelium, [135, 136] and this expression was unaffected by short-term androgen deprivation therapy. A progressive loss of expression of annexin I, a calcium- and phospholipids-binding protein, in PIN and with the increasing histological grade of prostate cancer may serve as a useful marker of prostate cancer development and progression. [137] Over-expression of Aurora-A (Aurora 2 kinase, STK-15), a protein found in centrosomes, is present in some normal and the majority of high-grade PIN. [138] Estrogen receptor alpha is present in up to 28% of cases of PIN and 43% of cancers, but estrogen receptor beta is absent; [139] prolactin receptor expression is increased in PIN. [140] Promoter methylation of GSTP1 gene is mainly observed in prostate carcinoma and in about 70% of high-grade PIN lesions and may represent an important marker for the transition of in situ to invasive neoplasia. [141]

A model of prostatic carcinogenesis has been proposed based on the morphologic continuum of PIN and the multistep theory of carcinogenesis. [1]

Microvessel Density Is Increased In PIN
PIN is virtually always accompanied by a proliferation of small capillaries in the stroma, despite separation from the underlying vasculature by a basal cell layer and basement membrane. It is likely that PIN initially coopts adjacent vessels, similar to other tumors, and that these vessels soon regress, only to be followed by vigorous angiogenesis at the cancer's edge. A critical balance exists between the proangiogenic vascular endothelial growth factor and the angiogenic antagonist angiopoietin-2. Angiogenin is a polypeptide involved in the formation and establishment of new blood vessels necessary for growth and metastasis of numerous malignant neoplasms, including prostatic cancer. In a recent study, the investigators reported a percentage of cells staining positively for angiogenin in benign prostatic glandular epithelium, high-grade prostatic intraepithelial neoplasia, and prostatic cancer, in 17%, 58%, and 60%, respectively, confirming the potential role that angiogenin plays in neoplastic progression. [142]

Microvessel density is higher in high-grade PIN than in adjacent benign prostatic tissue, and the capillaries are shorter, more widely spaced, have more open lumina and curvaceous external contours, and are lined by a greater number of endothelial cells. The degree of microvessel density in PIN is intermediate between benign epithelium and cancer, lending support to the concept of PIN as the precursor of prostate cancer. Microvessel density is significantly higher in cases with PIN associated with prostate cancer than those with isolated PIN or benign prostatic hyperplasia alone. [131] Inhibition of angiogenesis may be an effective method of chemoprevention, for men at high risk such as those who have high grade PIN. It should be well tolerated in most adults because angiogenesis under typical conditions is needed only for reproduction and wound healing. [58]

Animal Models of PIN and Prostate Cancer
Several different animal models of prostate cancer have demonstrated that high-grade PIN is in the direct causal pathway to prostate cancer. [143] The transgenic mouse model of prostate cancer (TRAMP) has been shown to mimic human prostate cancer. [144, 145] The transgenic mouse model of prostate cancer (TRAMP) has been shown to mimic human prostate cancer. In the TRAMP model, the Probasin promoter-SV40 large T antigen (PB-Tag) transgene is expressed specifically in the epithelial cells of the murine prostate under the control of the probasin promoter. The probasin promoter is androgen-dependent. As a result, this model has several advantages over currently existing models: 1) Mice develop progressive forms of prostatic epithelial hyperplasia and high-grade PIN as early as 10 weeks and invasive prostate adenocarcinoma around 18 weeks of age; [144] 2) The pattern of metastatic spread of prostate cancer mimics that of human prostate cancer with common sites of metastases being lymph node, lung, kidney, adrenal gland and bone; 3) The development as well as the progression of prostate cancer can be followed within a relatively short period of 10–30 weeks; 4) Spontaneous prostate tumors arise with 100% frequency; and 5) Animals may be screened for the presence of the prostate cancer transgene prior to the onset of clinical prostate cancer. Another animal model id the transgenic mouse model that contains a probasin promoter that controls the ECO:R1 gene. This gene product has been implicated in the induction of genomic instability. [146] Prostates from these animals were followed prospectively from 4 to 24 months of age and showed the progressive presence of mild to severe hyperplasia, low-grade PIN, high-grade PIN, and then well-differentiated adenocarcinoma of the prostate. [146] Some investigators demonstrated that transgenic mice that have prostatic overexpression of AR protein develop focal areas of high-grade PIN. [147]

