Home Translating Report News Physicians Diseases Body Sites Lab tests Search
Home Diseases and Health Information


Pathologists are faced with a daunting task of discerning numerous histopathologic patterns that characterize prostate cancer. Some of these patterns are classic while others exhibit very subtle changes that may be very difficult to discern from normal or benign prostate glands.


Histopathological Features and Variants

Agreement in Grading (Interobserver Variation)
Secretory Granules

Adenoid Cystic Carcinoma
Anti-Androgen Therapy (Lupron)
Clear Cell Adenocarcinoma
Corpora Amylacea
Foamy Gland Carcinoma
Giant Cell Carcinoma
Granulomatous Prostatitis
Hormonal Therapy
Intraductal Carcinoma
Metastatic Disease
Mucinous (Colloid)
Paneth Cell Differentiation
PIN (Prostatic Intraepithelial Neoplasia)
Pseudohyperplastic Carcinoma
Radiation Associated Changes
Small Volume Cancers
Squamous Cell Carcinoma
Stratified Epithelium
Stromal Tumors
Tubulocystic Clear Cell Carcinoma
Vanishing Cancer

Special Stains/
Electron Microscopy

AMACR (P504S, Racemase)
Cytokeratin 5/6
Cytokeratin HMWK (34betaE12)
PSA (Prostate Specific Antigen)
proPSA (Precursor Form of PSA)

Differential Diagnosis Peripheral Nerves
Benign Mimickers of Prostate Cancer
ASAP (Atypical Small Acinar Proliferation)
Atypical Adenomatous Hyperplasia (Adenosis)
Basal Cell Hyperplasia/Basaloid Proliferations
Central Zone Glandular Proliferations
Cribriform Proliferations
Mesonephric Hyperplasia
Nephrogenic Adenoma
Squamous Metaplasia
Transitional Cell Metaplasia
Radiation Induced Atypia
Rectal Glands
Post-operative Spindle Cell Nodule
Atypical Stromal Cells
Stromal Tumor
Extramedullary Hematopoiesis
Cowper Glands
Inverted Papilloma of the Prostatic Urethra
Commonly Used Terms  
Internet Links  

Update on the Gleason Grading System for Prostate Cancer: Results of an International Consensus Conference of Urologic Pathologists.

Epstein JI, Allsbrook WC Jr, Amin MB, Egevad LL.

From *Department of Pathology, Urology and Oncology, The Johns Hopkins Hospital, Baltimore, MD; daggerDepartments of Pathology and Surgery (Urology), Medical College of Georgia, Augusta, GA; double daggerDepartments of Pathology and Laboratory Medicine, Urology, Hematology, and Oncology, Atlanta, GA; section signDepartment of Pathology and Cytology, Karolinska Hospital, Stockholm, Sweden.

Adv Anat Pathol. 2006 Jan;13(1):57-59 Abstract quote.  

The Gleason system for prostate cancer was based on a study of 270 patients from the Minneapolis Veterans Administration Hospital in 1966-1967. In 1974, Gleason and the Veterans Administrative Cooperative Urological Research Group expanded this study to 1032 men. These studies formed the basis of the Gleason grading system, which is now endorsed as the primary grading system for prostate cancer by the World Health Organization, the Armed Forces Institute of Pathology Fascicle on prostate cancer, the Association of Directors of Anatomic and Surgical Pathology, and the College of American Pathologists.

In the nearly 40 years since its inception, several aspects about prostate cancer and its management have changed, most notably serum prostate-specific antigen, transrectal ultrasonography, 18-gauge needle biopsy sampling, immunohistochemistry for the diagnosis of cancer, and radical prostatectomy and radiation therapy as primary treatment modalities. Several aspects of the disease, and consequently the reporting needs, have changed such as reporting cancer on multiple cases in needle biopsies, multiple nodules in prostatectomy, tertiary patterns, variants and variations in prostate cancer. The application of the Gleason system, therefore, has varied considerably in contemporary surgical pathology practice.

An International Consensus Conference attended by 80 urologic pathologists from 20 countries was convened to discuss clarifications and modifications to the Gleason system. This article serves as a brief overview and summary of the proceedings that have been published in detail in recent literature.
Minute foci of Gleason score 8-10 on prostatic needle biopsy: a morphologic analysis.

Fine SW, Epstein JI.

Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA.
Am J Surg Pathol. 2005 Jul;29(7):962-8. Abstract quote  

Prostatic needle biopsies showing high-grade cancer typically contain abundant tumor. However, the histologic features of a minute focus of high-grade cancer on biopsy have not been well studied.

A total of 100 cases with a single minute focus (< or = 1 mm) of Gleason score (GS) 8-10 adenocarcinoma were identified from a large consultative service, systematically studied, and compared with the submitting institutions' provisional diagnoses. The mean size of the minute foci was 0.52 mm. A total of 29 cases were GS 8 with cribriform glands (n = 15), poorly formed glands (n = 6), fused glands (n = 3), or combinations of the three (n = 5). A total of 38 cases were GS 9, with: single cells and poorly formed glands (n = 20); extremely poorly formed glands/borderline pattern 4/5 (n = 4); combinations of single cells, sheets, or nests of cells mixed with glands that were either poorly formed, cribriform, or fused (n = 14). A total of 33 cases were GS 10, with single cells (n = 23), single cells with nests (n = 9), or single cells with sheets of cells (n = 1). A total of 69 foci were located adjacent to benign glands, while 31 were on the edge or at the end of the core. Perineural invasion was observed in only 1 case. A total of 72 cases showed moderate to abundant amphophilic cytoplasm. Frequent prominent nucleoli (n = 11), mitoses (n = 8), and apoptotic bodies (n = 11) were infrequently observed. Of 59 cases with known provisional diagnoses, 46 were diagnosed as atypical (n = 37) or as cancer with GS < 8 (n = 9).

Pathologists must be attuned to the complex and varied architectural patterns seen in low-volume, high-grade prostate cancer as its diagnosis has both important prognostic and therapeutic implications.
Current practice of Gleason grading among genitourinary pathologists.

Egevad L, Allsbrook WC, Epstein JI.

Hum Pathol. 2005 Jan;36(1):5-9. Abstract quote  

Summary There is consensus that the Gleason system should be used for grading of prostate cancer. However, a number of controversial issues remain as regards how this grading is applied. A questionnaire was sent to 91 genitourinary pathologists in countries around the world with the purpose to survey current practice of Gleason grading. The response rate was 74%, including 43 North American pathologists and 24 from other continents.

Of all participants, only 13% and 36%, respectively, ever diagnosed a Gleason score (GS) of 2 to 3 or 4 on needle biopsies (NBX), and 88% of those who did so assigned a GS 4 to <1% of cancers. Cribriform Gleason pattern (GP) 3 was acknowledged by 88% but a majority of them would classify </=20% of cribriform patterns as GP 3. One third only accepted cribriform or fusion patterns as GP 4, but two thirds also included incomplete or poorly defined glands. For GP 5 to be identified on NBX, 83% required clusters of individual cells, strands, or nests seen at less than x40 lens magnification. Only 26% defined GS on NBX as primary + tertiary GP, and a majority would mention a tertiary pattern separately. For NBX, global or highest GS was reported by 40% and 10%, respectively, whereas 46% only gave a separate GS for each individual NBX core.

In conclusion, there is a need to standardize practical application of Gleason grading both in terms of interpretation of patterns as well as how grading is reported. Our survey data provide information to general pathologists about the most common grading practices among genitourinary pathologists.

Prostate Needle Biopsy Reporting: How Are the Surgical Members of the Society of Urologic Oncology Using Pathology Reports to Guide Treatment of Prostate Cancer Patients?

Rubin MA, Bismar TA, Curtis S, Montie JE.

*Brigham and Women's Hospital, and daggerHarvard Medical School, Boston, MA; and double daggerDepartment of Urology, University of Michigan, and section signUniversity of Michigan School of Medicine, Ann Arbor, MI.
Am J Surg Pathol. 2004 Jul;28(7):946-952. Abstract quote  

Recent trends in prostate needle biopsy reporting have resulted in the inclusion of more information and new diagnostic categories.

The goal of the current study was to survey surgical Members of the Society of Urologic Oncology to determine what information academic urologists consider important in the management of their prostate cancer (PCa) patients.

A questionnaire was developed to investigate several areas of PCa biopsy reporting, which vary from institution to institution. Urologists were sent questionnaires and asked to return anonymous responses; 42 questionnaires were completely evaluated with a response rate of 76% (42 of 55). The urologists targeted for this survey were highly experienced with an average of 22 years in clinical practice (range, 6-35 years). On average, they performed 92 radical prostatectomies per year and 449 over the past 5 years (range, 60-1500) for a group total of 18,840 radical prostatectomies; 94% have their patient's biopsy reviewed prior to surgery.

The primary and secondary Gleason pattern was required by 60% (25 of 42) of the respondents. In prostate needle biopsies containing only a single minute focus of PCa, only 41% (17 of 42) of respondents would request a Gleason score if not provided in the initial report.

Interestingly, in biopsies with multiple positive cores from separate locations, 81% (34 of 42) use the highest Gleason score, regardless of the overall percentage involvement, to determine their treatment plan. Other pathology parameters requested by the respondents in descending order included: % involvement of the core by PCa (67%), the presence or absence of perineural invasion (38%), the number of cores with PCa (33%), and the length of core involvement (29%). Only 24% (10 of 42) of respondents use perineural invasion status to guide nerve-sparing surgery.

The more radical prostatectomies performed by a surgeon, the greater the likelihood that they considered perineural invasion clinically important (Mann-Whitney, two-tailed, P = 0.015).

The term atypical small acinar proliferation was uniformly considered sufficient to re-biopsy by 98% (41 of 42) of the urologists. This is the first study to survey urologists as to what information they require from prostate needle biopsy reports in their treatment planning of men with clinically localized PCa. With the exception of Gleason score, the use of detailed pathology information was variably used to guide treatment. PNI was not considered important by the majority of respondents. In contrast, atypical small acinar proliferation, a more recent diagnostic category, was recognized as important by nearly all respondents. Knowledge of how pathology biopsy reports are being used should help evaluate what data should be uniformly part of standard biopsy pathology report and help improve communication between pathologists and urologists.
Radical prostatectomy for carcinoma of the prostate.

Ohori M, Kattan M, Scardino PT, Wheeler TM.

1Baylor College of Medicine & Memorial Sloan Kettering Cancer Center, TX, USA.
Mod Pathol 2004;17:349-359 Abstract quote

Morphologic features of prostatic adenocarcinoma in the radical prostatectomy (RP) specimen are powerful prognostic indicators for prognosis for disease-free survival.

This review discusses the methods of sampling of the RP specimen to optimize the detection of these morphologic features, balanced against the added expense of submitting the entire gland for sectioning. Gleason grade, one of the most powerful prognostic factors, is discussed briefly, including the percent pattern 4/5 cancer compared to the standard Gleason grading. Pathologic stage, as defined by the TNM system, is discussed in detail, both in terms of precise histological definition of each category, as well as the associated prognostic implications. Surgical margin status is also important prognostically across all pathologic stages categories. Perineural invasion, which has been used diagnostically in prostate cancer for several decades, has emerged as a very important prognostic indicator as well, as determined by the quantitative aspects of tumor in the perineural space.

The effect of tumor volume on prognosis is discussed, as well as the newer concepts of the prognostic significance of zone of origin of the tumor and the presence or absence of intraductal carcinoma.

Am J Clin Pathol 2000;114:896-909

The clinical use of the 18 gauge needle biopsy has revolutionized the detection of early prostate cancer. One of the most pressing issues is how to prepare the needle biopsy specimens to optimize detection of cancer while preserving tissue should further studies be needed.

It is recommended that 3 levels (3 slides) each with several sections be prepared from each paraffin block. Some laboratories save unstained slides with interval sections taken between the 3 levels which can be used for H and E staining or ancillary immunohistochemical staining

In general, it is not necessary to serially section through the entire prostate needle core biopsy which would generally require a mean of 30 slides per block with a mean of 4 sections per slide

Additional levels beyond the first 3 standard slides are critical for diagnosing minimal adenocarcinoma only when a diagnosis of focal glandular atypia was made in the first 3 slides

In 10% of cases of focal glandular atypia, a single additional level allowed for a definitive diagnosis of carcinoma, based on a larger lesion size in the additional level-thus this additional level is recommended if focal glandular atypia is detected in the first 3 slides

Threshold for diagnosing prostate cancer over time.

Magi-Galluzzi C, Epstein JI.

Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland 21231, USA.
Hum Pathol. 2003 Nov;34(11):1116-8 Abstract quote.  

Paralleling the detection of earlier prostate cancer over the last several years, there have been numerous efforts to educate practicing pathologists on the diagnosis of limited prostate cancer on needle biopsy via journal articles, Web sites, books, and educational courses.

The current study was undertaken to assess whether the threshold for the diagnosis of prostate cancer on needle biopsy has lowered over time. One thousand twelve prostate needle biopsy cases obtained in consultation by 1 of the authors because of diagnostic concerns over a period of 12 weeks (November 15, 2001 to February 15, 2002) were reviewed. Cases referred by either the patient or clinicians were excluded.

The final diagnoses in this series were compared with a previously published series of needle biopsy cases of the prostate seen in consultation by the same author in 1993-1994. The percentage of cancer in the 2001-2002 series was 55.1%, compared with 69.6% for the 1993-1994 series. The mean and median numbers of malignant glands in the 2001-2002 series (mean, 21.9; median, 14; range, 2 to 296) were significantly smaller than in the 1993-1994 series (mean, 31.0; median, 20; range, 2 to 300; P<0.00001). The incidence of atypical glands that were suspicious for but not diagnostic of carcinoma was 23.9% in the 2001-2002 series and was 10.7% in the 1993-1994 series. The mean and median numbers of atypical glands in the 2001-2002 series were 9.4 and 6, respectively (range, 1 to 70); these parameters were not available for the previous series.

