Analysis of alpha-methylacyl-CoA racemase (P504S) expression in high-grade prostatic intraepithelial neoplasia

Alpha-methylacyl-CoA racemase (AMACR), also known as P504S, is a recently identified molecular marker for prostate cancer. The expression of AMACR/P504S has also been observed in high-grade prostatic intraepithelial neoplasia (PIN), a precursor lesion of prostate cancer. However, a detailed study focusing on the analysis of AMACR/P504S expression in high-grade PIN has not been performed. In this study, we analyzed AMACR/P504S expression by immunohistochemistry in 3954 prostatic ducts and acini with high-grade PIN from 140 prostatectomy specimens. AMACR/P504S immunoreactivity was measured as negative (0), weakly positive (+1), moderately positive (+2), and strongly positive (+3). AMACR/P504S immunoreactivity was detected in 90.0% (126/140) of high-grade PIN cases, although only 41.5% (1642/3954) of prostatic glands involved by PIN showed AMACR/P504S immunoreactivity. A significantly higher AMACR/P504S-positive rate (56.0%) was found in isolated high-grade PIN glands adjacent to cancer (distance less than 5 mm) compared with those away from cancer (distance more than 5 mm; 14%, P < 0.0001). High-grade PIN glands adjacent to cancer also showed a higher (P < 0.0004) AMACR/P504S intensity (1.62) than did those away from cancer (1.11). Our results suggest that PIN strongly positive for AMACR/P504S might be more closely associated with cancer than PIN negative or weakly positive for AMACR/P504S. This study provides additional evidence to link high-grade PIN as a precursor lesion to prostatic adenocarcinoma.     

Alpha-methylacyl-CoA racemase (AMACR/P504S) can distinguish hepatocellular carcinoma and dysplastic hepatocytes from benign nondysplastic hepatocytes.

Immunohistochemical staining with alpha-methylacyl-CoA racemase AMACR (P504S) has been described in a number of normal tissues and was found to be useful for detecting malignancies including hepatocellular carcinoma (HCC). Our aim was to determine whether AMACR is differentially expressed in benign nondysplastic liver tissue, hepatocellular dysplasia, and HCC. The study material consisted of paraffin blocks containing primary HCC and surrounding liver tissue from 20 patients who underwent hepatectomy at the time of liver transplantation. Immunohistochemical stains were performed with anti-AMACR by standard methods. Staining features were characterized on the basis of the pattern and distribution of reactivity. A positive AMACR immunostain was defined as either finely stippled or coarsely granular in pattern, in a diffuse or parabasal cytoplasmic distribution. A negative AMACR immunostain was defined as absence of reactivity. Anti-AMACR immunostains were positive in malignant, dysplastic, and benign nondyplastic hepatocytes in all cases. The staining pattern was the same in malignant and dysplastic hepatocytes. It consisted of coarsely granular reactivity in a parabasal or diffuse cytoplasmic distribution. In contrast, benign nondysplastic hepatocytes were distinguished by weak, finely stippled diffuse cytoplasmic staining. Malignant and dysplastic hepatocytes showed an identical pattern of immunostaining for AMACR that was distinct from benign hepatocytes. Prospective studies are needed to determine whether staining for AMACR can distinguish HCC or dysplasia in cytologic and small histologic specimens.     

Alpha-methylacyl-CoA racemase (P504S)/34betaE12/p63 triple cocktail stain in prostatic adenocarcinoma after hormonal therapy