The mechanism of prostate carcinogenesis appears to involve estrogenic signaling. Wang et al. [148] treated wild-type mice with testosterone propionate and estradiol for 4 months. These mice developed prostatic hyperplasia, high-grade PIN, and invasive prostate cancer. When α-ERKO mice, mice that have the ERα genetically knocked out, are treated the same way, they develop prostatic hyperplasia, but not high-grade PIN or invasive prostate cancer. [148] Similarly, a prospective, placebo-controlled study of TRAMP mice treated with an antiestrogen, Acapodene (toremifene) was performed to pharmacologically antagonize ERα. These acapodene-treated TRAMP mice had a reduction in high-grade PIN, significant decrease in prostate cancer incidence, and an increase in animal survival. Thus, estrogenic signally through ERα may play a key role; [20] prostate carcinogenesis and that high-grade PIN was observed to be in the direct causal pathway to prostate cancer.

The dog is the only nonhuman species in which spontaneous prostate cancer occurs, and, like humans, the rate of canine prostate cancer increases with aging. [149, 150, 151, 152, 153] High-grade PIN has been also observed in the prostates of these animals. [150, 151, 152, 153] Canine high-grade PIN shows cytological features identical to the human counterpart, including cell crowding, loss of polarity, and nuclear and nucleolar enlargement. Like prostatic adenocarcinoma, high-grade PIN also increases with aging. [153] High-grade PIN appears to represent an early event in prostate carcinogenesis that occurs with high frequency within the prostates of pet dogs sharing the same environment as humans. In this model, high-grade PIN was determined to be an intermediate step between benign epithelium and invasive carcinoma. Thus, like the transgenic mouse models, the canine model supports high-grade PIN as part of a continuum in the progression of prostate cancer.

Clinical Significance of PIN

PIN Does Not Elevate PSA
Biopsy remains the definitive method for detecting PIN and early invasive cancer. Serum PSA concentration may be elevated in patients with PIN, [154] although these results have been refuted. [155], [156] There is a poor correlation of PIN and PSA density according to studies of radical prostatectomy specimens and preoperative serum. [156] Mean PSA increased from 8.4 to 11.6 ng/mL in patients with PIN who developed cancer within two years; those with PIN who did not develop cancer during this interval had an increase in PSA from 4.8 to 5.9 ng/mL or decrease from 5.1 to 4.6 ng/mL; however, these findings have not been confirmed.

The ratio of free to total PSA is the same for patients with high-grade PIN and cancer, unlike low grade PIN and hyperplasia, although this has also been refuted. Many patients in these studies were later found to have cancer, so the elevation in serum PSA concentration and its derivatives may have resulted from the undetected cancer.

Transrectal Ultrasound Cannot Detect PIN
By transrectal ultrasound, PIN may be hypoechoic like carcinoma, although these findings have not been confirmed. [22, 157] Today, most urologists and radiologists do not believe that PIN is detectable by transrectal ultrasound because PIN is a microscopic finding which is below the detection threshold for this form of imaging.

Men with PIN Develop Prostate Cancer
As a risk factor, the presence of isolated PIN in a set of sextant needle biopsies connotes a risk ratio of 14.9. PIN is a far stronger predictor for subsequent cancer than the independent predictors of patient age (>65 years old vs. ≤ 65 years old) and serum prostate specific antigen (PSA) (>4 ng/ml vs. ≤ 4 ng/ml); for these, the respective risk ratios are 3.5 and 3.64. [158] PIN coexists with cancer in more than 85% of cases, according to studies employing whole-mounted totally embedded prostates. In one report, the likelihood of finding cancer increased with the biopsy time interval. The investigators reported a 32% incidence of cancer if repeat biopsy was performed within 1 year, compared with a 38% incidence in biopsies obtained after 1 year. [158] Other series have also found a high predictive value of PIN for cancer, although recent reports based on obtaining a greater number of cores shows a lower predictive value (Table 4). [43, 53, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183] These data underscore the strong association of PIN and adenocarcinoma and indicate that vigorous diagnostic follow up is needed.