The percentage of high-grade prostatic intraepithelial neoplasia diagnoses was similar in the 2001-2002 and 1993-1994 series (5.1% and 4.6%, respectively), as was the overall frequency of benign cases (15.8% and 15.1%, respectively). The percentage of cases that were accompanied by immunohistochemical stains for 34betaE12 in the 2001-2002 series was 44.4%, which was much more than the 2.5% seen in the 1993-1994 series; if anything, this should have resulted in a lower atypical rate in the current series. In more recent years, cases sent for consultation have more limited cancer, with a correspondingly higher percentage of cases that are diagnosed as atypical, yet not diagnostic of cancer. The number of atypical glands in the recent series was very limited, such that a change over time in the threshold for diagnosing cancer by the consultant is an unlikely explanation.

It appears that pathologists are becoming more skilled at diagnosing limited prostate cancer and are referring predominantly cases with fewer cancer glands and more difficult atypical cases with few glands.


Current practice of diagnosis and reporting of prostate cancer on needle biopsy among genitourinary pathologists

Lars Egevad, MD, PhD, William C. Allsbrook Jr., MD, Jonathan I. Epstein, MD

Hum Pathol 2006;37:292-297 Abstract quote

As there is a lack of hard data in the literature about many of the issues relating to diagnosing and reporting prostate cancer, we sought to survey current practices.

A questionnaire was sent to 93 genitourinary pathologists with a response rate of 69%. Almost all respondents (95%) used formalin as fixative for needle biopsies. Unstained intervening sections were retained by 47%. Three levels of needle biopsies were used routinely by 63%. For verification of a diagnosis of cancer, high-molecular-weight cytokeratin was still the most commonly used immunohistochemical marker (91%), followed by p63 (58%) and alpha-methylacyl-CoA-racemase (50%).

Features considered pathognomonic for cancer were glomeruloid bodies (58%), collagenous micronodules (64%), circumferential perineural invasion (84%), and growth in fat (36%). With none of these present, 39% required a minimum of 2 to 10 glands (median, 3) to diagnose cancer, whereas the others had no lower limit. A Gleason score was always given to even minute cancer foci by 86% and typically a Gleason score 6 was assigned (77%). Perineural invasion was mentioned by 86%. The extent of cancer on needle biopsies was quantified by all respondents with number of involved cores (80%) being the most commonly used measure. Linear extent was estimated by almost all, either as a percentage (80%) or millimeters of cancer length (41%) or both (22%). Measuring cancer from end to end or subtracting intervening benign tissue were almost equally common.

For those general pathologists who would like to be in the mainstream of most urological pathologists, our survey data provide a guideline on how to diagnose and report prostate cancer.

Current practice of diagnosis and reporting of prostatic intraepithelial neoplasia and glandular atypia among genitourinary pathologists.

Egevad L, Allsbrook WC, Epstein JI.

1Department of Pathology and Cytology, Karolinska Hospital, Stockholm, Sweden.

Mod Pathol. 2006 Feb;19(2):180-5. Abstract quote  

The criteria for diagnosing prostatic intraepithelial neoplasia (PIN) and lesions suspicious for cancer are described in the literature. However, it is unknown how these are applied in practice by experts in genitourinary (GU) pathology.

A questionnaire was sent to 93 GU pathologists in countries around the world with the purpose of surveying current practices. The response rate was 69% including 40 North American pathologists and 24 from other continents. For preneoplastic lesions, the term PIN was universally endorsed by the respondents. PIN was graded by 83%, usually as low/high-grade PIN (LGPIN/HGPIN) or as HGPIN only. Most respondents would usually not report lesions that may qualify for LGPIN. A majority (81%) did not specify architectural patterns of PIN. With both HGPIN and invasive cancer present, 69% would still mention HGPIN. Among the diagnostic criteria for HGPIN were any nucleoli visible (52%), or nucleoli seen in at least 10% of cells (33%). However, 56% would diagnose HGPIN in the absence of prominent nucleoli, most commonly based on prominent pleomorphism, marked hyperchromasia or mitotic figures. The number of cores involved with HGPIN was specified by 50%. Lesions suspicious for but not diagnostic of carcinoma were reported by 45% as atypia, atypical glands or suspicious for cancer and by 42% as atypical small acinar proliferation. The degree of suspicion was further defined by 41%.

Our survey data may serve as a guideline to general pathologists on how to diagnose and report atypia and PIN in prostate biopsies.
A comparison of interobserver reproducibility of Gleason grading of prostatic carcinoma in Japan and the United States.

Oyama T, Allsbrook WC Jr, Kurokawa K, Matsuda H, Segawa A, Sano T, Suzuki K, Epstein JI.

Department of Tumor Pathology, Gunma University Graduate School of Medicine, Gunma, Japan.

Arch Pathol Lab Med. 2005 Aug;129(8):1004-10. Abstract quote  

CONTEXT: Gleason grading is now the sole prostatic carcinoma grading system recommended by the World Health Organization. It is imperative that there be good interobserver reproducibility within this system worldwide. To our knowledge, there are no studies, using the same specimens, that compare the interobserver reproducibility of Gleason grading in Japan and the United States.

OBJECTIVE: To compare the interobserver reproducibility of Gleason grading of prostatic carcinoma in Japan and the United States using, in Japan, images from the identical biopsy glass slides that were originally graded in the United States.

DESIGN: Microsopic images from 37 needle biopsies of prostatic carcinoma were placed on CD-ROM and distributed to 14 Japanese pathologists for grading. These 14 physicians included 8 general pathologists and 6 pathologists with a special interest in urologic pathology. The needle biopsies had been previously reviewed so that a consensus diagnosis could be formed by a panel of urologic pathologists in the United States and Canada. Interobserver agreement with the consensus diagnoses was calculated by determining the overall kappa coefficient for the Japanese pathologists and then compared to the interobserver agreement among American general pathologists who had previously graded identical needle biopsies from which the CD-ROM images had been taken.

RESULTS: The interobserver agreement with the consensus diagnoses for the 4 Gleason grading groups (Gleason grades 2-4, 5-6, 7, and 8-10) among the Japanese urologic pathologists in this series of cases was substantial (overall kappa = 0.68), and for the Japanese general pathologists, it was moderate (overall kappa = 0.49), similar to that reported in the earlier study of American general pathologists (overall kappa = 0.44). The major interobserver reproducibility problem for both Japanese and American general pathologists is undergrading. The major areas of undergrading are the underdiagnosis of Gleason scores 5-6 as Gleason scores 2-4, and the underdiagnosis of cribriform sheets and fragments of cribriform Gleason pattern 4 carcinoma as Gleason pattern 3.

CONCLUSIONS: The interobserver reproducibility of the Gleason grading for this collection of specimens was similar among Japanese and American general pathologists. The overall kappa values for these generalists of 0.44 and 0.49 are only in the moderate (0.41-0.60) range of interobserver agreement when compared to 0.68, substantial (0.61-0.80) agreement, for Japanese urologic pathologists. Educational efforts to improve Gleason grading have been shown to be effective and are clearly warranted.
Gleason Grading of Prostate Cancer
Level of Concordance Between Pathologists at the University Hospital of the West Indies

Kathleen C. Coard, DM (Path), and Vincent L. Freeman, MD
Am J Clin Pathol 2004;122:373-376 Abstract quote

Our aim was to study the level of interobserver concordance in the Gleason scores of prostate needle biopsy specimens reported at 1 institution.

A retrospective review of all prostate needle biopsy specimens in which a diagnosis of adenocarcinoma was made during the year 2000 was conducted. Parameters evaluated included the Gleason score, Gleason grades identified, the percentage of Gleason grades 4 and 5, and the percentage of tumor in the biopsy specimen.

Our results demonstrated a 60% overall concordance in consensus Gleason scores, which increased to 80% when considered in groups of a Gleason score of less than 7 vs 7 or more. The greatest discordance seemed to be in distinguishing Gleason score 6 from 7 and was more frequent among biopsy specimens with lower tumor volumes, particularly among those with less than 30% involvement. A small percentage of Gleason grade 4 pattern might predict disagreement as well.

Strategies for improving accuracy of Gleason score 7 should be devised, and consensus diagnosis for biopsy specimens that demonstrate a low percentage of tumor volume is recommended.
Diagnosis and reporting of limited adenocarcinoma of the prostate on needle biopsy.

Epstein JI.

1Departments of Pathology and Urology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Mod Pathol 2004;17:307-315 Abstract quote

The diagnosis of limited adenocarcinoma of the prostate is one of the more difficult challenges in surgical pathology.

This paper highlights the methodological approach to diagnosing limited cancer, based on a constellation of features more commonly present in adenocarcinoma than benign glands. In assessing small foci of atypical glands on needle biopsy, one looks for differences between the benign glands and the atypical glands in terms of nuclear features, cytoplasmic features, and intraluminal contents. Only a few features, such as glomerulations, mucinous fibroplasia (collagenous micronodules), and perineural invasion are diagnostic in and of themselves for prostate cancer.

Immunohistochemistry may be a useful adjunct in the diagnosis of limited adenocarcinoma of the prostate, although as with any immunohistochemical studies, there are problems with both sensitivity and specificity. Basal cell markers, such as high molecular weight cytokeratin and more recently, p63, highlight basal cells found in benign glands, yet are absent in adenocarcinoma of the prostate.

However, not all benign glands label uniformly with basal cell markers. Certain mimickers of adenocarcinoma of the prostate are even less frequently labeled uniformly with these stains. Consequently, negative staining in a small focus of atypical glands for basal cell markers is not diagnostic of adenocarcinoma of the prostate. More recently, a marker has been identified that relatively selectively labels adenocarcinoma of the prostate. AMACR will label the cytoplasm of approximately 80% of limited adenocarcinoma of the prostate cases on needle biopsy.

In positive cases, not all of the glands will be positive and those that are positive are often not intensely positive. Certain variants of adenocarcinoma of the prostate that are a little more difficult to recognize, such as foamy glands adenocarcinoma, pseudohyperplastic adenocarcinoma, and atrophic adenocarcinoma, are labeled with AMACR in only approximately 60-70% of cases. In addition to problems with sensitivity, AMACR is not entirely specific for adenocarcinoma, and will label almost all cases of high-grade prostatic intraepithelial neoplasia, some foci of adenosis, and even some entirely benign glands.

Finally, this paper will briefly cover the significance of atypical or suspicious prostate needle biopsies, and how to report the key diagnostic and prognostic information on needle biopsy.

Gleason grading and prognostic factors in carcinoma of the prostate.

Humphrey PA.

1Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA.

Mod Pathol. 2004;17:292-306 Abstract quote

Gleason grade of adenocarcinoma of the prostate is an established prognostic indicator that has stood the test of time. The Gleason grading method was devised in the 1960s and 1970s by Dr Donald F Gleason and members of the Veterans Administration Cooperative Urological Research Group. This grading system is based entirely on the histologic pattern of arrangement of carcinoma cells in H&E-stained sections. Five basic grade patterns are used to generate a histologic score, which can range from 2 to 10. These patterns are illustrated in a standard drawing that can be employed as a guide for recognition of the specific Gleason grades.

Increasing Gleason grade is directly related to a number of histopathologic end points, including tumor size, margin status, and pathologic stage. Indeed, models have been developed that allow for pretreatment prediction of pathologic stage based upon needle biopsy Gleason grade, total serum prostate-specific antigen level, and clinical stage. Gleason grade has been linked to a number of clinical end points, including clinical stage, progression to metastatic disease, and survival. Gleason grade is often incorporated into nomograms used to predict response to a specific therapy, such as radiotherapy or surgery. Needle biopsy Gleason grade is routinely used to plan patient management and is also often one of the criteria for eligibility for clinical trials testing new therapies. Gleason grade should be routinely reported for adenocarcinoma of the prostate in all types of tissue samples. Experimental approaches that could be of importance in the future include determination of percentage of high-grade Gleason pattern 4 or 5, and utilization of markers discovered by gene expression profiling or by genetic testing for DNA abnormalities. Such markers would be of prognostic usefulness if they provided added value beyond the established indicators of Gleason grade, serum prostate-specific antigen, and stage.

Currently, established prognostic factors for prostatic carcinoma recommended for routine reporting are TNM stage, surgical margin status, serum prostate-specific antigen, and Gleason grade.

Accurate Gleason grading of prostatic adenocarcinoma in prostate needle biopsies by general pathologists.

Renshaw AA, Schultz D, Cote K, Loffredo M, Ziemba DE, D'Amico AV.

Department of Pathology, Baptist Hospital of Miami, Miami, Fla 33176, USA.

Arch Pathol Lab Med. 2003 Aug;127(8):1007-8. Abstract quote

CONTEXT: Gleason grading of prostatic adenocarcinoma in core needle biopsies is important for predicting prognosis and selecting appropriate therapy. Previous studies have shown that Gleason scores assigned by general pathologists have a low correlation with those assigned by urologic pathologists, and that general pathologists tend to undergrade prostate carcinoma.

OBJECTIVE: To determine if the performance of general pathologists grading prostate needle biopsies has changed over time.

DESIGN: Four hundred sixteen prostate biopsies from men treated at a single community-based institution between 1987 and 2000 were reviewed by one urologic pathologist (A.A.R.). The correlation between the original Gleason score and the reviewer's score was determined over time.

RESULTS: Cases were divided into those performed and originally interpreted in the first half of the study (1987-1996) and those performed and originally interpreted in the second half (1996-2000). Overall concordance for exact Gleason score was 59% (244/416). The exact concordance of the Gleason score assigned by the original pathologist and the reviewer during the first half of the study was 51%, whereas in the second half of the study the concordance was significantly greater (66.3%, P =.002). However, when grouped into score categories of 6 or less, 7, and 8 or greater, there was no significant difference in the exact concordance between the first half of the study (78.3%) and the second half (78.4%). Fifty-five percent of the cases in which there was discordance were graded as 7 by the reference pathologist and 6 or less by the original pathologist. There was no correlation between concordance in Gleason score and the percentage of tissue involved by carcinoma.

CONCLUSION: The concordance between general pathologists' Gleason grading and that of a reference pathologist in this study is much higher than that in previously reported studies. Although exact concordance has significantly improved over time, concordance by clinically significant groups has remained high throughout the study, is dominated by the difference between Gleason score 7 and 6 or less, and is unrelated to the size of the tumor focus.

Microfocal prostate cancer: biopsy cancer volume does not predict actual tumour volume.

Gardner TA, Lemer ML, Schlegel PN, Waldbaum RS, Vaughan ED Jr, Steckel J.

Department of Urology, New York Hospital-Cornell Medical Center, NY, USA.