Alpha-methylacyl-CoA racemase (AMACR) has recently been shown to be a highly sensitive marker for the diagnosis of prostate cancer. However, there is limited information concerning its utility as a marker for prostate carcinoma after hormonal therapy. Our current investigation was conducted to evaluate the expression of AMACR in patients with prostate carcinoma after hormonal therapy and assess its diagnostic utility in combination with p63 and high molecular weight cytokeratin (34betaE12) staining. Prostate tissues from 49 patients who had been treated with hormonal therapy were immunohistochemically analyzed for AMACR, 34betaE12, and p63 expression by a triple antibody cocktail stain. The staining intensities and the percentages of positively staining tumor cells were recorded. The correlations between AMACR expression and metastatic status, associated hormonal therapy regimens, and the extent of hormone therapy effect were analyzed. All malignant acini were completely negative for both basal cell markers (34betaE12 and p63). Tumor cells failed to demonstrate expression of AMACR in 14 (29%) of 49 cases. In the remaining 35 cases (71%), positive immunostaining for AMACR was noted, but with variable intensities and percentages of cells stained. Positive staining for AMACR in benign glands was not seen in any case. In all cases, basal cells were strongly stained by p63 in benign acini with a mean positive percentage of 96%. Similarly, basal cells in benign acini displayed moderate staining intensities for 34betaE12 in 3 (7%) of 41 cases and strong immunostaining for this marker in the remaining 38 cases (93%); the mean percentage of positive cells was 92%. alpha-methylacyl-CoA racemase expression may be substantially diminished or entirely lost in prostate carcinoma after hormonal therapy. This variation in AMACR expression does not correlate with the metastatic status, the modality of hormonal therapy, or the extent of therapy-related effect. It is important that pathologists be aware that some hormonally treated prostate carcinomas do not express AMACR, and that immunostaining in such cases must be interpreted with caution. A triple cocktail stain using AMACR, 34betaE12, and p63 can be helpful in evaluating prostate specimens for the presence of residual or recurrent carcinoma after hormonal therapy for cancer.     

Alpha-methylacyl-CoA racemase (AMACR/P504S) protein expression in urothelial carcinoma of the upper urinary tract correlates with tumour progression

Alpha-methylacyl-CoA racemase (AMACR/P504S) is a useful biomarker of prostate cancer. We evaluated the expression of AMACR in upper urinary tract urothelial carcinomas with respect to associations with tumour stage, grade and metastasis-free survival. A total of 268 tumours were investigated immunohistochemically using a tissue microarray technique. AMACR expression was noted in 127 of 261 (48.7%) evaluated tumours and was associated with high tumour stage [58 of 139 (41.7%) pTa/pT1 vs. 69 of 122 (56.6%) pT2–pT4, P=0.019] and high tumour grade [44 of 137 (32.1%) low vs. 83 of 124 (66.9%) high grade, P<0.001]. In addition, AMACR expression was associated with the presence of tumour necrosis (P<0.001) and marked stromal desmoplasia (P=0.0026). This correlation indicates that increased AMACR expression might be related to hypoxia-induced changes in cancer cell metabolism, such as increased dependence on fatty acid oxidation for energy generation. Progressive disease was observed in 73 of 183 (39.9%) patients with solitary invasive carcinomas and was associated with AMACR expression (P=0.017). Multivariate analysis, however, proved only pT-stage >1 (P<0.001) and high tumour grade (P<0.001) to be independent predictors of patient outcome. In conclusion, AMACR expression correlated with advanced tumour stage and grade and may serve as an additional prognostic indicator in upper urinary tract urothelial cancer.     

Alpha-methylacyl-CoA racemase/P504S overexpression in colorectal carcinoma is correlated with tumor differentiation.

Alpha-methylacyl-CoA racemase (AMACR)/P504S is an enzyme involved in the metabolism of branched-chain fatty acids. Little is known about correlation of AMACR expression with colorectal carcinoma (CRC) differentiation and prognosis. We investigated the expression of AMACR in 106 cases of primary CRC, and in 47 lymph nodes with metastatic CRC by immunohistochemical analysis. These cases were divided into 3 groups according to the histologic differentiation of the primary tumors. group A included 50 cases of histologically well and moderately differentiated CRCs, 20 of these with lymph node metastasis; group B included 23 cases of well and moderately differentiated CRCs, histologically similar to group A, except these tumors had small foci (less than 20%) of high-grade carcinoma, and 10 of these had lymph node metastasis; group C included 33 cases of poorly differentiated adenocarcinoma and undifferentiated carcinoma, 17 with lymph node metastasis. The results showed the overall positive rates of expression in primary and metastatic CRCs were 59.4% and 46.8%, respectively. Expression in groups A (76.0%) and B (69.6%) was much higher than that in group C (27.3%). In group B, although overexpression of AMACR in primary tumors was similar to that of group A, it was only seen in 30.0% of group B metastatic tumors, which was similar to the rate of expression in group C (23.5%). In contrast, rates of expression in group A primary and metastatic tumors were similar (80.0% and 75.0%). Positive staining for AMACR in benign epithelium adjacent to tumor was rare (<2%). No relation was found between AMACR expression and overall survival. Our findings support the view that the expression of AMACR in CRC is correlated with tumor differentiation.     