Multiple factors account for the decline in the predictive accuracy of high-grade PIN for cancer. The main factor is use of extended biopsy techniques that result in more thorough prostate sampling and in higher cancer detection rates; thus, there is a smaller pool of patients with an isolated diagnose of PIN. Another factor is the lower detection rate for, and difficulty in the detection of, the remaining small cancers; larger significant tumors may also escape detection. These factors lead to a higher frequency of negative repeat biopsies. These results may reflect a new steady state and a newly reached low plateau in the predictive accuracy of these markers. In a recent report, the investigators demonstrated that with 6 core biopsies for both the initial and re-biopsy the risk of cancer was 14.1% compared to 31.9% in the group that had 8 core or more biopsy on followup with an initial 6 core biopsy. They found that the risk of cancer on biopsy within 1 year following a diagnosis of PIN (13.3%) is relatively low if good sampling (8 or more cores) is initially performed. [180]

Table 4. Cancer Detection In Patients With High Grade

Publication Date Study Dates Cores Reference No. of Subjects With Repeat Biopsy (ies) PIN cases With PCa at Follow-Up (%)
1995 1987-1993 1-8 Davidson [158] 100 35
1996 1990-1994 NS Raviv [160] 48 48
1996 1991-1993 F Langer [43] 53 27
1996 Not stated 4 Shepherd [161] 66 47
2000 1995-1998 Mixed Kamoi [174] 45 22
2000 1994-1998 Mixed O'dowd [53] 1,306 23
2001 1991-1998 NS Kronz [159] 245 32
2001 1998-1999 NS Alsikafi [175] 21 14
2001 Not stated 6 Maatman [176] 86 16
2001 1995-2000 6 Borboroglu [164] 45 44
2001 1999-2001 12 Lefkowitz [168]43 2
2002 1995-2002 10-12 Roscigno [162] 47 45
2003 1996-1997 EXT San Francisco [163] 47 24
2003 2001-2003 6 Goeman [166] 63 27
2004 1997-2003 EXT Naya [165] 47 11
2004 1999-2002 4-15 Bishara [167] 132 29
2004 Not stated 20 Rabets [183] 38 18
2004 1997-2002 11 Abdel-Khalek [177] 83 36
2004 2000-2003 6 Postma [170] 101 13
2005 1998-2003 EXT Moore [169] 22 5
2005 2000-2002 6-18 Schlesinger [171] 204 23
2005 1996-2000 6 Gokden [172] 190 30
2005 1998-2003 6 or EXT El-Fakharany [178] 585 25
2005 2001-2003 NS Leite [179] 142 13
2006 1997-2001 Mixed Herawi [180] 332 21
2006 1997-2001 Mixed Herawi [180] 323 13
2006 1998-2004 2-4 Girasole CR [173]358 22
2006 1999-2004 6 Hussein [181] 17 41
2006 1999-2005 12 Keith [182] 48 31

EXT, extended in all cases (>8); F, fewer than sextant; NS, not specified; PCa, prostate cancer.



Another plausible explanation regarding those results may be related to the fact that backward probability is usually based on retrospective evidence, whereas forward probability is usually based on prospective evidence; consequently, backward probability is often easier to determine. Many researchers do not distinguish between these two probabilities, falsely concluding that the probability of a risk factor in patients with the disease is the probability of the disease occurring in people with the risk factor. The use of backward probability as a substitute for forward probability is a common fallacy in medical practice and may result in false attribution of causation. [184]