Br J Urol 1998 Jun;81(6):839-43 Abstract quote

OBJECTIVE: To determine whether microfocal prostate cancer on needle biopsy predicts clinically insignificant disease in men undergoing radical prostatectomy.

PATIENTS AND METHODS: The records of 726 men who underwent radical prostatectomy between January 1990 and September 1995 were reviewed; 83 men had pre-operative prostatic needle biopsies which revealed microfocal prostate cancer. In these men, tumour volume (length) in the biopsy was compared to the percentage of tumour in the total prostatectomy specimen, and the pathological stage and clinical outcome reviewed.

RESULTS: Of the 83 men with microfocal prostate cancer on biopsy 75 (90%) had clinically significant disease. Pre-operative variables were of no use in identifying patients with clinically insignificant tumour volumes. When comparing those with microfocal tumour and those without at one institution, 69% had organ-confined (pT2) disease and 31% had capsular penetration (pT3), compared with 61% and 39%, respectively (P < 0.05). Additionally, the positive surgical margin rate for those with microfocal tumour was only 6%, compared with 26% for those without microfocal disease (P < 0.05). Biochemical failures during the median follow-up period of 24 months occurred in 6% of the men with microfocal cancer and in 15% of those undergoing total prostatectomy (P < 0.05).

CONCLUSIONS: Microfocal prostate cancer determined from the needle biopsy does not predict clinically insignificant disease.

The association of selected pathological features with prostate cancer in a single-needle biopsy accession.

Hu JC, Palapattu GS, Kattan MW, Scardino PT, Wheeler TM.

Department of Pathology, The Methodist Hospital, the Matsunaga-Conte Prostate Cancer Research Center, Baylor College of Medicine, Houston, TX 77030-2707, USA.

Hum Pathol 1998 Dec;29(12):1536-8 Abstract quote

Isolated high-grade prostatic intraepithelial neoplasia (PIN) has been shown to be a positive predictor of prostate cancer (PCa) on follow-up biopsy. However, the incidence of isolated high-grade PIN in needle biopsy specimens has been reported with a highly variable frequency of 1% to 15%.

The current study examined the relationship of various pathological features with PCa on a single biopsy accession.

A study population of 388 community-based consecutive needle biopsy accessions was prospectively recorded by a single pathologist (T.M.W.). All of the individual biopsy specimens were coded for the presence of PCa, high-grade PIN, low-grade PIN, chronic inflammation (CI), intraluminal prostatic crystalloids (IPC) in benign glands, and mucinous metaplasia (MM). One hundred twenty-nine (33%) of the patients were diagnosed with PCa.

The 8% incidence of isolated high-grade PIN was consistent with previous studies. The incidence of other pathological features were as follows: high-grade PIN, 14%; low-grade PIN, 13%; CI, 30%; IPC, 4%; and MM, 8%. Of the patients with high-grade PIN, 47% had PCa on a separate core biopsy, whereas 31% of patients without high-grade PIN were observed to have PCa (P=.021). Of the patients with CI, 21% were found to have PCa on a separate core, whereas 38% of patients without CI were found to have PCa (P=.0009).

None of the other pathological features surveyed showed any significant association with PCa. High-grade PIN was a relatively common finding (14%) in this study and was positively associated with PCa on a separate core from the same accession biopsy. The negative association of CP with PCa within the same accession has not been reported previously and may be an artifact related to the clinical indications for a prostatic biopsy.

Histologic Features for minimal prostatic adenocarcinoma

Am J Clin Pathol 2000;114:896-909

NOTE: Most minimal cancers (78%) are of intermediate grade (Gleason score 5 or 6). This scoring was within 1 score unit in 94% of cases where follow-up radical prostatectomy specimen was present

Major Criteria:
Architectural: infiltrative small glands or cribriform glands too large or irregular to represent high grade PIN
Single cell layer (absence of basal cells)
Nuclear atypia: nuclear and nucleolar enlargement

Minor criteria:
Intraluminal wispy blue mucin (blue-tinged mucinous secretions)
Pink amorphous secretions
Mitotic figures
Intraluminal crystalloids
Adjacent high-grade PIN
Amphophilic cytoplasm
Nuclear hyperchromasia

Patterns of invasion:
Presence of small glands between benign glands (most common)
Haphazard growth without adjacent benign glands
Uncommon: cords of cells, single cells, cribriform structures

Should a Gleason Score Be Assigned to a Minute Focus of Carcinoma on Prostate Biopsy?

Mark A. Rubin, M.D.; Rodney Dunn, M.S.; Neeraja Kambham, M.D.; Carolyn Pearsall Misick, M.D.; Kathleen M. O'Toole, M.D.

From the Department of Pathology (M.A.R., C.P.M.), Urology Section (M.A.R.), and Comprehensive Cancer Center Biostatistics Unit (R.D.) of the University of Michigan, Ann Arbor, Michigan, U.S.A.; and the Department of Pathology (N.K., K.M.O.), College of Physicians and Surgeons of Columbia University, New York, New York, U.S.A.

Am J Surg Pathol 2000;24:1634-1640 Abstract quote

The grading system for prostate carcinoma devised by Gleason is a strong prognostic indicator. The primary and secondary patterns are combined to give a tumor score, referred to as Gleason score or sum. Gleason scores on biopsy correlate with the prostatectomy Gleason scores, and in combination with pretreatment serum prostate-specific antigen and digital rectal examination results, predict tumor stage and lymph node status. However, when only a minute focus of tumor is present on biopsy, the Gleason score is assigned by doubling the Gleason pattern.

The goal of this study was to determine if a Gleason score assigned to a minimal focus of adenocarcinoma had predictive value.

Paired biopsies and prostatectomy specimens from 963 cases of men with clinically localized prostate cancer were examined. Minimal tumor on biopsy was defined as less than 1 mm or 5% involvement of one biopsy core; excluded from this definition were biopsies where two Gleason patterns could be identified and/or tumor was seen on more than one biopsy core. Terms often used to describe these lesions include ``single minute focus of carcinoma'' or ``adenocarcinoma, too small to give a Gleason grade.'' One hundred five cases (10.9%) met the above criteria for minimal carcinoma. The correlation of Gleason scores between biopsies and prostatectomy specimens overall was good with exact agreement for 57% of cases and a difference of ±1 unit in 92% of cases. The correlation for the minimal tumors on biopsy and prostatectomy was slightly worse with exact agreement in 52.4% (55 of 105) and a difference of ±1 unit in 87.6% (92 of 105). The majority of minimal tumors (83.8% or 88 of 105) were assigned a Gleason score of 6. A total of 31.8% of these 88 cases were upgraded and 5.7% were downgraded. Multivariate analysis on all cases looking for predictors of tumor stage found biopsy Gleason score, perineural invasion, pretreatment prostatic-specific antigen, and digital rectal examination all predicted higher tumor stage with odds ratios of 1.86 (95% confidence interval [CI], 1.53–2.27; p = 0.0001), 2.06 (95% CI, 1.43–2.95; p = 0.0001), 1.08 (95% CI, 1.05–1.11; p = 0.0001), and 1.41 (95% CI, 1.04–1.91; p = 0.0289), respectively. In a model restricted to the 105 cases with minimal carcinoma, pretreatment prostatic-specific antigen was the only independent predictor of higher tumor stage with an odds ratio of 1.15 (95% CI, 1.01–1.31; p = 0.0380); Gleason score was not found to significantly predict higher tumor stage (odds ratio, 1.156; p = 0.6680).

The results of this study confirm that biopsy Gleason score in most cases predicts prostatectomy Gleason score and tumor stage. However, for cases with minimal tumor on biopsy, the assigned Gleason score did not predict tumor stage. To properly convey this uncertainty to clinicians, a cautionary note should accompany Gleason scores derived from a minimal focus of carcinoma.

Analysis of repeated biopsy results within 1 year after a noncancer diagnosis.

O'dowd GJ, Miller MC, Orozco R, Veltri RW.

Pathology Group, UroCor, Inc., Oklahoma City, Oklahoma, USA.

Urology 2000 Apr;55(4):553-9 Abstract quote

OBJECTIVES: A prostate biopsy data base derived from patients referred to private practice urologists was analyzed for the cancer diagnosis rates of the "initial" biopsy and the repeated biopsy performed within 1 year for those patients with a noncancer diagnosis.

METHODS: A retrospective analysis assessed 132,426 prostate biopsies received and processed by a single pathology laboratory between March 1994 and September 1998; none had had a previous biopsy processed at this laboratory. Prostate cancer was diagnosed in 50,521 of the patients (38.2%). The remaining 81,905 patients (61.8%) had a noncancer diagnosis of either no evidence of malignancy (NEM), high-grade prostatic intraepithelial neoplasia (HGPIN), small acinar glands suspicious for cancer (suspicious), or suspicious with HGPIN (Susp-HGPIN). We identified 6380 (7.8%) of these "noncancer" patients who underwent a repeated biopsy within 1 year.

RESULTS: The incidence of NEM, HGPIN, suspicious, and Susp-HGPIN biopsy diagnoses in the "noncancer" patients (81,905) was 55.3%, 3.7%, 2.5%, and 0.3%, respectively. The rate at which these "noncancer" patients (81,905) underwent a repeated biopsy was 4.8% for patients with a diagnosis of NEM, 26.6% for HGPIN, 40.4% for suspicious, and 47.5% for Susp-HGPIN. The overall cancer diagnosis rate in the repeated biopsy patient sample (6380) was 25.7%. When stratified by the initial biopsy diagnosis, the cancer diagnosis rate for the repeated biopsies was 19.8%, 22.6%, 40.0%, and 53.1%, for the patients with NEM, HGPIN, suspicious, and Susp-HGPIN, respectively. The repeated biopsy diagnosis rates did not vary dramatically when analyzed at 3-month intervals during the 1-year period. Also, a strong correlation (79%) was observed between the number of tissue samples obtained at the initial and repeated biopsy procedures. In a subset of patients with free and total prostate-specific antigen (PSA) results obtained before the repeated biopsy (n = 813), we were able to construct a multivariate logistic regression algorithm using the patients' age, initial biopsy diagnosis, total PSA, and free/total PSA ratio that could predict the likelihood of cancer on the repeated biopsy with an accuracy of 70%.

CONCLUSIONS: Men who have an initial noncancerous biopsy diagnosis remain at risk of prostate cancer, especially if the initial diagnosis was suspicious or Susp-HGPIN. These data suggest that the initial biopsy strategy needs to be improved and/or expanded to increase the overall cancer detection rate in the primary biopsy. In addition, combining factors such as the initial biopsy diagnosis, family history, digital rectal examination results, prostate gland volume, age, total PSA, and free/total PSA ratio could provide valuable information for predicting the likelihood of cancer.

Morphologic criteria for the diagnosis of prostatic adenocarcinoma in needle biopsy specimens.

Varma M, Lee MW, Tamboli P, Zarbo RJ, Jimenez RE, Salles PG, Amin MB.

Departments of Pathology, Henry Ford Hospital, Detroit, Mich (Drs Varma, Lee, Tamboli, and Zarbo), and Emory University Hospital, Atlanta, Ga (Drs Jimenez, Salles, and Amin).

Arch Pathol Lab Med 2002 May;126(5):554-61 Abstract quote

Context.-The diagnosis of prostate adenocarcinoma in needle core biopsy specimens is based on multiple diagnostic criteria and supportive features, most of which have been defined mainly from observations in transurethral resection and prostatectomy specimens. There is little information on the frequency with which diagnostic and supportive features of prostate cancer occur within benign glands. The few reports dealing with diagnostic criteria of cancer in needle biopsies have been largely confined to analysis of selected cases that posed particular diagnostic difficulty.

Objective.-To analyze the frequency with which numerous diagnostic or supportive features of prostate cancer occur in an unselected, consecutively performed series of 18-gauge prostate needle biopsy specimens.

Design.-Two hundred fifty consecutive 18-gauge prostate needle biopsy specimens (150 malignant and 100 benign) were evaluated, using hematoxylin-eosin-stained histologic sections.

Results.-The frequency of the histologic features in malignant and benign glands was as follows: prominent nucleoli (94% and 25% of malignant and benign specimens, respectively), marginated nucleoli (88% and 7%), multiple nucleoli (64% and 0%), blue-tinged mucinous secretions (52% and 0%), intraluminal crystalloids (40.6% and 1%), intraluminal amorphous eosinophilic material (86.7% and 2%), collagenous micronodules (2% and 0%), glomerulations (15.3% and 0%), perineural invasion (22% and 0%), retraction clefting (38.6% and 7%), and invasion of fat (0.7% and 0%).

Conclusions.-Since not all diagnostic or supportive features of cancer are evident in any single case of cancer, particularly in needle biopsy specimens in which sampling is limited, awareness of these data would be helpful in the assessment of small foci of atypical glands being considered for cancer.

Carcinoma extent in prostate needle biopsy tissue in the prediction of whole gland tumor volume in a screening population.

Lewis JS Jr, Vollmer RT, Humphrey PA.

Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University School of Medicine, St Louis, MO 63110, USA.

Am J Clin Pathol 2002 Sep;118(3):442-50 Abstract quote

Increasing prostate tumor volume has been shown to correlate with numerous adverse prognostic indicators for patients with prostate carcinoma The ability to predict tumor volume from pretreatment parameters is potentially critical in the stratification of patients for different management strategies.

We assessed the capacity of preoperative variables to predict tumor volume in 100 men diagnosed with prostate cancer in a prostate-specific antigen (PSA)-based screening program. Preoperative information included total serum PSA concentration and needle biopsy tissue variables, including Gleason score, number of positive cores, linear extent of carcinoma in millimeters, greatest percentage of carcinoma (in a single core), total percentage of carcinoma (all cores), presence of perineural invasion, and percentage of high-grade carcinoma. The postoperative end point was total tumor volume in radical prostatectomy tissue, calculated by image analysis. We determined independently significant factors and generated a predictive modelfor whole gland tumor volume. Total tumor volume was related significantly in multivariate analysis to 3 preoperative variables: linear extent of carcinoma, exponential number of positive cores, and serum PSA. A predictive model generated based on these 3 variables accounted for only 65% of the natural deviance of the data owing to data-point scatter for individual patients, suggesting that additional variables are needed to more accurately predict tumor volume.