Alpha-methylacyl-CoA racemase (AMACR) expression in epithelial ovarian cancer

Alpha-methylacyl-CoA racemase (AMACR) is involved in the cellular metabolism of fatty acids. It is a prognostic factor in prostate and colorectal cancer. So far, little is known about its expression and prognostic role in ovarian cancer. We investigated the expression of AMACR in a total of 420 ovarian tumors (388 carcinomas, 32 borderline tumors) by immunohistochemistry on tissue microarrays of two independent patient cohorts. In both cohorts, cytoplasmic AMACR expression was identified in 11.8% (16/136) and 5.4% (13/239), respectively, of the ovarian carcinomas. In contrast, borderline tumors did not show any AMACR expression. AMACR expression was significantly associated with histological subtype, FIGO stage, and grade in one cohort and low estrogen receptor levels in the other cohort. In univariate analysis, AMACR expression was significantly associated with poor overall survival (log rank, p = 0.006) and an independent prognostic factor in a multivariate analysis (HR 3.3; CI 1.3–7.9; p = 0.008) but could not be verified in the second cohort. Unlike in other tumor entities, AMACR expression does not seem to have an unequivocal prognostic impact in ovarian cancer. The prevalence may limit the value of AMACR for the differential diagnosis between metastatic colorectal carcinomas and primary ovarian carcinomas, whereas the association with estrogen receptor expression deserves further studies.     

Diagnostic utility of alpha-methylacyl CoA racemase (P504S) on prostate needle biopsy

Alpha-methylacyl CoA racemase (AMACR), also known as P504S, was identified by the analysis of cDNA library subtraction in conjunction with high throughput microarray screening from prostate tissue and has been proven to be one of the very few biomarkers that can distinguish cancer from benign cells with high sensitivity and specificity for prostate carcinoma. It is a successful example of the translation of molecular findings into clinical practice. This review focuses on the study of AMACR (P504S) expression in small focal prostate cancer and atypical small acinar proliferation (ASAP) on needle biopsies and emphasizes the utility of AMACR (P504S) in routine surgical pathology practice. We also discuss the potential pitfalls and caveats in the interpretation of immunostaining results.     

Discovery and clinical application of a novel prostate cancer marker: alpha-methylacyl CoA racemase (P504S)

The recent discovery of the overexpression of P504S/alpha-methylacyl coenzyme A racemase (AMACR) in prostate cancer is a successful example of translating an advanced molecular finding into clinical practice. AMACR (P504S) has been proven to be one of the few biomarkers that can help distinguish cancer from benign cells, with high sensitivity and specificity for prostate carcinoma. It is the first gene identified by the analysis of complementary DNA microarray profiles from prostate tissue to be used as a tissue tumor marker in clinical practice and to improve the diagnosis of prostate cancer. This review focuses on the study of AMACR (P504S) expression in prostate cancer, premalignant lesions, benign prostate tissues, and other normal and malignant tissues and a discussion of its clinical usefulness. We emphasize the interpretation of the AMACR immunohistochemical results in routine surgical pathology practice and also discuss the potential future applications of this marker and the possible role of AMACR in the pathogenesis of cancer development.     

Comparison of monoclonal antibody (P504S) and polyclonal antibody to alpha methylacyl-CoA racemase (AMACR) in the work-up of prostate cancer

AIM: Studies using a monoclonal (P504S) and a polyclonal antibody (p-AMACR) to alpha-methylacyl-CoA racemase (AMACR) have shown variable expression in prostate cancer (PCa). The goal is to compare the sensitivity of both antibodies in PCa and evaluate their utility in the work-up of atypical prostate needle biopsies (NBXs). METHODS AND RESULTS: A tissue microarray (TMA) with 248 samples of benign prostate, high-grade prostatic intraepithelial neoplasia (HGPIN) and PCa samples, 20 NBXs with minute PCa and 32 NBXs with 'atypical' foci were stained with P504S and p-AMACR. Ninety percent of PCa (76/76 TMA, 16/20 NBXs) showed predominantly strong p-AMACR expression while 87% (65/69 TMA, 16/20 NBXs) showed variable P504S expression (sensitivity 90% versus 87%, P = 0.10). In HGPIN, P504S and p-AMACR were positive in 77% and 91% of samples, respectively. In the 'atypical' NBXs group, 53% were classified as PCa, 12% benign and 35% atypical, suspicious for PCa, after review of the basal marker. Of atypical, suspicious for PCa, P504S/p-AMACR helped convert the diagnosis to PCa in 5/11 (45%) cases, where, despite negative basal cell markers, morphology was less than optimal. CONCLUSIONS: Differences between P504S and p-AMACR appear marginal and clinically insignificant. AMACR is negative in a subset of unequivocal minute PCa with both antibodies. However, when utilized in proper context, AMACR may offer significant advantage in converting an 'atypical' diagnosis to PCa where morphology and basal markers are less than optimal in resolving the diagnosis.     