High-grade PIN in transurethral resection specimens is also an important predictive factor for prostate cancer. [47, 185, 186] Among 14 patients with PIN and BPH followed for up to 7 years (mean, 5.9 years), three (21.4%) developed prostatic cancer. [186] Mean serum PSA concentration was higher than in those who did not develop cancer (8.1 vs 4.6 ng/ml, respectively). All subsequent cancers apparently arose in the peripheral zone and were detected by needle biopsy. Thus, all tissue should be submitted by the pathologist for examination when high-grade PIN is found in TURP specimens. The high predictive value of PIN for the development of subsequent cancer warrants reporting the presence of PIN in TURP specimens, according to the Cancer Committee of the College of American Pathologists. Conversely, a study showed that PIN in the transition zone and central zone from Norwegian men is not predictive of subsequent cancer development. [185]

As the significance of PIN in initial biopsies as a marker of prostate cancer in repeat biopsies has been extensively investigated (see Table 4), little is known of the actual rate of cancer in the whole prostate in this setting because repeat biopsies may miss the area of cancer. Some investigators aimed to define a more precise positive predictive value of isolated PIN in initial biopsies in predicting cancer in the prostate gland and found that clinically significant prostate cancer were associated with 4 out of 11 biopsies positive for PIN as compared with 3 out of 21 biopsies negative for PIN. The positive predictive value of PIN was 64%, with a sensitivity of 28% and a specificity of 81%. [187]

Androgen Deprivation Therapy Eliminates PIN
There is a marked decrease in the prevalence and extent of high-grade PIN in cases after androgen deprivation therapy when compared with untreated cases. [188, 189, 190] This decrease is accompanied by epithelial hyperplasia, cytoplasmic clearing, and prominent glandular atrophy, with decreased ratio of glands to stroma. These findings indicate that the dysplastic prostatic epithelium is hormone dependent. In the normal prostatic epithelium, luminal secretory cells are more sensitive to the absence of androgen than basal cells, and these results indicate that the cells of high-grade PIN share this androgen sensitivity. The loss of some normal, hyperplastic, and dysplastic epithelial cells with androgen deprivation is probably due to acceleration of programmed single cell death. A report suggested that PIN is not substantially decreased after hormonal therapy, but those authors failed to use current criteria for PIN, so the results are not comparable. [191]

Neoadjuvant hormone deprivation with monthly leuprolide and flutamide 250mg p.o. t.i.d. for three months resulted in a 50% reduction in high-grade PIN. Longer therapy with 6 months of neoadjuvant androgen deprivation therapy prior to radical prostatectomy in the European Randomized Study of Screening for Prostate Cancer (ERSPC) study reduced high-grade PIN even more. [39] Flutamide decreased the prevalence and extent of high-grade PIN and induced epithelial atrophy. [192] There is also evidence that cessation of flutamide resulted in return of high-grade PIN. [193, 194]

The results of 5-alpha-reductase (finasteride) treatment in high-grade PIN are controversial and the cumulative number of cases studied is probably too small to draw firm conclusions. [195] Two reports found no apparent effect on the histologic appearance or extent of high-grade PIN, [196, 197] whereas a third study of three cases described atrophy and involution with decreased prevalence. [198]

Radiation Therapy Eliminates PIN
The prevalence and extent of PIN is decreased after radiation therapy. [199, 200, 201] However, one study paradoxically noted a higher incidence (70%) of PIN after radiation therapy than expected, [200] but they failed to employ accepted diagnostic criteria for PIN, so their results are not comparable with others. A report from Memorial Sloan-Kettering found PIN in 8.8% of biopsies following a course of 3-dimensional external beam conformal radiation therapy. [201]

Following radiation therapy, PIN retains the features characteristic of untreated PIN, and is readily recognized in tissue specimens. The key pathologic features include nuclear crowding, nuclear overlapping and stratification, nuclear hyperchromasia, and prominent nucleoli. The basal cell layer is present, but often fragmented; racemase shows strong apical to diffuse cytoplasmic staining. [202]The most common patterns of PIN are tufting and micropapillary, similar to those reported in untreated PIN.