Findings highlight the importance of reporting quantitative measures of tumor amount in prostate needle biopsy specimens; several measures of tumor extent (vs 1 measure) provide maximal information on prostate cancer size.

Number and location of nucleoli and presence of apoptotic bodies in diagnostically challenging cases of prostate adenocarcinoma on needle biopsy.

Aydin H, Zhou M, Herawi M, Epstein JI.

Department of Pathology, Baskent University Hospital, Ankara, Turkey.

Hum Pathol. 2005 Nov;36(11):1172-7 Abstract quote  

There is limited published data regarding the significance of the number or position of nucleoli and the presence of apoptotic bodies in diagnostically challenging cases of adenocarcinoma of the prostate on needle biopsy material.

One hundred consecutive prostate cancers on needle biopsy were sent because of diagnostic difficulty to an expert in urological pathology, and the remaining normal benign prostatic glands on the same core were evaluated for the number and location of nucleoli and for the presence of mitotic figures and apoptotic bodies.

The Gleason scores of the cases were 6 (86%), 7 (9%), and 8 to 10 (5%). For comparison, the same parameters were evaluated in mimickers of cancer on needle biopsy from other cases, including partial atrophy (n = 135), fully developed atrophy (n = 89), adenosis (n = 50), prostate glands with acute inflammation (n = 50), and high-grade prostatic intraepithelial neoplasia (n = 100). Findings were recorded under high dry magnification (x40) using hematoxylin and eosin-stained sections. Although the number and position of nucleoli did not discriminate between cancer and benign mimickers, mitotic figures and apoptotic bodies were more commonly seen in cancer. Apoptotic bodies in particular were seen fairly frequently (34%) in prostatic adenocarcinoma (also seen in 13% of high-grade prostatic intraepithelial neoplasia), yet rarely in benign mimickers on needle biopsy.

Our findings indicate that the presence of apoptotic bodies should be added to the list of histological features that are helpful in the diagnosis of challenging cases of prostate cancer on needle biopsy.

Hum Pathol 2000;31:1515-1519
Quantitation of 150 sequential core biopsies

80% of carcinomas and 63% of high grade PIN were markedly depleted with the contrast especially prominent between benign and malignant epithelium in small carcinomatous foci

There was an advantage to glutaraldehyde fixed tissue over formalin fixation

Unusual subtypes of prostate cancer.

Grignon DJ.

1Department of Pathology, Harper University Hospital and Wayne State University School of Medicine, Detroit, MI, USA.

Mod Pathol 2004;17:316-327 Abstract quote

The vast majority of prostatic tumors developing in adult males are adenocarcinomas. For the most part, variations in histology have not received specific designations and, from a practical approach, have had any specific prognostic implications handled through application of the Gleason grading system. Nonetheless, some of the adenocarcinoma variants have specific clinical features and differential diagnoses. Furthermore, there has been some controversy regarding the appropriate application of the Gleason grading scheme in these tumors. In addition, there are carcinomas that are in fact not adenocarcinomas and that should be kept as distinct entities.

In this paper, the histologic variants of adenocarcinoma are reviewed with emphasis on clinicopathologic features and the clinical relevance of these subtypes. Other carcinomas that occur in the prostate gland are also discussed again with a focus on the clinicopathologic characteristics.

Adenoid cystic/basal cell carcinoma of the prostate: clinicopathologic findings in 19 cases.

Iczkowski KA, Ferguson KL, Grier DD, Hossain D, Banerjee SS, McNeal JE, Bostwick DG.

Veterans Affairs Medical Center, and Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32608-1197, uSA.
Am J Surg Pathol. 2003 Dec;27(12):1523-9. Abstract quote  

Adenoid cystic/basal cell carcinoma (ACBCC) of the prostate has been considered to have indolent biologic potential. However, outcome data are scant, with only one documented metastasis and death.

We describe clinicopathologic features of ACBCC in 19 patients and document outcome in 15. Patients ranged in age from 43 to 83 years. All but one presented with urinary obstruction. ACBCC was diagnosed by transurethral resection in 15 cases, by needle biopsy in 3 cases, and unexpected in 1 case. Four patients had concurrent acinar adenocarcinoma. Histologically, cribriform or adenoid cystic patterns predominated in 12 cases and basal cell carcinoma pattern in 7. Five cases had prominent perineural invasion. ACBCC was immunoreactive for p63 and cytokeratins 7 and 34 beta E12 but not cytokeratin 20. After diagnosis, 5 patients underwent radical prostatectomy, 2 underwent pelvic exenteration, and the rest had no treatment.

ACBCC showed extraprostatic extension in 5 cases and involved the bladder margin in 3. Metastases developed in 4 (21%) patients: liver (2), lung (2), bowel (1), and corpus cavernosum (1). In 15 cases with follow-up (0.3-11.8 years), two patients died of cancer (at 1.5 and 3 years after diagnosis), 3 remain alive with cancer, and 10 have no evidence of cancer. Thus, ACBCC of the prostate is a potentially aggressive neoplasm requiring ablative therapy.


Pathologic Effects of Neoadjuvant Cyproterone Acetate on Nonneoplastic Prostate, Prostatic Intraepithelial Neoplasia, and Adenocarcinoma: A Detailed Analysis of Radical Prostatectomy Specimens From a Randomized Trial

Martin J. Bullock, M.D.; John R. Srigley, M.D.; Lawrence H. Klotz, M.D.; S. Larry Goldenberg, M.D.

Am J Surg Pathol 2002; 26(11):1400-1413 Abstract quote

Neoadjuvant hormonal therapy (NHT; androgen ablation) is used prior to radical prostatectomy (RP) in an attempt to pathologically "downstage" prostatic adenocarcinoma and ultimately to improve disease-free survival.

This study describes the pathologic effects of NHT with the antiandrogen cyproterone acetate, 300 mg/day for 12 weeks, on the RP specimens from men with clinically localized (stage T1 or T2) prostatic adenocarcinoma. There were 101 men in the pretreatment group (CPA) and 91 men in a control group who were treated with surgery alone. The prevalence and extent of morphologic effects were recorded for the nonneoplastic prostate, high-grade prostatic intraepithelial neoplasia, and invasive adenocarcinoma.

The commonest effects on the nonneoplastic prostate were atrophy and basal cell hyperplasia and prominence. High-grade prostatic intraepithelial neoplasia was more commonly identified in the surgery alone group than the CPA group (p <0.01). In the CPA group, flat and low tufted patterns of high-grade prostatic intraepithelial neoplasia predominated. Following NHT, the adenocarcinoma showed characteristic morphologic alterations, including reduction in cytoplasmic quantity, cytoplasmic vacuolation, nuclear pyknosis, reduced gland diameter, and mucinous breakdown. In many cases there was prominence of collagenous stroma, obscuring malignant glands. Compared with the surgery alone group, the CPA group RP specimens had a significantly lower mean specimen weight (40.3 g vs 46.5 g, p = 0.025) and less tumor extent by several measures. Organ-confined tumor (stage pT2, margin negative) was found in 41.6% of the CPA group compared with 19.8% of the surgery alone group (p = 0.0017).

The overall rate of margin positivity was lower in the CPA group (27.7% vs 64.8%, p = 0.001). We consider that the difference in margin positivity is the result of tumor shrinkage with a decreased likelihood of sampling in routine sections. There was no significant difference in the rate of extraprostatic extension between the two groups. There was elevation of the Gleason score in the RP specimens versus baseline biopsy in 60% of the CPA group compared with 33% of the surgery alone group (p = 0.02). The higher rate of elevation in the CPA group largely resulted from an increase in primary or secondary Gleason score 5 tumor, a morphologic artifact introduced by NHT. Because of this, we recommend not giving a Gleason grade to RP specimens following NHT.

Monotherapy with CPA has similar pathologic effects on benign and malignant prostate tissue as does dual agent androgen blockade. Prolonged follow-up of these patients is required to determine if NHT with CPA leads to improved disease-free survival.

Effect of androgen deprivation therapy on prostatic intraepithelial neoplasia.

Bostwick DG, Qian J. Bostwick Laboratories, (DGB, JQ),

Richmond, Virginia, USA

Urology 2001 Aug;58(2 Suppl 1):91-3 Abstract quote

There is a marked decrease in the prevalence and extent of high-grade prostatic intraepithelial neoplasia (PIN) in men with prostate cancer after androgen deprivation therapy (ADT) when compared with untreated cases. Basal cell hyperplasia, cytoplasmic clearing, and prominent atrophy of benign acini, with decreased ratio of acini to stroma, accompany this decrease.

These findings indicate that the benign and dysplastic prostatic epithelium is androgen dependent. In the normal prostatic epithelium, luminal secretory cells are more sensitive to the absence of androgen than basal cells, and the proliferative cells of high-grade PIN share this androgen sensitivity. The loss of some normal, hyperplastic, and dysplastic epithelial cells with ADT is probably because of acceleration of programmed single-cell death. Remarkably little is known about the comparative effect of different forms of chemical ADT on PIN and cancer, although there appears to be a limited and consistent repertoire of morphologic responses to all forms of this therapy. Conversely, blockade of 5alpha-reductase with finasteride has little or no effect on PIN (or benign epithelium and cancer), unlike other forms of ADT.

A recent international consensus conference sponsored by the World Health Organization concluded that identification of high-grade PIN offered the possibility of chemoprevention with hormonal therapy to block the development of clinical cancer. Multiple chemoprevention trials are planned or under way to address this hypothesis.

Clear cell adenocarcinoma of the prostatic utricle in an adolescent.

Gualco G, Ortega V, Ardao G, Cravioto F.

Department of Pathology, Central Armed Forces Hospital, Montevideo, MDEO 11600, Uruguay.
Ann Diagn Pathol. 2005 Jun;9(3):153-6. Abstract quote  

We present a case of a 16-year-old boy with a primary clear cell adenocarcinoma of the prostatic utricle. The patient presented with a 6-month history of intermittent, nonpainful, gross hematuria and an associated right renal agenesis.

Radiographic studies revealed the presence of a solid and cystic mass between the bladder neck and the cranium of the prostate. Serum tests, including prostate-specific antigen, carcinoembryonic antigen, CA-19-9, and human chorionic gonadotropin, were performed and found to be within normal limits. A surgical resection of the mass including prostate and seminal vesicles was performed. Grossly, a polypoid exophytic tumor was present at the prostatic utricle.

Histologically, the tumor shows the classical clear cell morphology reminiscent of the so-called mesonephric adenocarcinomas. At clinical follow-up, the patient is alive and well 18 months after surgical resection.

The present case highlights an unusual phenomenon of the development of an unusual form of adenocarcinoma in an adolescent.
Corpora amylacea in adenocarcinoma of the prostate: incidence and histology within needle core biopsies.

Christian JD, Lamm TC, Morrow JF, Bostwick DG.

1Bostwick Laboratories, Richmond, VA, USA.

Mod Pathol. 2005 Jan;18(1):36-9. Abstract quote

Corpora amylacea in the prostate are a frequent finding in benign acini, but are only rarely observed in adenocarcinoma.

To determine the incidence and comparative histopathology of this finding, we prospectively reviewed all consecutive needle core biopsies (excluding consultations) received at Bostwick Laboratories between December 2001 and July 2003. Among 5130 cases of adenocarcinoma (34% of 15 279 total needle biopsy cases), we identified 19 (31 biopsy specimens) with corpora amylacea within cancerous acini (0.4% incidence).

Patients ranged in age from 51 to 89 years (mean, 68 years). The corpora amylacea were located within cancers with Gleason pattern 3 (28 of 31 specimens), Gleason pattern 4 (one specimen), and Gleason pattern 5 (two specimens), and ranged from less than 0.1-0.3 mm in diameter. Coexistent eosinophilic proteinaceous debris was noted in all 31 specimens, luminal mucin in 19, crystalloids in 15, and collagenous micronodules in two specimens.

Our results indicate that the incidence of corpora amylacea in adenocarcinoma is low, but the presence of such inclusions cannot be used to exclude malignancy.

Adenocarcinoma of the prostate with endometrioid features. A light microscopic and immunohistochemical study of ten cases.

Epstein JI, Woodruff JM.

Cancer 1986 Jan 1;57(1):111-9 Abstract quote

The authors reviewed the histologic slides of 2600 prostatic carcinomas seen at Memorial Hospital from 1963 to 1983.

In ten cases, resection specimens had a predominantly endometrioid appearance. Six patients had polypoid lesions in and around the verumontanum, and one had a polypoid lesion away from the verumontanum. Two patients had no mucosal lesions and one was not cystoscoped. Histologically, the tumors showed a tall pseudostratified columnar epithelium, usually with amphophilic cytoplasm. The cells were arranged either along papillae or in complexes of large acini or in single glands. In eight of the ten cases, the endometrioid carcinomas were associated with a prior or coexistent typical microacinar prostatic adenocarcinoma. In four cases, the endometrioid pattern existed in a pure form, although in two such cases with urethral tumors, the patients had histories of successfully treated microacinar adenocarcinomas of the posterior prostatic lobe. In one case, a urethral endometrioid tumor coexisted with a small posterior lobe microacinar adenocarcinoma.

In five cases, both endometrioid and microacinar carcinomas were seen, including endometrioid and microacinar carcinomas found at the same site at different times (2 cases), tumors with a predominantly endometrioid, yet focally microacinar pattern (1 case), and primary tumors where lymph node metastases had different histologic features (2 cases). Of the three patients with a pure or predominantly endometrioid pattern treated with diethylstilbestrol, two had a marked clinical response.

All ten endometrioid prostatic adenocarcinomas showed prostate-specific antigen and prostate-specific acid phosphatase immunoreactivity, in contrast to none of the control uterine endometrial carcinomas. In material spanning a 20-year period, the authors have not seen a single prostatic tumor entirely analogous to the uterine endometrial carcinoma. Until such proof exists, prostatic carcinomas with endometrioid features are best classified and treated as variants of prostatic duct carcinomas.


Foamy Gland Pattern of Pancreatic Ductal Adenocarcinoma A Deceptively Benign-Appearing Variant

Volkan Adsay, M.D.; Sanjay Logani, M.D.; Fazlul Sarkar, Ph.D.; John Crissman, M.D.; Vainitus Vaitkevicius, M.D.

From The Departments of Pathology and Internal Medicine (V.V.), The Karmanos Cancer Institute, Harper Hospital, Detroit Medical Center, Wayne State University, Detroit, Michigan, U.S.A.

