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.     

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.     

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.     

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.     

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.     

Prospective evaluation of AMACR (P504S) and basal cell markers in the assessment of routine prostate needle biopsy specimens

Distinguishing benign prostate glands from malignant ones, based purely on morphology, on prostatic core needle biopsy specimens (PNBs) may prove difficult, particularly if the suspicious focus is small. In recent years, several immunohistochemical markers, including the basal cell cocktail (BCC), 34betaE12 and p63, and the prostate cancer (PCa) biomarker alpha-methylacyl-CoA-racemase (AMACR), have been used as adjuvants to morphology, in these diagnostically challenging cases. We prospectively address the diagnostic utility of using the BCC, in combination with the commercially available AMACR monoclonal antibody, P504S, on PNBs that required immunohistochemistry (IHC) studies to make a diagnosis. The goals of this prospective study were to assess the day-to-day practice in an academic setting, to determine how often these IHC tests were used on routine PNBs, and to establish how often a combination of the BCC and P504S were helpful in diagnosing prostate cancer. A total of 772 prospectively collected PNB cases were examined over a 7-month period. IHC staining was performed in 171 cases (22%); 123 cases were stained with the BCC in addition to the commercially available monoclonal AMACR antibody. In 86 of these 123 cases (70%), both stains contributed to the final diagnosis: PCa in 44 cases, benign in 33 cases and high-grade prostatic intraepithelial neoplasia in 9 cases. Of the remaining 37 cases (30%), 18 were called benign or PCa, based solely on appropriate staining with the BCC, with AMACR being noncontributory because the focus of interest had been cut through (12 cases), there was negative staining with AMACR (in 4 PCa cases), or there was positive staining with AMACR (in 2 benign cases showing atrophy). Nineteen of 37 cases were diagnosed as atypical small acinar proliferation. In these 19 cases either the focus had been cut through on one or both of the stains (11 cases), both AMACR and BCC failed to work (2 cases), AMACR was positive in the presence of patchy BCC staining (1 cases), AMACR was negative in the absence of BCC staining (3 cases), or despite appropriate staining the focus consisted of 1 gland and was considered too small to call carcinoma (2 cases). Additional IHC stains were performed in 171 of 772 cases; of these, 123 had sufficient material to perform both the BCC and P504S. The BCC when used in combination with AMACR rendered a diagnosis in almost 70% of cases. Using these stains in combination may be a better approach in diagnostically difficult cases as it increases the likelihood that a definitive diagnosis can be rendered while decreasing the likelihood of an equivocal diagnosis. However, a limitation of this approach is the loss of tissue in these small lesions, suggesting that combining AMACR and the BCC on a single slide would be superior to using either marker separately.     

An analysis of the p63/alpha-methylacyl coenzyme A racemase immunohistochemical cocktail stain in prostate needle biopsy specimens and tissue microarrays

We studied the usefulness of a p63/P504S immunostain "cocktail" in evaluation of prostate biopsy specimens containing atypical acini suspicious for adenocarcinoma (AASA), high-grade prostatic intraepithelial neoplasia (HPIN), and small foci of adenocarcinoma and tested the sensitivity and specificity of the immunostain with tissue microarrays (TMAs) constructed from prostatectomy and lymphadenectomy specimens. We selected 40 cases containing a focus of adenocarcinoma (14 cases), AASA (7 cases), AASA with HPIN (7 cases), HPIN (6 cases), and atypical favor benign (6 cases). After p63/P504S immunostaining, 13 cases (33%) were reclassified: AASA with HPIN to HPIN only in 5 cases (13%), atypical favor benign to benign in 4 cases (10%), AASA to adenocarcinoma in 2 cases (5%), and atypical favor benign to AASA and atypical favor benign to HPIN in 1 case (3%) each. The diagnosis of adenocarcinoma was supported by immunostain in 14 cases. In TMA studies, the p63/P504S immunostain for adenocarcinoma and HPIN had sensitivity values of 97.2% and 86.2%, respectively, and specificity values of 99.7% and 81.6%, respectively. P504S stained 64 (74%) of 87 cores of metastatic cancers, and no p63-positive cells were identified in the metastases. The p63/P504S immunohistochemical stain is a sensitive, specific marker for prostatic adenocarcinoma and HPIN and useful in the evaluation of AASA in biopsy specimens.     

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.     

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.     

Utility of alpha-methylacyl coenzyme A racemase (p504s antibody) as a diagnostic immunohistochemical marker for cancer.