Paneth cell-like change in benign prostate can account for P504S (AMACR) reactivity

Paneth cell-like neuroendocrine metaplasia of benign and cancerous prostate was described in 1992. Here, we note that P504S (AMACR), the cytoplasmic marker for prostate cancer used alone or in concert with basal cell markers, can be strongly reactive in benign prostatic acini with Paneth cell-like change.     

Alpha-methylacyl CoA racemase (P504S): overview and potential uses in diagnostic pathology as applied to prostate needle biopsies

The diagnosis of prostatic adenocarcinoma remains dependent on the recognition of basic haematoxylin and eosin criteria. The discovery of alpha-methylacyl CoA racemase/P504S (AMACR/P504S) overexpression in prostate cancer represents a triumph of high throughput microarray technology, and is a powerful demonstration of how this methodology can be used to facilitate the rapid development of diagnostically relevant antibodies. Immunohistochemistry with anti-AMACR/P504S is useful for detecting prostate cancer in the full range of prostate specimens encountered in surgical pathology, be they needle biopsies, transurethral resection of prostate chips, or prostatectomies. In particular, studies to date with AMACR/P504S clearly demonstrate the ability of this marker to support a diagnosis of malignancy in prostate needle biopsies. This is particularly true when it is combined with negative staining for a basal cell marker, such as 34betaE12 or p63. Although it has limitations with respect to sensitivity and specificity, AMACR/P504S will no doubt become a standard adjunctive stain used by pathologists seeking to reach a definitive diagnosis in prostate biopsies considered to be atypical, but not diagnostic of malignancy on haematoxylin and eosin sections alone.     

α-甲酰基辅酶A消旋酶在前列腺腺癌诊断和鉴别诊断中的作用

目的观察α-甲酰基辅酶A消旋酶(α—methylacyl—CoA racemase,P504S)在前列腺腺癌的诊断和鉴别诊断中的价值。方法对前列腺腺癌及其需要鉴别的病变：前列腺上皮内瘤变、不典型腺瘤样增生、不典型小腺泡增生以及正常前列腺组织(包括萎缩的腺体)和良性增生进行光镜观察,用EnVision二步法免疫组织化学方法检测P504S、细胞角蛋白(CK)34βE12、p63在各类病变组织中的表达情况。根据P504S阳性表达部位区分其表达形式为：胞质型、腔缘型、顶端胞质型及胞膜型。结果78例前列腺腺癌中,91％(71／78)阳性表达P504S,多表现为癌细胞弥漫性胞质内阳性着色较深的颗粒状物,少数为腺腔内缘或顶端胞质内及膜表达,9％(7／78)阴性表达P504S者均为亮细胞型;前列腺上皮内瘤变(9例),不典型腺瘤样增生(6例)以及不典型小腺泡增生(2例)中均见P504S不同程度的表达;96％(65／68)的正常及良性增生前列腺组织未见P504S阳性表达;增生的基底细胞也未见P504S阳性表达。结论P504S的免疫组织化学染色对判断前列腺腺癌具有重要参考价值,若与CK34βE12或p63联合应用则更有帮助。     

Immunohistochemical detection of P504S in primary and metastatic renal cell carcinomas.

P504S/alpha-methylacryl CoA racemase has been shown to be a relatively sensitive and specific positive marker for prostatic adenocarcinoma. The potential utility of P504S in renal cell neoplasms has not been explored in a large series. We assessed the diagnostic value of P504S in 332 cases of nonprostatic neoplasms using the avidin-biotin-peroxidase complex technique, including 115 renal neoplasms, 28 metastatic renal cell carcinomas (RCCs), and 189 nonrenal neoplasms. The results demonstrated that a granular, cytoplasmic staining pattern for P504S was observed in 48 of 70 (68.6%) conventional (clear cell) RCCs, 15 of 15 (100%) papillary RCCs, 2 of 7 (29%) chromophobe RCCs, and 2 of 8 (25%) oncocytomas. Among the 70 cases of clear cell RCC, positivity of P504S was seen in 40%, 71%, 94%, and 75% of RCCs with Furhman nuclear grade I, II, III, and IV, respectively. Strong immunostaining was present in each case (86/86) in the proximal tubules adjacent to the renal neoplasm. Eighty-two percent of metastatic RCCs (23/28) were positive for P504S. However, only 24 of 189 (13%) nonrenal malignancies were positive. The 24 positive cases included 12 of 13 (92%) colorectal adenocarcinomas, 6 of 30 (20%) ductal carcinomas of the breast, and 4 of 23 (17%) adenocarcinomas of the lung. These findings suggest that P504S is a useful marker in diagnosing primary and metastatic RCCs, although it has little value in differentiating chromophobe RCC from oncocytoma.     