Am J Surg Pathol 2000;24:493-504 Abstract quote

Pathologic diagnosis of pancreatic adenocarcinoma is frequently a challenge, particularly in small biopsies, frozen sections, and in metastatic foci.

Here we report a deceptively benign-appearing and morphologically distinctive pattern of ductal adenocarcinoma with prominent microvesicular cytoplasm, giving the cells a foamy appearance similar to that described in the prostate (Am J Surg Pathol 1996;20:419). This variant, which we refer to as foamy gland pattern (FGP), was frequently misdiagnosed in frozen sections or biopsies and its pathologic stage underestimated in surgical specimens.

Histologically, the diagnostic features were: (1) white and crisply foamy, ``microvesicular'' cytoplasm; (2) often basally located and compressed, hyperchromatic nuclei reminiscent of endocervical glands (and so-called ``adenoma malignum'') or gastric foveolar glands; (3) irregular nuclear contours forming wrinkled (raisinoid) nuclei in some areas; and (4) a distinctive chromophilic condensation of the cytoplasmic material in the luminal aspect of the cells forming a brush border-like zone (BLZ).

Histochemically, this BLZ was positive for mucicarmine, alcian blue, and high iron diamine, but not PAS. The remainder of the cytoplasm was negative for all these stains. In contrast, benign mucinous ducts, which constitute the major differential diagnosis, had more homogeneous acidophilic cytoplasm, lacked BLZ, and showed cytoplasmic staining with PAS. Immunohistochemically, the tumor cells were diffusely and strongly positive for CEA and cytokeratin 8 whereas B72.3 staining was focal and weak. MUC1 staining was largely confined to the BLZ. MUC2 was negative. P53 staining was detected in 16 of the 20 cases studied and was strong and diffuse in five. K-ras mutation was detected in 6 of 8 cases studied.

The clinical findings in the 20 patients in this study (4 pure and 16 mixed with usual ductal carcinoma) did not appear to differ significantly from those of ordinary ductal adenocarcinoma of the pancreas. Eleven patients were men and nine were women; the mean age was 62 years and the mean tumor size was 4.4 cm. Follow-up information was available in 17 patients of whom 7 were alive at an average follow up of 23 months (range, 7–104 mos), and 10 were dead of disease at a median follow up of 15 months (range, 4–42 mos). The median survival of the four patients with pure FGP was 18 months. The median survival did not appear to be significantly longer than that of the patients with resectable ordinary ductal adenocarcinoma in the authors' experience (109 patients, median survival of 12 mos, p = 0.48).

In conclusion, foamy gland pattern of invasive pancreatic ductal carcinoma is morphologically distinctive and is prone to misdiagnosis as a benign process. The pathologic stage is often underestimated as a result of the lack of its recognition and misinterpretation as mucinous ducts. Careful attention to its microscopic features is adequate for accurate diagnosis. Histochemical and immunohistochemical stains are useful in confirming the diagnosis of malignancy in challenging cases.

Prostatic Foamy Gland Carcinoma With Aggressive Behavior Clinicopathologic, Immunohistochemical, and Ultrastructural Analysis

Thuy T. Tran, etal.

Am J Surg Pathol 2001;25:618-623 Abstract quote

Foamy gland carcinoma is a recently described histologic variant of prostatic adenocarcinoma characterized by abundant foamy cytoplasm and minimal cytologic atypia. The biologic behavior and biochemical nature of the foamy adenocarcinoma cells are unknown.

Six cases of prostatic adenocarcinoma with marked foamy appearance were identified from radical prostatectomies. Clinicopathologic, histochemical, immunohistochemical, and ultrastructural analyses were conducted. The patients ranged in age from 50 to 73 years (mean age, 65 years) with preoperative serum prostate-specific antigen levels ranging from 2.7 to 37.5 ng/mL (mean, 15.2 ng/mL).

All six cases were bilateral high-volume tumors. Five of six patients had high-grade tumors with extraprostatic extension. The foamy tumor cells were negative for mucin and lipid stains, but were positive for colloidal iron and Alcian blue stain. Ultrastructurally, the foamy cells displayed numerous intracytoplasmic vesicles and numerous polyribosomes.

The authors conclude that the foamy appearance of these tumor cells is the result of the presence of numerous intracytoplasmic vesicles, and not the result of the presence of lipid or neutral mucin. This study illustrates that foamy gland carcinoma is a distinctive histologic variant of prostatic adenocarcinoma and is often associated with an aggressive behavior despite its deceivingly benign histologic appearance

Pleomorphic Giant Cell Adenocarcinoma of the Prostate: Report of 6 Cases.

*Department of Pathology, University of Pittsburgh Medical Center-Shadyside, Pittsburgh, PA daggerDepartment of Pathology, The Johns Hopkins Hospital, Baltimore, MD.

Am J Surg Pathol. 2006 Oct;30(10):1254-1259 Abstract quote

Pleomorphic tumors with giant cells have been described in a variety of primary sites. However, only a few cases have been described among prostatic carcinomas with only 1 on diagnostic biopsy material.

Five cases were retrieved from the consultation files of one of the authors. One of the cases was retrieved from the surgical pathology files at our institute. Patient ranged in age from 59 to 76 years (mean=65.8 y). The diagnosis was made on needle biopsy (n=3), urethral biopsy (n=1), transurethral resection (n=1), or radical prostatectomy (n=1). In all cases, giant, bizarre, anaplastic cells were present. In 4 of the cases, marked pleomorphism occupied 5% of the specimen, with 20% and 70% bizarre giant cells in the other 2 cases. In one case, the bizarre cells had atypical mitotic figures, with other cases showing no mitoses in the markedly pleomorphic cells. In addition to the pleomorphic giant cell component, multiple coexistent histologic components were seen including Gleason score 9 conventional prostate cancer (n=6), small cell carcinoma (n=1), squamous carcinoma (n=1), and prominent ductal adenocarcinoma differentiation with intraductal spread (n=1).

Immunohistochemically, 4 cases were for negative for prostate-specific antigen in the giant cells, 1 had 5% staining, and the other had 50% positivity in the giant cells. Staining for prostate-specific antigen in the conventional prostate carcinoma component was 1%, 5%, 20%, 50%, 100%, and 100%. The bizarre giant cells were strongly positive for cytokeratins AE1/AE3 and/or Cam 5.2 (n=3). Two cases had a history of conventional prostate cancer 4 years before the giant cell component, 1 treated with Lupron and the other with radiation. Follow-up after diagnosis of the giant cell component: Case 1: dead in 1 year of disease; Case 2: progressive metastases in 2 years; Case 3: alive at 1 year with disease; Case 4: large perineal recurrence after brachytherapy at 3 years; Case 5: radical prostatectomy with extraprostatic extension and seminal vesicle invasion; and Case 6: alive at 3 months, free of disease. Conventional prostate cancer, even when very high grade, typically consists of cells with relatively uniform nuclei.

Our study expands the histology described in prostate cancer to include in very rare cases with prominent pleomorphism and bizarre giant cells. This giant cell component heralds a particularly aggressive clinical outcome.
Pleomorphic giant cell carcinoma of the prostate.

Lopez-Beltran A, Eble JN, Bostwick DG.

Department of Pathology, Cordoba University Medical School, Cordoba, Spain.
Arch Pathol Lab Med. 2005 May;129(5):683-5. Abstract quote  

We report the clinical and pathologic features of 2 cases of pleomorphic giant cell carcinoma of the prostate.

One case was found at autopsy in a 77-year-old man and was composed of high-grade prostatic adenocarcinoma with prominent anaplastic giant cells. The patient presented with metastases to multiple retroperitoneal lymph nodes, liver, and lumbar vertebrae. The second case occurred in a 45-year-old man who underwent transurethral resection of the prostate and was found to have high-grade prostatic adenocarcinoma with an extensive anaplastic giant cell component. The patient presented with distant metastases and died within 9 months. Both regular adenocarcinoma and anaplastic giant tumor cells displayed cytoplasmic immunoreactivity for prostate-specific antigen, prostatic acid phosphatase, and keratin AE1/AE3; in one case, scattered cells were also positive for chromogranin and epithelial membrane antigen.

Pleomorphic giant cell carcinoma is a rare variant of prostatic adenocarcinoma with a poor prognosis that should be considered in the differential diagnosis of prostatic pleomorphic tumors.
Nonspecific (idiopathic) granulomatous prostatitis associated with low-grade prostatic adenocarcinoma.

Val-Bernal JF, Zaldumbide L, Garijo MF, Gonzalez-Vela MC.

Ann Diagn Pathol. 2004 Aug;8(4):242-6. Abstract quote  

Nonspecific granulomatous prostatitis (NSGP) is uncommon and may simulate carcinoma both clinically and microscopically. Concurrent NSGP and prostatic adenocarcinoma is rare. To our knowledge this association has been documented once and it was only rarely mentioned in two large series of NSGP.

We describe a 67-year-old man who presented with a history of prostatism of 1 month's duration. Suprapubic prostatectomy revealed NSGP associated with nodular hyperplasia and low-grade prostatic adenocarcinoma. The pathologist should be aware of the rare association of NSGP and prostatic adenocarcinoma.

Wide sampling of the prostatectomy specimens with NSGP is mandatory to exclude an occult prostatic adenocarcinoma.
Alpha-methylacyl-CoA racemase (P504S)/34betaE12/p63 triple cocktail stain in prostatic adenocarcinoma after hormonal therapy.

Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.


Hum Pathol. 2007 Feb;38(2):332-41. Epub 2006 Nov 28. Abstract quote

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.
Intraductal carcinoma of the prostate on needle biopsy: histologic features and clinical significance.

1Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.


Mod Pathol. 2006 Dec;19(12):1528-35. Abstract quote

Intraductal carcinoma of the prostate (IDC-P) has been described in radical prostatectomies. However, there is limited information as to its histologic features and clinical significance when seen on prostate biopsy. A total of 27 cases of prostate biopsies with only IDC-P (ie no infiltrating cancer anywhere on the biopsy) were studied from the consult files of one of the authors.

IDC-P was defined as malignant epithelial cells filling large acini and prostatic ducts, with preservation of basal cells forming either: (1) solid or dense cribriform patterns or; (2) loose cribriform or micropapillary patterns with either marked nuclear atypia (nuclear size 6 x normal or larger) or comedonecrosis. The numbers of cores involved by IDC-P in the biopsies ranged from 1 to 7, with >1 core involved in 17 cases. The architectural patterns of IDC-P were solid (12), dense cribriform (19), loose cribriform (17), and micropapillary (5). More than one pattern was present in 24 of 27 cases. The cytological features frequently observed in IDC-P were marked pleomorphism (18), non-focal comedonecrosis (22), and mitoses (20). Basal cells were observed on regular hematoxylin and eosin stained slides in 14 cases; in all the cases, basal cells were confirmed by immunohistochemical stains for high molecular weight cytokeratin (n=25) and/or p63 (n=4). After the diagnosis of IDC-P on prostate biopsies, patients were treated by radical prostatectomy (6), radiation (7), hormone (5), combined radiation and hormone (1), or watchful waiting (2).

The follow-up information was not available for six patients. The follow-up times ranged up to 4 years with an average of 2.1 years. In all six radical prostatectomy specimens, high-grade infiltrating carcinoma with Gleason score 8 or 9 was present with five cases also revealing prominent IDC-P. Non-focal extraprostatic extension of carcinoma was observed in five of the six prostatectomy cases with two cases also demonstrating vascular invasion. Three of 16 patients who did not receive radical prostatectomy developed bone metastases.

Our study indicates that IDC-P on prostate biopsies is frequently associated with high-grade cancer and poor prognostic parameters at radical prostatectomy as well as potentially advanced disease following other therapies. These findings support prior studies that IDC-P represents an advanced stage of tumor progression with intraductal spread of tumor. Consideration should be given to treat patients with IDC-P on biopsy aggressively even in the absence of documented infiltrating cancer.

Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone.

Roudier MP, True LD, Higano CS, Vesselle H, Ellis W, Lange P, Vessella RL.


Hum Pathol. 2003 Jul;34(7):646-53 Abstract quote

To better understand the clinical and pathologic features of end-stage, androgen-independent carcinoma of the prostate (CaP), we performed rapid autopsies on 14 men who died of progressive CaP and recorded relevant clinical data.

The timing of tumor progression varied widely. The median time to androgen independence was 2 years (range, 4 months to 13.6 years). The median survival after androgen independence was 1 year (range, 1 month to 3.6 years). Because osseous metastases are prevalent in progressive CaP, up to 20 bone sites were systematically sampled in each patient. Bone metastases were widespread; tumor filled the marrow in an average of 14 bone sites.

Tumor histology and expression of prostate-specific antigen (PSA) and chromogranin A (CGA) were examined in all metastases and were compared with the primary tumor. Five histological patterns of metastatic tumor were observed: solid (10 patients), macroacinar (1 patient), microacinar (1 patient), clear cell (1 patient), and comedocarcinoma (1 patient). Gleason grade of the primary tumor did not predict the histological pattern of the metastases. Although >70% of tumor cells expressed PSA, the fraction of PSA-positive cells varied widely in separate metastases in some patients (standard deviation >25). Likewise, the fraction of neuroendocrine (NE) (CGA-positive) tumor cells in different metastases varied widely. For example, between 0 and 95% of tumor cells in different metastases in 1 patient had a NE phenotype.

The present study highlights the heterogeneity-histologically and immunophenotypically-of metastatic CaP. Consequently, therapy directed to the phenotype of 1 metastasis may have no effect on other metastases in the same patient because of phenotypic heterogeneity.


Mucin-producing urothelial-type adenocarcinoma of prostate: report of two cases of a rare and diagnostically challenging entity.

Curtis MW, Evans AJ, Srigley JR.

1Department of Pathology and Laboratory Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.
Mod Pathol. 2005 Apr;18(4):585-90. Abstract quote  

The differential diagnosis of mucin-producing adenocarcinoma of the prostate includes conventional prostatic adenocarcinoma with mucin production, secondary adenocarcinoma usually of colorectal origin and, very rarely, urothelial-type adenocarcinoma arising from either the prostatic urethra or proximal ducts. Conventional prostatic adenocarcinoma with mucin production is readily identified by routine microscopy and immunohistochemistry. The distinction between secondary adenocarcinoma and urothelial-type adenocarcinoma, however, can present a significant diagnostic challenge. In addition, documented examples of the latter in the prostate are exceptionally rare.