Alpha-methylacyl-coenzyme A racemase (AMACR; P504S) is a mitochondrial and peroxisomal enzyme involved in the metabolism of branched-chain fatty acid and bile acid intermediates. Recently, AMACR has been demonstrated to be overexpressed in localized and metastatic prostate cancer and in high-grade prostatic intraepithelial neoplasia but not in normal prostatic glands, suggesting that it may be an important tumor marker. This study examines AMACR expression in a variety of human cancers to assess its viability as a tumor marker in the clinical setting. Two hundred sixty-three cancers from different sites were examined in three multitumor tissue micro arrays, which included two or three tissue cores (1.0 mm in diameter) from each neoplastic and normal tissue specimen. Cancers studied included breast (94 cases), prostate (38), lung (28), endometrium (27), colon (29), ovary (26), and melanoma (21). Normal tissues in the microarray were prostate (15), lung (6), endometrium (5), colon (4), ovary (2), and skin (3). Sections were immunostained, after prior pressure cooker antigen retrieval, using rabbit monoclonal AMACR antibody (1:40) (Zeta Corp, Sierra Madre, CA) and horseradish peroxidase-labeled polymer conjugated secondary antibody (Envision, Dako, Carpinteria, CA). A section of prostate cancer and prostatic intraepithelial neoplasia was used as positive control. Protein expression was scored as negative, weak (faint cytoplasmic or granular apical staining), moderate (diffuse granular cytoplasmic stain), and strong (diffuse intense cytoplasmic stain). Only moderate and strong staining was considered as positive staining, based on prior work. AMACR protein overexpression was found in several cancers, including prostate (34/38 [89.5%]), colon (13/29 [44.8%]), lung (4/28 [14.3%]), melanoma (2/21 [9.5%]), endometrium (2/27 [7.4%]), and breast (3/94 [3.2%]). None of the ovarian cancers (26 cases) demonstrated AMACR overexpression. AMACR expression was not present in any of the normal tissues nor in benign prostatic tissue associated with prostate carcinomas. This study suggests that AMACR is potentially an important tumor marker, particularly for prostate and colon cancer. It may be a useful adjunct to an immunohistochemical panel employed in the differential diagnosis of colon versus ovarian and breast carcinoma; the latter two infrequently express AMACR.     

P504S immunostaining boosts diagnostic resolution of "suspicious" foci in prostatic needle biopsy specimens

From 1.5% to 9.0% of prostatic needle biopsy specimens disclose atypical small acinar proliferations (ASAPs) suggestive of malignancy, carrying an approximate 45% predictive value for cancer. We applied keratin 34 beta E12 and P504S monoclonal immunostains to 93 cases that were judged as ASAP after H&E staining alone. Forty-one ASAP foci survived recutting for both immunostains. Three urologic pathologists independently assigned post-keratin 34 beta E12 diagnoses of cancer, ASAP, high-grade prostatic intraepithelial neoplasia, or benign and then reviewed P504S slides and assigned final diagnoses. Eight foci (20%) were resolved unanimously after keratin 34 beta E12 staining; 18 (44%) were resolved by 1 or 2 evaluators and 29 (71%) by at least 1. According to whether post-keratin 34 beta E12 ASAP designation was given by 3, 2, or 1 evaluator(s), P504S immunostaining unanimously resolved an additional 5 (12%), 10 (24%), or 23 (56%) of 41 ASAP foci and cumulatively, 31 foci (76%). Among 35 men (excluding 6 with cancer in other cores of the original biopsy), these immunostains could have permitted cancer diagnosis in 11 (31%), without repeated biopsy. Thus, the consensus diagnosis rate improved from poor to good after supplementing 34 beta E12 immunostaining with P504S.     

Using an AMACR (P504S)/34betaE12/p63 cocktail for the detection of small focal prostate carcinoma in needle biopsy specimens