Sensitivity of P504S/alpha-methylacyl-CoA racemase (AMACR) immunohistochemistry for the detection of prostate carcinoma on stored needle biopsies.

Alpha methylacyl-CoA-racemase (AMACR), also known as P504S, has been widely used as a positive marker for the diagnosis of prostate carcinoma in clinical practice. The utility of this assay is highly dependent on the sensitivity of AMACR detection in routinely processed biopsies. It is common practice to store precut prostate biopsy sections. Hence, it is important to determine the effect on the immunoreactive of P504S/AMACR in stored, unstained glass slides as compared with freshly cut sections of paraffin-embedded tissue. The purpose of this study was to determine the sensitivity of AMACR immunostaining for the detection of prostate carcinoma on stored needle biopsies. A total of 63 prostate biopsies with prostate carcinoma were transferred onto glass slides, baked, and stored for 1.6 to 9.2 months. The Gleason scores were 3+3(6) (n=40) including 10 small focal carcinomas (< or = 1.0 mm), 4+3(7) (n=16), and 4+4(8) or higher (n=7). The slides were then stained with a monoclonal antibody to P504S, and the staining intensity was compared with sections cut from the same blocks just prior to immunostaining, without an intervening storage period. There was no loss of sensitivity of AMACR for prostate adenocarcinoma, regardless of the length of the storage interval. The sensitivity was preserved and was independent of Gleason scores. The sensitivity of AMACR for small foci of adenocarcinoma was also not affected by the length of storage. Overall, stored slides had no observable increase in nonspecific background staining over freshly cut sections. These results indicate that the time interval between mounting and staining does not affect the sensitivity of the AMACR immunohistochemistry (IHC) stain in the detection of prostate cancer even with small foci of carcinoma on needle biopsies.     

Routine immunohistochemical staining for high-molecular weight cytokeratin 34-beta and alpha-methylacyl CoA racemase (P504S) in postirradiation prostate biopsies.

A total of 43 cases of postirradiation prostate cores were assessed in an attempt to determine if routine use of alpha-methylacyl-CoA racemase (AMACR) in conjunction with high-molecular weight cytokeratin (HMWCK) would increase the recognition of carcinoma in postirradiation prostate biopsies. We concluded that in most cases the addition of AMACR in conjunction with HMWCK does not increase the recognition of prostatic adenocarcinoma, however it is supportive in nature. In one case the use of AMACR highlighted the extent of the adenocarcinoma which otherwise would have been designated as atypical small acinar proliferation (ASAP). Further evaluation is required to assess the significance of a diagnosis of atypical small acinar proliferation in postirradiation prostate biopsies.     

Detection of prostate cancer by alpha-methylacyl CoA racemase (P504S) in needle biopsy specimens previously reported as negative for malignancy

AIMS : To investigate the possibility of detecting small focal prostatic cancer by alpha-methylacyl CoA racemase (AMACR)/P504S immunohistochemistry on needle biopsy specimens that were previously interpreted as negative for carcinoma on routine haematoxylin and eosin (H&E)-stained sections. METHODS: Prostate needle biopsy specimens (n = 793) previously interpreted as benign prostatic tissue by conventional morphology from 239 patients with prostatic cancer diagnosed in other biopsy cores taken at the same biopsy session were stained with the P504S monoclonal antibody. If a biopsy specimen stained positively, two pathologists independently reviewed the original corresponding H&E-stained sections to establish the malignant diagnosis. RESULTS: Eighty-four of the 793 biopsy specimens showed AMACR immunoreactivity; nine of these (9/793, 1.1%) contained previously unrecognized small focal prostatic carcinoma (Gleason 6, N = 8; Gleason 8, N = 1). Six of nine (67%) carcinomas showed foamy/pseudohyperplastic (N = 3) or atrophic (N = 3) features. Additionally, five biopsy specimens (5/793, 0.6%) with positive AMACR staining that did not meet the criteria for prostatic cancer on the original H&E slides were considered to be atypia. CONCLUSIONS: In this study, we found a 1.1% false-negative rate for carcinoma on routine H&E-stained sections. AMACR immunohistochemical staining has shown the ability to improve detection of small focal prostatic carcinoma that could be missed by conventional histological examination.     