A transurethral resection of prostate specimen and prostatic needle biopsies from two patients showing urothelial-type adenocarcinoma of the prostate were identified in our consultation files. One of the patients subsequently underwent a radical prostatectomy. Both patients had negative gastrointestinal endoscopic workups. Transurethral resection of prostate material from two patients with clinically confirmed secondary adenocarcinoma of colonic origin involving the prostate and a prostatectomy specimen with mucinous conventional prostatic adenocarcinoma were also identified for comparison purposes. Formalin-fixed, paraffin-embedded sections were stained for prostate-specific antigen (PSA), prostatic acid phosphatase, carcinoembryonic antigen, cytokeratin 7, cytokeratin 20 and high molecular weight cytokeratin 34betaE12. The urothelial-type adenocarcinoma cases were diffusely positive for cytokeratin 7 and focally positive for 34betaE12 and cytokeratin 20, consistent with an origin from the urothelium of the prostatic urethra or proximal prostatic ducts. In contrast, the secondary adenocarcinoma of colonic origin cases were diffusely cytokeratin 20 positive and either negative or focally positive for cytokeratin 7 and negative for 34betaE12.

The mucinous conventional prostatic adenocarcinoma was positive for PSA and prostatic acid phosphatase and negative for cytokeratin 7, cytokeratin 20 and 34betaE12. All tumors were positive for carcinoembryonic antigen.

Mucinous adenocarcinoma of the prostate gland.

Epstein JI, Lieberman PH.

Am J Surg Pathol 1985 Apr;9(4):299-308 Abstract quote

Mucinous adenocarcinoma of the prostate gland is one of the least common morphologic variants of prostatic carcinoma. A lack of precision in the definition of these mucinous neoplasms has resulted in reports which have overstated the incidence of this lesion.

Of approximately 1,600 carcinomas of the prostate gland seen at Memorial Hospital from 1963 to 1983, excluding cases with only needle biopsy material, six mucinous prostatic adenocarcinomas were identified. Mucinous prostatic carcinomas were diagnosed when at least 25% of the resected tumor contained lakes of extracellular mucin, and an extraprostatic tumor site was ruled out. In five of the six cases, a cribriform pattern predominated in the mucinous areas. All of the mucinous prostatic tumors had prostate-specific acid phosphatase (PSAP) and prostate-specific antigen (PSA) immunoreactivity.

Our experience and our review of the literature indicate that these tumors do not respond well to hormonal therapy. Contrary to prevalent opinion, they have an aggressive biologic behavior and, like nonmucinous prostate carcinomas, have a propensity to develop bone metastases and increased serum acid phosphatase levels with advanced disease.

Mucinous adenocarcinoma of the prostate: histochemical and immunohistochemical studies.

Ro JY, Grignon DJ, Ayala AG, Fernandez PL, Ordonez NG, Wishnow KI.

Department of Pathology, University of Texas, M.D. Anderson Cancer Center, Houston 77030.

Hum Pathol 1990 Jun;21(6):593-600 Abstract quote

Twelve patients with primary mucinous adenocarcinoma of the prostate were included in a clinicopathologic study; criteria included a total tumor volume more than 25% mucinous and single or clustered tumor cells floating in mucin lakes.

Patient ages were 57 to 81 years; tumor stages were C (three), D (five), and unknown (four). Bone was the most frequent metastatic site (usually osteoblastic), followed by lymph nodes and lungs. Serum levels of prostatic acid phosphatase and prostate-specific antigen were frequently elevated (five of 10 and three of three measured, respectively).

All mucinous adenocarcinomas also contained other histologic patterns: microglandular (four), cribriform (three), comedo (two), solid (two), and hypernephroid (one). Mucinous components composed less than 50% of three tumors, 50% and 75% of six, and more than 75% of three. No tumor contained signet-ring cells. Immunoperoxidase staining was positive for prostatic acid phosphatase and prostate-specific antigen and negative for carcinoembryonic antigen.

Treatment was radiation, estrogen, orchiectomy, or a combination. In two of four patients, serum prostatic acid phosphatase levels normalized after therapy. Seven patients died of disease (mean follow-up, 56 months), and five patients are alive with disease (mean, 32.2 months). The proportion of mucinous component did not affect prognosis.

Mucinous differentiation in prostatic adenocarcinoma.

McNeal JE, Alroy J, Villers A, Redwine EA, Freiha FS, Stamey TA.

Division of Urology, Stanford University School of Medicine, CA 94305-5118.

Hum Pathol 1991 Oct;22(10):979-88 Abstract quote

Morphologic and histochemical analysis was performed on 33 carcinomas with mucin-secreting areas that were identified among 100 carcinomas from radical prostatectomy specimens. The most common mucin-secreting pattern was Gleason grade 3, which usually showed distinctive luminal distention. The "colloid carcinoma" pattern with mucinous lakes was the only histologic pattern that was unique to mucinous areas. Its frequent association with cribriform Gleason grade 4 carcinoma suggests that it is a variant of grade 4 cancer, whose deviant appearance is a consequence of mucus hypersecretion.

Collagenous stromal micronodules, found in 13 cases, are a previously undescribed and distinctive pattern thought to be a stromal reaction to contact with acidic extraluminal mucin. In grade 3 carcinoma, glands that secreted into the stroma rather than the gland lumen accounted for the stromal mucin, which appeared to lead to micronodule formation. In the grade 4 "colloid cancer" pattern, collagenous micronodules sometimes completely obliterated mucinous lakes, isolating residual cribriform glands in a "pseudo-grade 3" pattern.

Lectin histochemical staining showed similar sialated and/or sulfated acidic mucin in all cases. Immunohistochemical staining showed downregulation of several differentiation antigens accompanying the alteration to mucinous differentiation.

Mucinous carcinomas involving the prostate: atypical findings at MR imaging.

Outwater E, Schiebler ML, Tomaszewski JE, Schnall MD, Kressel HY.

Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia 19104.

J Magn Reson Imaging 1992 Sep-Oct;2(5):597-600 Abstract quote

The magnetic resonance (MR) imaging findings in four patients with mucinous tumors involving the prostate are presented. The MR appearance of these tumors differed from that of typical prostatic adenocarcinomas in that the signal intensity on T2-weighted images approximated or exceeded that of the uninvolved peripheral zone.

The unusual appearance of mucinous prostate tumors may present problems in diagnosis and staging with MR imaging

Mucin-producing carcinoma of the prostate: review of 88 cases.

Saito S, Iwaki H.

Art Park Urology Hospital and Clinic, Department of Pathology, Sapporo Medical University, Japan.

Urology 1999 Jul;54(1):141-4 Abstract quote

OBJECTIVES: To report on a case of mucinous carcinoma of the prostate and discuss the clinical and histopathologic features of the mucin-producing carcinoma of the prostate from a review of published reports.

METHODS: Our case and 87 other previously reported cases were evaluated clinically and histologically.

RESULTS: We encountered a case of mucinous carcinoma of the prostate, Stage C, which was treated by radical prostatectomy. After reviewing it and the 87 other cases, we believe that these cases of mucin-producing carcinomas can be divided into three groups: 60 cases of mucinous carcinoma, 17 cases of primary signet-ring cell carcinoma, and 11 cases of mucinous carcinoma with signet-ring cells. Mucinous carcinoma is a variant of high-grade adenocarcinoma of the prostate, wherein there is a 77.8% rate of prostate-specific antigen elevation and a similar rate (77.8%) of response to endocrine therapy. Fifty percent of patients survived 3 years and 25%, 5 years. In contrast, primary signet-ring cell carcinoma conveys one of the worst prognoses among patients with prostate cancer. There are no reliable tumor markers, and there was no response to endocrine therapy. Patients with primary signet-ring cell carcinoma had a 27.3% 3-year survival rate; none survived to 5 years. The clinical features of mucinous carcinoma with signet-ring cells are very similar to primary signet-ring cell carcinoma; again, there was no response to endocrine therapy and the 3-year survival rate was 16.7%.

CONCLUSIONS: Although it has been suggested that mucinous carcinoma is a variant of high-grade adenocarcinoma of the prostate, signet-ring cell carcinoma and mucinous carcinoma with signet-ring cells are other variants of carcinoma that develop in the prostate, and their prognoses are very poor.

Small Cell Carcinoma of the Prostate: An Immunohistochemical Study.

Yao JL, Madeb R, Bourne P, Lei J, Yang X, Tickoo S, Liu Z, Tan D, Cheng L, Hatem F, Huang J, Anthony di Sant'agnese P.

Departments of *Pathology and Laboratory Medicine daggerUrology, University of Rochester Medical Center **Department of Pathology, Rochester General Hospital, Rochester, NY double daggerDepartment of Pathology, Northwestern Memorial Hospital, Chicago, IL section signDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY parallelDepartment of Pathology, Carle Clinic, Urbana, IL paragraph signDepartment of Pathology, University of Texas Health Science Center at Houston musical sharpDepartment of Pathology, Indiana University School of Medicine, Indianapolis, IN.

Am J Surg Pathol. 2006 Jun;30(6):705-712. Abstract quote  

Small cell carcinoma of the prostate (SCPC) is morphologically similar to small cell carcinoma of the lung (SCLC) and maybe misinterpreted as Gleason pattern 5b prostate adenocarcinoma (HGPC). Recognition of SCPC is important because of its different clinical behavior.

This study aims to characterize the immunophenotype of histologically classic SCPC using a comprehensive panel of markers, to better understand its histogenesis, aid in its classification, and evaluate potential therapeutic targets. Using the World Health Organization morphologic criteria for SCLC, 18 SCPC cases were identified; and studied for the following tumor marker groups: prostate specific/related, neuroendocrine, sex steroid hormone receptors, and prognostic/treatment target-related. Ten cases of UPC were used as controls. PSA was positive in 17% of SCPC and neuroendocrine markers were expressed in HGPC. PSA, TTF-1 and CD56 were the most helpful markers in differentiating between SCPC and HGPC (P<0.01), whereas bombesin/GRP, c-kit, bcl-2, and EGFR expression was more frequent in SCPC. SCPC is best diagnosed by following the World Health Organization diagnostic criteria for SCLC.

Immunohistochemical markers can help separate SCPC from HGPC and may be useful in histologically borderline cases. Potential therapeutic targets are identified immunohistochemically in SCPC (Bombesin/GRP, c-kit, bcl-2, and EGFR).
Large Cell Neuroendocrine Carcinoma of Prostate: A Clinicopathologic Summary of 7 Cases of a Rare Manifestation of Advanced Prostate Cancer.

Evans AJ, Humphrey PA, Belani J, van der Kwast TH, Srigley JR.

*Department of Pathology and Laboratory Medicine, University Health Network section signDepartment of Pathology and Laboratory Medicine, Mt Sinai Hospital, Toronto parallelThe Credit Valley Hospital, Mississauga, ON, Canada Department of daggerPathology double daggerDivision of Urology, Washington University School of Medicine, St Louis, MO.

Am J Surg Pathol. 2006 Jun;30(6):684-693. Abstract quote  

Neuroendocrine (NE) differentiation in prostate cancer is typically detected by immunohistochemistry as single cells in conventional adenocarcinoma. Prostatic NE tumors, such as carcinoid or small cell carcinoma, are rare and large cell NE carcinoma (LCNEC) is described only in case reports.

We identified 7 cases of LCNEC and compiled their clinicopathologic characteristics. In 6 cases, there was a history of adenocarcinoma treated with hormone therapy for a mean of 2.4 years (range: 2 to 3 y). The remaining case was de novo LCNEC. LCNEC was incidentally diagnosed in palliative transurethral resection specimens in 5 cases. The mean patient age at diagnosis with LCNEC was 67 years (range: 43 to 81 y). LCNEC comprised solid sheets and ribbons of cells with abundant pale to amphophilic cytoplasm, large nuclei with coarse chromatin and prominent nucleoli along with brisk mitotic activity and foci of necrosis. In 6 cases, there were foci of admixed adenocarcinoma, 4 of which showed hormone therapy effects. LCNEC was strongly positive for CD56, CD57, chromogranin A, synaptophysin, and P504S/alpha methylacyl CoA racemase. There was strong bcl-2 overexpression, expression of MIB1, and p53 in >50% of nuclei, focally positive staining for prostate specific antigen and prostatic acid phosphatase and negative androgen receptor staining. Follow-up was available for 6 patients, all of who died with metastatic disease at mean of 7 months (range: 3 to 12 mo) after platinum-based chemotherapy.

LCNEC of prostate is a distinct clinicopathologic entity that typically manifests after long-term hormonal therapy for prostatic adenocarcinoma and likely arises through clonal progression under the selection pressure of therapy.
Prognostic Significance of Paneth Cell-like Neuroendocrine Differentiation in Adenocarcinoma of the Prostate.

Tamas EF
Epstein JI.

Departments of *Pathology daggerUrology double daggerOncology, Johns Hopkins Hospital, Baltimore, MD.


Am J Surg Pathol. 2006 Aug;30(8):980-985 Abstract quote

The prognostic significance of Paneth cell-like neuroendocrine differentiation in adenocarcinoma of the prostate has not yet been established.

We studied 36 cases of adenocarcinoma of the prostate showing Paneth cell-like neuroendocrine differentiation, including needle biopsy specimens (n=27), radical prostatectomies (n=8), and transurethral resection specimens (n=1). Paneth cell-like neuroendocrine cells (NECs) were observed as either patchy isolated cells or diffusely involving glands or nests. With Gleason pattern 3, a patchy pattern of NECs was seen in 18/19 cases with only 1/19 (5.3%) case showing diffuse NECs. All the 4 Gleason pattern 4 cases had patchy NECs. Of the 21 cases with Gleason pattern 5, 18 (85.7%) had diffuse NECs with the remaining 3 exhibiting patchy NECs. Radical prostatectomy was performed in 16/36 (44.4%). Tumor was organ confined in 10/16 cases (62.5%). Extraprostatic extension (EPE) with positive surgical margins was seen in 6/16 cases (37.5%). In 4 cases, seminal vesicles were positive for cancer. Pelvic lymph nodes were free of tumor in all cases. The actuarial prostate specific antigen progression-free risk at 5 years and 7 years was 92% and 80%, respectively. Only 2 patients progressed after radical prostatectomy and they both had Gleason score 7 cancer with extraprostatic extension and seminal vesicle invasion.