We assessed the usefulness of immunohistochemical analysis with a 3-antibody cocktail (alpha-methylacyl coenzyme A racemase [AMACR, or P504S], 34betaE12, p63) and a double-chromogen reaction for detection of limited prostate cancer in 138 needle biopsy specimens, including 82 with small foci of prostatic adenocarcinoma and 56 benign prostates. When carcinoma was present, red cytoplasmic granular staining (AMACR) in the malignant glands and cells and dark brown nuclear (p63) and cytoplasmic (34betaE12) staining in basal cells of adjacent nonmalignant glands were found. Of 82 cases of small foci of prostatic adenocarcinoma, 78 (95%) expressed AMACR; all malignant glands were negative for basal cell staining. All benign glands adjacent to malignant glands were recognized easily by basal cell marker positivity and little or no AMACR expression. No benign glands were simultaneously positive for AMACR and negative for basal cell markers (specificity, 100%). There were no differences in intensity and numbers of positive glands with double-chromogen staining compared with using 1-color staining. Our results indicate that immunohistochemistry with a 3-antibody cocktail and double chromogen is a simple and easy assay that can be used as a routine test, which overcomes the problems of studying small lesions in prostate needle biopsies with multiple immunohistochemical stains.     

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.     

Diagnostic utility of immunohistochemical markers alpha methyl acyl coA racemase (AMACR) and Ets related gene (ERG) in prostate cancer

Objectives: To study the sensitivity and specificity of IHC markers AMACR and ERG in prostatic adenocarcinoma. Methods: The study was a prospective one and samples were collected from August 2014 to June 2016. A total of 186 samples were obtained from the Department of Urology, in which 112 of these were benign prostatic hyperplasia (BPH), and 71 were prostatic adenocarcinoma. The adenocarcinoma cases were evaluated by two histopathologists, and appropriate Gleason score was given according to the modified ISUP Gleason grading system (2016). IHC markers AMACR & ERG were performed on the adenocarcinoma cases and their sensitivity and specificity were calculated. Results: AMACR was a highly sensitive and specific marker for detecting prostatic carcinoma with a sensitivity and specificity of 95.8% and 96.5% respectively. ERG was a very specific marker with poor sensitivity in detecting prostate cancer. The sensitivity and specificity of ERG were 35.2% and 100% respectively. ERG expression decreased with increasing Gleason grade, PSA level, and tumour volume, which was statistically significant while the association of AMACR with Gleason grade or with tumor volume was not significant. Conclusion: ERG is a marker of early prostatic carcinogenesis and tumors may be positive or negative subtypes. Special histomorphologic features like perineural invasion, glomerulations, and intraluminal blue mucin were also studied. AMACR was a highly sensitive marker for detecting prostatic adenocarcinoma, while ERG was highly specific.     

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.     

Diagnostic utility of a p63/alpha-methyl-CoA-racemase (p504s) cocktail in atypical foci in the prostate.

Prostatic needle biopsy is the preferred method for diagnosing early prostate cancer, providing specific information. In cases of histological cancer mimics, a diagnosis of atypical small acinar proliferation suspected of but not diagnosed as malignancy can be made. In such cases, and in small focus carcinomas, pathologists use 34betaE12, cytokeratin (CK) 5/6 or p63 immunostaining to label basal cells, and alpha-methylacyl-CoA racemase (AMACR/p504s) immunostaining as a positive prostate cancer marker on two distinct slides. However, in cases of small foci, ambiguous lesions might disappear. The purpose of our study was to improve the sensitivity of a cocktail of two antibodies (p63/p504s) with a sample incubation on 260 prostatic specimens, in order to help make a decision in conjunction with standard histology and CK 5/6 immunostaining. We tested 101 small focus prostatic cancers, 104 atypical small acinar proliferation, 19 high-grade prostatic intraepithelial neoplasia, two atypical adenomatous hyperplasia and 34 benign mimics of cancer. After p63/p504s immunostaining, the final diagnoses retained were as follows: 154 prostatic cancers, 14 atypical small acinar proliferation, 30 high-grade prostatic intraepithelial neoplasia, three atypical adenomatous hyperplasia and 62 benign mimics of cancer. To differentiate malignant from benign lesions, we used the criteria of greater sensitivity to p504s/p63 (95%) than to CK 5/6 (57%) or p63 (86%), and higher specificity for p504s/p63 (95%) than for CK 5/6 (88%) or p63 (81%). With the p504s/p63 cocktail, 89% of the ambiguous lesions were classified vs 53% for CK 5/6. Combined use of the two antibodies, one (p504s) as a positive marker and the other (p63) as a negative marker, with a simple immunostaining procedure, may improve diagnostic performance, sensitivity and specificity, leading to a reduction in the risk of false negatives; this technique in cases of atypical small acinar proliferation should reduce the percentage of residual ambiguous lesions and the need for additional biopsies.     