The long-term efficacy of radiation treatment may depend on eradication of cancer as well as pre-cancerous lesions that may otherwise lead to evolution of secondary metachronous invasive cancers. Identification of residual or recurrent cancer portends a worse prognosis. The questions remain whether recurrent cancer after irradiation is due to regrowth of incompletely eradicated tumor or progression from incompletely eradicated PIN. Further studies of salvage prostatectomy specimens and post-RT needle biopsies are justified in an attempt to establish the significance of high-grade PIN as a source of long-term treatment failure among these patients. If PIN is associated with treatment failure, adjuvant chemoprevention strategies that ablate this lesion may reduce the risk of late cancer recurrence.

Should Men with High Grade PIN Be Treated?
The clinical importance of recognizing PIN is based on its strong association with prostatic carcinoma. PIN has a high predictive value as a marker for adenocarcinoma, so its identification in biopsy specimens warrants further search for concurrent invasive carcinoma. If all procedures fail to identify coexistent carcinoma, close surveillance and follow-up are indicated. As high-grade PIN progresses, the likelihood of basal cell layer disruption increases, very much like what is observed for carcinoma in situ (CIS) of the urinary bladder. CIS of the urinary bladder, like PIN, may become invasive and is treated aggressively. The standard of care for management of CIS of the bladder is intravesical instillation of chemotherapy or BCG, and, in some cases, radical cystectomy.

Follow-up biopsy is suggested for patients with PIN at three to six month intervals for two years, and thereafter at twelve-month intervals for life. [158, 203] Some urologists perform "saturation" biopsies, consisting of more than 12–15 biopsies in one session, often with brief general anesthesia in the operating theatre, in an effort to definitively exclude cancer. Most authors agree that the identification of PIN in the prostate should not influence or dictate therapeutic decisions. [203] We are aware of 21 radical prostatectomies that were purposely (3 cases) or inadvertently performed (18 cases) in patients whose biopsies contained only high grade PIN; all but two of the cases contained adenocarcinoma in the surgical specimen (DG Bostwick, personal communication, 2003).

Currently, routine treatment is not available for patients who have high-grade PIN. Prophylactic radical prostatectomy or radiation is not an acceptable treatment for patients who have high-grade PIN only. [204] The development and identification of acceptable agents to treat high-grade PIN would fill a therapeutic void. As noted above, androgen deprivation therapy and radiation therapy induce acinar atrophy and apoptosis that result in regression of high-grade PIN. [63, 188, 189, 190, 198], [204, 205, 206]

Chronic therapy, however, would most likely be required to prevent new high-grade PIN lesions from invading and becoming clinical prostate cancer. Although more toxicity is likely to be tolerated for the treatment agents targeted to regress or inhibit high-grade PIN, as compared to treating healthy patients to reduce prostate cancer incidence, androgen deprivation therapy has too many adverse effects in men to be clinically useful. New agents with better safety and lower side effect profile are greatly needed since patients may be taking the agent at least until they attain 70 years of age. [204] Toremifene (AcapodeneTM) is a selective estrogen receptor modulator that eliminates high-grade PIN and reduces the incidence of prostate cancer. After 4 months of toremifene (60 mg/day orally for 4 months), 72% of men treated (vs. 17.9% of controls) had no high-grade PIN on subsequent prostate biopsies. [207] In another study, cumulative risk of prostate cancer was reduced in patients taking toremifene 20 mg compared with placebo (24.4% vs. 31.2%) with an annualized rate of prevention of 6.8 cancers per 100 men treated. [208] Among patients with no biopsy evidence of cancer at baseline and 6 months, the 12-month incidence of prostate cancer was reduced by 48.2% with toremifene 20 mg compared with placebo (9.1% vs. 17.4%). The 20-mg dose was most effective, but the cumulative and 12-month incidences of prostate cancer were lower with each toremifene dose versus placebo (cumulative risk: 29.2% for 40 mg, 28.1% for 60 mg; 12-month incidence 14.3% for 40 mg, 13.0% for 60 mg). [208]

Green tea catechins (GTCs) also may reduce the incidence of prostate cancer. Catechins are antioxidants in the class of polyphenols called flavonols. After 6 months of green tea catechins (600 mg/day orally), 3.3% of the men with PIN had cancer compared with 30% of those who took placebo. Selenium and Vitamin E are also under investigation as putative chemopreventive agents.