Of the 16 radical prostatectomy cases, 8 (50%) had a Gleason pattern 5 component either on needle biopsy or at radical prostatectomy, with nests, cords, or single cells containing Paneth cell-like neuroendocrine differentiation. Five of these 6 cases with Gleason pattern 5 and available follow-up information had no evidence of progression with mean and median follow-ups of 46 months. Radiation therapy either as monotherapy or combined with hormonal therapy was used to treat patients in 13/36 cases.

Overall only 2 patients progressed, one with clinical T2 and the other T3 disease. Of the 5 cases with Gleason pattern 5 composed in part or totally by NECs treated by radiation therapy, all are without evidence of recurrence with a mean and median follow-up of 47 and 45 months, respectively. Of the remaining 5 cases with available follow-up treated with watchful waiting, hormone therapy, or cryotherapy, 4 had Gleason pattern 5 tumor with NECs. Of these 4 cases, 3 had no progression with a mean and median follow-up of 42.5 and 60.5 months, respectively. Despite the cells' bland histologic appearance, strictly applying the Gleason grading system one would have to assign a Gleason pattern 5 to these foci with no glandular differentiation.

The current study demonstrates that applying the Gleason score to these foci does not accurately reflect their clinical behavior. In cases with Paneth cell-like NECs, only the conventional adenocarcinoma component should be assigned a Gleason score. In cases in which the entire tumor is composed of Paneth cell-like cells and areas of the tumor lack glandular differentiation, the tumors should not be assigned a Gleason score and a comment should be provided as to the generally favorable prognosis of this morphologic pattern of neuroendocrine differentiation.
PIN For prognostic and pathogenetic signficance of PIN, see Pathogenesis section
Widespread High-grade Prostatic Intraepithelial Neoplasia on Prostatic Needle Biopsy: A Significant Likelihood of Subsequently Diagnosed Adenocarcinoma.

Departments of *Pathology daggerUrology, and double daggerOncology, The Johns Hopkins Hospital, Baltimore, MD.


Am J Surg Pathol. 2006 Sep;30(9):1184-1188. Abstract quote

In comparison with earlier studies, recent reports have demonstrated a lower incidence of prostate carcinoma after an initial diagnosis of high-grade prostatic intraepithelial neoplasia (HGPIN). The latter has led to a general tendency to reconsider the absolute need for a rebiopsy in this setting.

The current retrospective study assesses the subsequent likelihood of identifying prostatic adenocarcinoma (PCa) in 41 patients with an initial diagnosis of "widespread" HGPIN defined as HGPIN present in 4 or more biopsy cores. All patients underwent at least 1 follow-up (F/U) sampling procedure in a period of 1 to 41 months. PCa was found in 16/41 patients (39%), all except 1 identified on the first F/U biopsy with the remaining patients diagnosed on a transurethral resection after a negative first F/U biopsy. All but 1 prostatic carcinoma diagnoses were obtained within 2 years from initial biopsy with 10 rendered within the first year. On average, prostate cancer was identified at 10.4 months (range: 1 to 36). One-fourth of all identified prostatic carcinomas were of Gleason score 7 or more. In 4 additional patients (9.7%), F/U biopsy revealed HGPIN with adjacent atypical small glands suspicious but not diagnostic of carcinoma (PINATYP). Of 41 patients, 10 (24.3%) continued to show HGPIN with the remaining 11/41 patients (26.8%) showing benign prostatic tissue. Patients >/=70 years of age at the time of initial biopsy had a statistically significant higher rate of PCa or HGPIN/PINATYP diagnosis on repeat biopsy compared with younger patients (P=0.02), with 55% of older men being diagnosed with cancer as compared with 33% in younger men. Patients with fewer cores sampled on initial biopsy were more likely to be diagnosed with carcinoma as opposed to HGPIN/PINATYP on F/U (P=0.015). Other factors such as the number of F/U procedures, serum prostate-specific antigen level before initial HGPIN biopsy, number of cores per F/U biopsy, and F/U interval length did not affect the likelihood of finding carcinoma.

In summary, our study reveals a 39% risk of finding PCa on repeat biopsies obtained after an initial diagnosis of widespread HGPIN. Our findings support the need for a repeat biopsy in this subset of patients.
The utility of Ki-67 expression in the differential diagnosis of prostatic intraepithelial neoplasia and ductal adenocarcinoma.

Rioux-Leclercq N, Leray E, Patard JJ, Lobel B, Guille F, Jouan F, Bellaud P, Epstein JI.

Hum Pathol. 2005 May;36(5):531-5. Abstract quote  

Summary Cribriform and/or papillary prostatic lesions observed on limited tissue, such as needle biopsy, can pose diagnostic dilemmas. One such area of difficulty is the distinction between papillary and/or cribriform prostatic high-grade prostatic intraepithelial neoplasia (HG-PIN) and ductal adenocarcinoma.

Over 48 months, we identified 17 cases of ductal adenocarcinoma and 17 cases of HG-PIN from radical retropubic prostatectomy specimens. The HG-PIN lesions were in all cases associated with an acinar prostatic adenocarcinoma component. For each case, we evaluated the proliferative activity, assessed by Ki-67 immunohistochemistry. The majority (82%) of ductal adenocarcinomas were composed of mixed papillary and cribriform patterns, with the remaining demonstrating pure papillary or cribriform patterns. The HG-PIN lesions showed a papillary, cribriform, or mixed papillary/cribriform architecture.

The proliferative activity, defined as Ki-67 labeling index, was statistically higher in ductal adenocarcinoma (mean 33%, range 21%-66%) as compared with HG-PIN (mean 6%, range 2%-15%), with no overlap in the Ki-67 indices ( P = 0001). A combination of histological features and measurements of cellular proliferation may be helpful to distinguish HG-PIN from ductal adenocarcinoma in limited prostatic tissue samples.

Use of interphase fluorescence in situ hybridization in prostate needle biopsy specimens with isolated high-grade prostatic intraepithelial neoplasia as a predictor of prostate adenocarcinoma on follow-up biopsy.

Bastacky S, Cieply K, Sherer C, Dhir R, Epstein JI.

Hum Pathol 2004;35:281-289 Abstract quote

Isolated high-grade prostatic intraepithelial neoplasia (HGPIN) on needle biopsy confers an increased risk of prostate carcinoma (CaP) on follow-up biopsy.

The aim of this study is to determine whether paraffin-section fluorescence in situ hybridization (FISH) of specific chromosome/oncogene copy number abnormalities (CNAs) in biopsy specimens with isolated HGPIN increases the predictive value for CaP on repeat biopsy. Cases were divided into 3 groups: controls (n = 8) and sextant biopsy specimens with isolated HGPIN without CaP (group A; n = 11) and with CaP (group B; n = 14) on follow-up biopsy. Dual-color FISH assessing c-myc, HER-2/neu, chromosome region 7q31 (D7S486), and corresponding chromosome centromeres was performed. An amplification ratio (AR) for each marker centromere was derived for each biopsy specimen, with AR ranges designated as no/low, low-intermediate, and high. Also calculated for each marker were the percentage of cells with marker amplification, hyperdiploidy, and monosomy.

A composite score for each biopsy specimen was calculated based on these parameters, with a possible range of 0 to 15. The specific chromosomal oncogene CNAs were as follows: for chromosome 7/7q31, 2 of 11 (18%) in group A and 6 of 14 (43%) in group B; for chromosome 8/c-myc, 4 of 11 (36%) in group A and 9 of 13 (69%) in group B; and for chromosome 17/HER-2/neu, 10 of 10 (100%) in group A and 13 of 14 (93%) in group B. The mean composite score was 0 for controls, 2.5 for group A, and 4.7 for group B. Composite scores >/=4 for the 3 groups were 0 of 9 (0%) for controls, 1 of 11 (12%) for group A, and 8 of 14 (57%) for group B. These differences were statistically significant (P = 0.015). One group A patient with a high composite score (6) had atypical small glands on follow-up biopsy at <1 year. Chromosome/oncogene CNAs are uncommon in control patients, occurring with increasing frequency and magnitude in patients with isolated HGPIN without and with follow-up CaP. Chromosome/oncogene CNAs in HGPIN are mostly of the low to intermediate level and display intercellular heterogeneity. HER-2/neu amplification is common in HGPIN with and without follow-up CaP. Chromosome 7 and 8 aneusomy and 7q31 and c-myc amplification are greater in HGPIN with follow-up CaP. Patients with isolated HGPIN and high composite score without follow-up CaP are uncommon; these patients may have a small, unsampled CaP.

Although patients with HGPIN without CaP are more likely to have a low composite score, a subset of patients with follow-up CaP have low composite score, suggesting (1) mutational pathways independent of chromosomes 7, 8, and 17 and HER-2/neu, c-myc, and chromosome region 7q31 CNAs; (2) CaP derived from an independent, unsampled focus of HGPIN; or (3) CaP not derived from HGPIN.

High-grade prostatic intraepithelial neoplasia.

Bostwick DG, Qian J.

1Bostwick Laboratories, Richmond, VA, USA.
Mod Pathol 2004;17:360-379 Abstract quote

High-grade prostatic intraepithelial neoplasia (PIN) is now accepted as the most likely preinvasive stage of adenocarcinoma, almost two decades after its first formal description. PIN has a high predictive value as a marker for adenocarcinoma, and its identification warrants repeat biopsy for concurrent or subsequent invasive carcinoma.

The only method of detection is biopsy; PIN does not significantly elevate serum prostate-specific antigen (PSA) concentration or its derivatives and cannot be detected by current imaging techniques, including ultrasound.

Most patients with PIN will develop carcinoma within 10 years. PIN is associated with progressive abnormalities of phenotype and genotype, which are similar to cancer rather than normal prostatic epithelium, indicating impairment of cell differentiation with advancing stages of prostatic carcinogenesis. Androgen deprivation therapy decreases the prevalence and extent of PIN, suggesting that this form of treatment may play a role in chemoprevention.

Architectural patterns of high-grade prostatic intraepithelial neoplasia.

Bostwick DG, Amin MB, Dundore P, Marsh W, Schultz DS.

Department of Pathology, Mayo Clinic, Rochester, MN 55905.

Hum Pathol 1993 Mar;24(3):298-310 Abstract quote

High-grade prostatic intraepithelial neoplasia (PIN) is characterized by cellular proliferations within pre-existing ducts and glands with cytologic changes mimicking adenocarcinoma, including prominent nucleoli, but lacking stromal invasion.

To determine the architectural spectrum of high-grade PIN, 60 serially sectioned radical prostatectomy specimens with PIN and cancer were reviewed.

Four common patterns of high-grade PIN were identified, usually with multiple patterns in each case: tufting (in 87% of cases), micropapillary (in 85% of cases), cribriform (in 32% of cases), and flat (in 28% of cases). Tumor grade was not significantly associated with any pattern of PIN.

Luminal cytoplasmic apical blebs were found in all cases regardless of the pattern of PIN. A variety of associated architectural and cytologic features were observed with high-grade PIN: epithelial arches (in 60% of cases), cellular trabecular epithelial bars (in 22% of cases), "Roman" bridges (in 30% of cases), partial gland involvement (in 82% of cases), basal cell layer disruption with glandular budding (in 23% of cases), large cystic gland involvement (in 10% of cases), involvement by nodular hyperplasia (in 5% of cases), microcalcifications (in 8% of cases), proteinaceous luminal secretions (in 62% of cases), corpora amylacea (in 55% of cases), exfoliated cells of PIN (in 42% of cases), luminal crystalloids (in 3% of cases), and mucinous metaplasia (in 2% of cases).

High-grade PIN exhibits a variety of architectural patterns while retaining the distinctive cytoplasmic apical blebs and diagnostic nuclear and nucleolar features. Identification of high-grade PIN warrants a further search for invasive carcinoma, but should not influence or dictate decisions regarding definitive therapy.

Prevalence and distribution of prostatic intraepithelial neoplasia in salvage radical prostatectomy specimens after radiation therapy.

Cheng L, Cheville JC, Pisansky TM, Sebo TJ, Slezak J, Bergstralh EJ, Neumann RM, Singh R, Pacelli A, Zincke H, Bostwick DG.

Department of Pathology, Indiana University School of Medicine, Indianapolis 46202, USA.

Am J Surg Pathol 1999 Jul;23(7):803-8 Abstract quote

High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostate cancer. The effect of radiation therapy (RT) on the prevalence of PIN is uncertain.

We studied 86 patients who underwent salvage radical prostatectomy after irradiation failure at the Mayo Clinic. The prevalence, volume, multicentricity, spatial proximity to cancer, and architectural patterns of PIN were evaluated. High-grade PIN was identified in 53 (62%) of 86 prostatectomy specimens. Multiple architectural patterns were usually observed, including tufting in 87%, micropapillary in 66%, cribriform in 38%, and flat in 17%. The mean volume of PIN was 0.12 cm3 (range, 0.05-1.20 cm3). PIN was usually multicentric (70%), with a mean number of PIN foci of 2.5 (range, 1-10). Ninety-four percent of PIN foci were located within 2 mm of invasive cancer. There was no correlation between PIN and pathologic stage, surgical margin, tumor size, DNA ploidy, post-RT Gleason score, time interval from RT to biopsy-proven recurrence, postoperative prostate-specific antigen level, distant metastasis-free survival, or cancer-specific survival.

Our examination of salvage radical prostatectomy specimens indicated that the prevalence and extent of PIN appeared to be reduced after RT compared to published studies of prostatectomies without prior RT.

Foamy gland high-grade prostatic intraepithelial neoplasia.

Berman DM, Yang J, Epstein JI.

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Am J Surg Pathol 2000 Jan;24(1):140-4 Abstract quote

A 60-year-old man underwent radical prostatectomy for biopsy-proved adenocarcinoma of the prostate.