Alpha-methylacyl-CoA racemase (P504S) expression in evolving carcinomas within benign prostatic hyperplasia and in cancers of the transition zone

Carcinomas of the transition zone (TZ) constitute approximately 20% of all prostate cancers. The TZ is the site of origin of grade 1 and grade 2 cancers, the most well-differentiated of the Gleason grade tumors, as well as for benign prostatic hyperplasia (BPH). In this regard, grade 1 carcinoma has architectural features that closely mimic gland-rich BPH nodules. Although a relationship between cancers arising in this zone and BPH has been suspected, such an association remains undefined. To gain insight into the origin, development, and progression of cancers arising in the TZ, we used a highly specific rabbit monoclonal antibody (P504S) directed against alpha-methylacyl-CoA racemase (AMACR) to study the expression of the enzyme in 25 cases of evolving and fully developed carcinomas of this zone. AMACR has been proposed as a new molecular marker for prostate cancer, because the enzyme is reportedly overexpressed in high-grade dysplasias, also termed prostatic intraepithelial neoplasia, a purported precursor of prostatic carcinoma, and in all grades of prostatic carcinoma of the peripheral zone. Using P504S, P63, or antikeratin 34beta E12 antibodies, we found it possible to define areas of transition from hyperplasia to carcinoma in 6 BPH nodules. In 3 other cancer-containing BPH nodules, staining for AMCAR was observed in benign hyperplastic glands that were juxtaposed to carcinoma. Enzyme expression was also evident in 5 additional cases in which BPH was found adjacent to cancer. In contrast; AMACR was not visualized in any other BPH nodules that we studied. Thus, using the enzyme as a marker, we document for the first time that some carcinomas of the TZ arise from an AMCAR-positive transition lesion within a subset of BPH nodules. Moreover, the finding of enhanced AMACR expression in benign glands within cancer-containing nodules as well as in BPH lesions adjacent to carcinoma suggests that in some cases, up-regulation of the enzyme may precede morphological evidence of neoplastic transformation. AMACR was lightly expressed in transition lesions and grade 1 carcinomas but more strongly expressed in higher-grade TZ cancers, suggesting that enzyme expression is enhanced with progression in this zone. Because AMACR is involved in the beta oxidation of branched fatty acids and their derivatives, enhanced expression of the enzyme in evolving carcinomas in BPH nodules, as well as its up-regulation in juxtaposed morphologically benign glands and grade 1 carcinomas, suggests that increased utilization of fatty acids may play an important role in carcinoma development and progression in the TZ.     

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.     

Diagnostic effect of an improved preembedding method of prostate needle biopsy specimens

The authors compared the influence of a conventional and an optimized submitting method of prostate core needle biopsy specimens on the frequency of cancer detected and the pathologic characteristics of the adenocarcinoma bearing biopsy specimens. The patients included were part of the prostate-specific antigen (PSA) screening program of Tyrol/Austria. Of the systematic core needle biopsy specimens from 500 unselected men obtained within 1 year from the Urological Department, University of Innsbruck, the core biopsy specimens of 250 cases were submitted conventionally, floating free in formalin-filled containers, whereas the biopsy specimens of the other 250 cases were stretched and orientated between 2 meshes in tissue cassettes at the time of biopsy before formalin fixation. On 136 cases diagnosed as adenocarcinoma the number and the length of cores as well as number of the cores involved by cancer and the tumor size were morphometrically determined. The diagnosis of benign prostatic hyperplasia, isolated high-grade prostatic intraepithelial neoplasia (PIN), atypical foci suspicious for cancer, and carcinoma was made in 66%, 5.6%, 4.8%, and 23.6% after conventional submission and in 61.6%, 6.4%, 1.2%, and 30.8% of the cases after optimized preembedding respectively. In the adenocarcinoma cases the optimizedly preembedded material showed higher mean total core length (126.5 mm versus 93.9 mm; P < .0001), a higher mean total tumor length (14.1 mm versus 8.6 mm; P = .01), and more cores involved by cancer (2.9 versus 2.4; P = .01) compared with the conventionally worked-up biopsy specimens. Optimized preembedding of core needle biopsy specimens in tissue cassettes could be quickly and routinely done by the assistance of the urologists at the time of biopsy. The significant improvement of the histologic yield of optimizedly preembedded prostatic needle biopsy specimens led to a higher frequency of cancer diagnosis, a reduction of cases with atypical foci suspicious for cancer and a significantly lower number of cases with only 1 core biopsy involved by cancer.