PIN offers promise as an intermediate endpoint in studies of chemoprevention of prostatic carcinoma. Recognizing the slow growth rate of prostate cancer and the considerable amount of time needed in animal and human studies for adequate follow-up, the non-invasive precursor lesion PIN is a suitable intermediate histologic marker to indicate subsequent likelihood of cancer.

PIN Does Not Predict Cancer Recurrence
PIN was not predictive of PSA (biochemical) failure at 32 months in patients undergoing radical prostatectomy and androgen deprivation therapy. [188]


Section 4 - Figure 9 - Atypical Basal Cell Hyperplasia
Section 4 - Figure 10 - Cribriform Hyperplasia

Section 4 - Figure 11 - Radiation Changes
Section 4 - Figure 12 - Ductal Adenocarcinoma

Differential Diagnosis of PIN
The histologic differential diagnosis of PIN includes lobular atrophy, post-atrophic hyperplasia, atypical basal cell hyperplasia (Figure 9), cribriform hyperplasia (Figure 10), and metaplastic changes associated with radiation (Figure 11), infarction, and prostatitis (Table 5). Many of these display architectural and cytologic atypia, including enlarged nucleoli, and small specimens, and cauterized or distorted specimen. Cribriform adenocarcinoma, ductal (endometrioid) carcinoma, and urothelial carcinoma involving prostatic ducts and acini may also be confused with PIN (Figure 12). Biopsies submitted with incomplete patient history should be interpreted with caution. In one study, the authors reported that the proliferative activity, defined as Ki-67 labeling index, was higher in ductal carcinoma than in PIN (33% vs. 6%).(209) Stratified epithelium in non-cribriform glands of prostate cancer can also resemble high grade PIN. Recognition of this fact and immunohistochemical evaluation of stratified glands may be indicated to correctly diagnose those glands as prostate cancer. [210]

PIN may be overdiagnosed as adenocarcinoma. Our retrospective review of transurethral resections from the Mayo Clinic files between 1960 and 1970 revealed that PIN was often diagnosed as adenocarcinoma. [211] Similarly, fine needle aspiration of the prostate may yield cell clusters of PIN that are overdiagnosed as cancer; this issue is critically important to consider in evaluating studies from Sweden and other countries that have, perhaps erroneously, relied on fine needle aspiration diagnoses for patients treated with watchful waiting (expectant management).

Table 5
Mimics of high-grade PIN (overdiagnosis of PIN) in 60 consecutive cases
(Bostwick DG, Ma J. In press, 2006)
Mimic of PIN Number of Cases (%)
Basal cell hyperplasia 12 (20%)
Benign proliferative epithelium (non-central zone) 10 (17%)
Low-grade PIN 10 (17%)
Reactive changes 10 (17%)
Atypical basal cell hyperplasia 7 (12%)
Central zone epithelium 5 (8%)
Urothelium 2 (3%)
Seminal vesicle 1 (2%)
Cribriform hyperplasia 1 (2%)
Post-atrophic hyperplasia 1 (2%)
Atrophy 1 (2%)

Conclusion
High grade PIN is the most likely precursor of prostatic adenocarcinoma, according to virtually all available evidence. PIN is associated with progressive abnormalities of phenotype and genotype, which are intermediate between normal prostatic epithelium and cancer, indicating impairment of cell differentiation and regulatory control with advancing stages of prostatic carcinogenesis. There is progressive loss of some markers of secretory differentiation, whereas other markers show progressive increase.

The clinical importance of recognizing PIN is based on its strong association with prostatic carcinoma. PIN has a high predictive value as a marker for adenocarcinoma, and its identification in biopsy specimens of the prostate warrants further search for concurrent invasive carcinoma. Studies to date have not determined whether PIN remains stable, regresses, or progresses, although the implication is that it can progress.

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