Diagnostic usefulness of monoclonal antibody P504S in the workup of atypical prostatic glandular proliferations

We stained 37 prostate needle biopsies and 3 transurethral resections (TURP) containing atypical foci and 20 morphologically unequivocal prostate cancer biopsies, including 4 with foamy features, with P504S. Of 20 biopsies with unequivocal cancer, 18 showed variable P504S staining (sensitivity, 90%); 1 minute cancer and 1 foamy cancer lacked P504S staining. Of 40 cases with atypical foci (biopsies, 37; TURP, 3), 9 were diagnosed as high-grade prostatic intraepithelial neoplasia (HGPIN), 2 were excluded, and 29 had foci of atypical small glandular proliferation. Of these 29 cases, 7 were highly suggestive of cancer, 2 of which lacked P504S staining. In 22 cases with benign atypical foci, 11 were diagnosed as postatrophic hyperplasia (none expressed P504S) and 7 as atypical adenomatous hyperplasia (AAH; 1 showed focal weak P504S staining). Of 9 HGPIN specimens, 8 showed predominantly diffuse, moderate P504S staining. P504S has slightly lower sensitivity for detection of prostate cancer than found previously. Heterogeneous expression patterns may explain negativity in some biopsy specimens with minute cancer. In atypical small glandular proliferations, diffuse positive P504S staining in atypical glands strongly supports a cancer diagnosis, but negative staining does not exclude it. P504S seems to have low sensitivity for detecting foamy prostate cancer. Most HGPINs show diffuse moderate P504S staining. AAH may show focal P504S staining. We recommend using P504S along with morphologic examination and conventional basal cell markers.     

Lactoferrin in benign hypertrophy and carcinomas of the prostatic gland

Summary Using immunoperoxidase procedures, the presence of lactoferrin was investigated in benign hypertrophy (40 cases), differentiated adenocarcinomas (20 cases) and undifferentiated carcinomas (10 cases) of the prostate. In benign hypertrophy, the glandular epithelium and the secretory product were consistently negative. Strong staining for lactoferrin was always observed in neoplastic cells of differentiated adenocarcinomas and in their endoluminal material; in contrast, a very slight positivity was noted in undifferentiated carcinomas.These findings are discussed in relation to the different degree of neoplastic glandular differentiation and functional activity of prostatic carcinomas.     

The significance of the P504S expression pattern of high-grade prostatic intraepithelial neoplasia (HGPIN) with and without adenocarcinoma of the prostate in biopsy and radical prostatectomy specimens

Diagnosis of prostatic adenocarcinoma is usually not difficult in biopsy specimens. Problems may occur in biopsy specimens, containing only a few suspicious lesions. Recently, P504S has been tested as a new marker for prostatic carcinoma. When over-expressed in atypical glands without basal cells, it establishes the diagnosis of prostatic carcinoma. We analysed the staining intensity of P504S in 208 biopsy specimens from prostates (1) with adenocarcinoma (n=132), (2) with high-grade prostatic intraepithelial neoplasia (HGPIN) with adenocarcinoma (n=36), (3) with HGPIN alone (n=40) and in radical prostatectomy specimens with HGPIN adjacent to (n=54) or distant from adenocarcinoma (n=64). P504S expression was negative to weakly positive in biopsy specimens showing HGPIN without carcinoma and weakly positive in radical prostatectomy specimens revealing HGPIN distant from adenocarcinoma. In biopsy specimens with a combination of HGPIN and adenocarcinoma and in radical prostatectomy specimens with HGPIN adjacent to adenocarcinoma, P504S was strongly expressed. The same findings were made in radical prostatectomy specimens containing adenocarcinoma and HGPIN adjacent to or distant from adenocarcinoma and in preoperative biopsies revealing adenocarcinoma and HGPIN. These results suggest that moderate to strong P504S expression in HGPIN of biopsy specimens is indicative of an associated adenocarcinoma and may be helpful in the choice of therapy.