Histologic examination of the entirely embedded prostatectomy specimen revealed extensive ordinary adenocarcinoma, Gleason's grade 3 + 3 = 6, involving both sides of the gland, and extending into extraprostatic soft tissue at the left base. Adjacent to the carcinoma, and separately, extensive high-grade prostatic intraepithelial neoplasia (PIN) was identified, much of which showed bland nuclei and abundant xanthomatous cytoplasm, identical morphologically to that seen in foamy gland prostate carcinoma. However, unlike foamy gland carcinoma, the foamy glands in the current patient were large, showed papillary infolding, and were associated with a discontinuous layer of basal cells, demonstrated by immunostaining for high-molecular weight cytokeratin. No invasive foamy gland carcinoma was identified in the prostatectomy specimen. Immunostains for Ki-67 showed an increased proliferation rate in foamy high-grade PIN glands when compared with adjacent benign glands. Review of additional outside biopsy material revealed foamy gland high-grade PIN on four of seven needle cores, two of which showed no carcinoma.

This patient demonstrates a new subtype of high-grade PIN that is difficult to recognize on needle biopsy. It is important to distinguish foamy gland high-grade PIN from its infiltrating counterpart, and it is critical to recognize because of the association of high-grade PIN with prostate carcinoma.

High-grade prostatic intraepithelial neoplasia with adjacent small atypical glands on prostate biopsy.

Kronz JD, Shaikh AA, Epstein JI.

Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD 21231, USA.

Hum Pathol 2001 Apr;32(4):389-95 Abstract quote

With high-grade prostatic intraepithelial neoplasia with adjacent small atypical glands (PINATYP), the issue is whether the small glands represent budding or tangentially sectioned glands off of adjacent high-grade prostatic intraepithelial neoplasia (PIN) or invasive cancer next to high-grade PIN. The histology and significance of PINATYP on biopsy have not been described.

Among 574 cases of high-grade PIN lesions on needle biopsy, we identified 71 cases of PINATYP. Most cases were consultations, and 51 cases were available for histologic review. At least 1 follow-up prostate biopsy was performed in each of 55 cases. Immunohistochemistry for high-molecular-weight cytokeratin (HMWCK) was performed on cases in which material was available. The average patient age at diagnosis was 65.5 years (range, 48 to 103 years). The initial digital rectal examination, transrectal ultrasound, serum prostate-specific antigen (PSA) level, PSA velocity, and family history of prostate cancer did not predict cancer on repeat biopsy.

In 39% of cases, high-grade PIN had a predominantly flat pattern, and remaining cases showed a predominance of other patterns (tufting, micropapillary, cribriform). The average number of high-grade PIN glands and adjacent small atypical glands were 11.5 (1 to 60) and 5.3 (1 to 21), respectively. The farthest adjacent small atypical gland averaged 0.12 mm from the high-grade PIN (0.01 mm to 0.4 mm), as measured with an ocular micrometer. The following histologic features did not predict cancer on repeat biopsy: more than 1 core involved by the high-grade PIN; number of high-grade PIN glands; number of small atypical glands; distance of small atypical glands from the high-grade PIN; size and percentage of nucleoli; marked nuclear pleomorphism; and mitoses.

Overall, the risk of cancer on repeat biopsy was 46%. Two findings predicted a lower risk of cancer on repeat biopsy: younger age (62.2 years benign v 68.3 years cancer; P =.004) and predominantly flat high-grade PIN (P =.007).

In our material, PINATYP appears to be a greater risk factor than high-grade PIN alone in predicting cancer on rebiopsy. Although age and predominant pattern of associated high-grade PIN may be helpful in predicting which men with this lesion will have cancer on rebiopsy, they cannot be used reliably; therefore, all men with PINATYP should undergo repeat biopsy.

Inverted (Hobnail) High-Grade Prostatic Intraepithelial Neoplasia (PIN) Report of 15 Cases of a Previously Undescribed Pattern of High-Grade PIN

Pedram Argani, M.D. ; Jonathan I. Epstein, M.D.

From the Department of Pathology (P.A., J.I.E.) and the Brady Urologic Institute (J.I.E.), Johns Hopkins Hospital, Baltimore, Maryland, U.S.A.

Am J Surg Pathol 2001;25:1534-1539 Abstract quote

We report 15 cases of a distinctive and previously unrecognized variant of high-grade prostatic intraepithelial neoplasia (HGPIN) that is characterized by polarization of enlarged secretory cell nuclei toward the glandular lumen.

We designate this lesion inverted or hobnail HGPIN. In all cases inverted HGPIN was identified on needle biopsy where it merged with typical micropapillary–tufted HGPIN. Inverted secretory cell nuclei frequently demonstrated less prominent nucleoli than adjacent noninverted secretory cell nuclei, yielding a sense of maturation that falsely suggested a non-neoplastic process. Inverted HGPIN was associated with concurrent prostatic adenocarcinoma in seven cases and with atypical glands suspicious for carcinoma in two other cases, whereas in six other cases inverted HGPIN was the only lesion identified. In both radical prostatectomies that followed these biopsies that were available for review, inverted HGPIN was localized to the peripheral zone of the prostate where it merged with usual forms of HGPIN and carcinoma.

Inverted HGPIN is a morphologically distinctive form of HGPIN that shares the association with carcinoma and peripheral zone localization with other recognized forms of HGPIN.


Pseudohyperplastic Prostatic Adenocarcinoma on Needle Biopsy and Simple Prostatectomy

Angelique W. Levi, M.D.; Jonathan I. Epstein, M.D.

From the Departments of Pathology (A.W.L., J.I.E.) and Urology (J.I.E.), The Johns Hopkins Medical Institutions, Baltimore, Maryland

Am J Surg Pathol 2000;24:1039-1046 Abstract quote

Prostatic adenocarcinoma resembling benign hyperplastic glands architecturally is a recently recognized entity. In the only prior study on this entity, 100 needle biopsies were studied and only two contained carcinoma with pseudohyperplastic features, which occupied a small percentage of the cancer.

The current study investigates histologic attributes of pseudohyperplastic prostatic adenocarcinoma on needle biopsy and simple prostatectomy in which the pseudohyperplastic regions represent the majority of the cancer. The authors reviewed outside cases received in consultation by one of the authors (J.I.E.) and the surgical pathology files of Johns Hopkins Hospital from January 1991 to August 1998 and identified 20 cases of needle biopsy and simple prostatectomy in which 60% of the cancer had benign architectural features.

The majority (19 of 20) were consult cases. Of the 20 cases studied, 16 were needle biopsies, two were transurethral resections of the prostate, and two were enucleations. Cancer involved one core in 75% of the needle biopsies. In 13 of the 20 cases (65%), 90% of the cancer had pseudohyperplastic features. Benign features included papillary infoldings in all cases, large atypical glands in 95% of cases, branching in 45% of cases, and corpora amylacea in 20% of cases. The extent of pseudohyperplastic cancer ranged from 1.0 to 10.0 mm (average, 3.7 mm).

Within the pseudohyperplastic foci, features helpful in establishing a malignant diagnosis were nuclear enlargement in 95% of cases, pink amorphous secretions in 70% of cases, occasional to frequent nucleoli in 45% of cases, and crystalloids in 45% of cases. Other features associated with malignancy (mitoses, blue-tinged mucin, adjacent high-grade prostatic intraepithelial neoplasia, and perineural invasion) were seen infrequently. Immunohistochemical stains for high-molecular weight keratin showed an absence of basal cells in the pseudohyperplastic areas in all 20 cases, confirming the diagnosis of cancer.

It is critical to recognize pseudohyperplastic prostatic adenocarcinoma and the features needed to establish a malignant diagnosis so these carcinomas are not misdiagnosed as benign.


Atypia in nonneoplastic prostate glands after radiotherapy for prostate cancer: duration of atypia and relation to type of radiotherapy.

Magi-Galluzzi C, Sanderson H, Epstein JI.


Am J Surg Pathol 2003 Feb;27(2):206-12 Abstract quote

It is unknown how long postradiation atypia of benign prostate glands persists and whether the type of radiation is a factor. Forty-four cases consisting of 37 needle biopsies and 7 transurethral resections of the prostate seen in consultation (January 1997 to September 2000) were studied. In two men (5%), the cases were initially sent without a history of radiotherapy. Thirteen patients had minimal cancer (one core) with the remaining showing no residual tumor. Twenty patients were treated with interstitial radiotherapy (brachytherapy) (IRT), 17 with external beam radiation (XRT), and 7 with a combination of both (CT). The time interval between the treatment and tissue sampling ranged from 8 to 72 months (mean 3 months). Slides were reviewed blindly to the type of radiation and the time interval.

Radiation-induced atypia in nonneoplastic glands, stromal fibrosis, and vascular changes was scored separately 0-3, with 0 showing no radiation injury and grade 3 showing prominent nuclear atypia, stromal fibrosis, and vascular hyalinization.

We derived a combined score for the epithelial atypia from 0 to 300 (% of glands x grade) for each biopsy. For each case, an overall grade from 0 to 3 was given separately for the stromal and vascular changes. Cases were divided into three groups based on time between treatment and biopsy: <24 months (n = 14), between 24 and 48 months (n = 19), and >48 months (n = 11). Because the scores for epithelial atypia with IRT and CT were the same, we combined them into one group.

There was more atypia in cases treated with IRT/CT (mean score 190) than XRT (mean score 105) (p <0.00001). There was also a greater degree of stromal fibrosis with IRT/CT than XRT (p <0.04). There was no correlation between the type of treatment and the effect on vessels. There was no change over time in epithelial atypia in men treated with IRT/CT. With XRT, there was less epithelial atypia in cases biopsied >48 months after treatment (mean score 57) compared with those with a shorter interval between biopsy and treatment (mean score 132) (p = 0.02).

Radiation atypia in benign prostate glands may persist for a long time after the initial treatment, resulting in a significant pitfall in evaluating prostate biopsies. Prominent radiation effect (100% of the glands showing grade 2 and 3 atypia) was detected up to 72 months in one of the patients treated with IRT. In some cases, the clinician may not be aware of a prior remote history of radiation or does not relay this history to the pathologist.

The pathologist must recognize radiation atypia without relying on the clinician to provide this history. The type of radiation therapy (IRT/CT vs XRT) is a major factor in the degree and duration of postradiation epithelial atypia.

Distorted Rectal Tissue on Prostate Needle Biopsy: A Mimicker of Prostate Cancer.

Schowinsky JT, Epstein JI.

Departments of *Pathology daggerUrology and Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD.

Am J Surg Pathol. 2006 Jul;30(7):866-870. Abstract quote  

Rectal tissue is often seen in needle biopsies of the prostate gland. On rare occasion distorted rectal glands can mimic prostatic adenocarcinoma, an issue not previously addressed in the peer-reviewed literature.

We evaluated 16 prostate needle biopsies received in consultation where the submitting pathologist questioned whether a focus of rectal tissue was prostate cancer. In addition to the distorted architecture, features mimicking prostate cancer included: (1) blue-tinged intraluminal mucinous secretions in 10 cases (63%), (2) prominent nucleoli in 6 cases (37%), (3) mitotic activity in 6 cases (37%), (4) extracellular mucin in 5 cases (31%), and (5) adenomatous changes of the rectal tissue in 1 case (6%).

Immunohistochemical results further mimicked prostate cancer with negative stains for the basal cell markers high-molecular weight cytokeratin (n=6) and p63 (n=4), and positive stains for racemase in 4 of 5 biopsies. Diagnostic clues to recognizing that these foci were distorted rectal fragments were the presence of (1) lamina propria in 12 cases (75%), (2) rectal tissue located on a detached fragment of tissue in 10 biopsies (63%), (3) associated inflammation in 10 cases (63%), (4) goblet cells in 7 cases (44%), and (5) muscularis propria in 6 cases (37%). In 2 cases, there was negative staining for prostate specific antigen (PSA) and in 1 case negative staining for cytokeratin 7 and positivity for cytokeratin 20.

Rectal glands are associated with many of the classical features of prostate cancer, and immunohistochemistry may be misleading. Recognition of these features mimicking prostate cancer and awareness of other findings that are diagnostic of rectal tissue on biopsy can prevent a misdiagnosis of atypical prostate glands or prostate cancer.
Sarcomatoid Carcinoma of the Prostate: A Study of 42 Cases.

Departments of *Pathology daggerUrology double daggerOncology, The Johns Hopkins Hospital, Baltimore, MD.


Am J Surg Pathol. 2006 Oct;30(10):1316-1321 Abstract quote

Sarcomatoid carcinoma of the prostate is a rare type of prostatic cancer. With the exception of 1 study, the morphologic features and patient outcomes have been reported only in relatively small case series and individual reports.

We examined transurethral resection, needle biopsy, and radical prostatectomy specimens from 42 patients with sarcomatoid carcinoma of the prostate, all of which were received in consultation. Clinical information on 32 patients was obtainable. Five patients were lost to follow-up and information on the 5 remaining patients could not be obtained. Prior prostatic adenocarcinoma: The majority of patients (n=21; 66%) had a prior history of acinar adenocarcinoma of the prostate. Of the 14 men with available data, reported Gleason scores were 6 (n=7), 8 (n=4), and 10 (n=3). Of the remaining patients for whom this information was known, 11 patients presented with de novo sarcomatoid carcinoma. The time between the original diagnosis of acinar adenocarcinoma and diagnosis of sarcomatoid carcinoma ranged from 6 months to 16 years (mean 6.8 y).

Concurrent adenocarcinoma: The majority of patients demonstrated a concurrent high grade acinar carcinoma of Gleason score 7 (n=3), 8 (n=9), 9 (n=10), and 10 (n=10). A subset of patients contained an admixed ductal adenocarcinoma (n=4), small cell carcinoma (n=3), squamous cell carcinoma (n=3), or other unusual pattern of prostate carcinoma (n=3). In 1 case, the diagnosis was based on immunohistochemical evidence of epithelial differentiation along with the history of prior adenocarcinoma. Morphology of the sarcomatoid component: The percentage of sarcomatoid growth ranged from 5% to 99% (mean 65%). Bizarre atypia with giant cells was present in 55% of cases. Admixed heterologous elements were identified in 10 cases (29%), including osteosarcomatous (n=7), chondrosarcomatous (n=5), and rhabdomyosarcomatous (n=2) elements. Of the 12 cases with received immunostains of the sarcomatoid component, 5/7 cases were at least focally positive for cytokeratin, 1/1 case was focally positive for Cam5.2, and 3/6 cases were focally positive for prostate acid phosphatase. The sarcomatoid component did not demonstrate immunoreactivity for prostate-specific antigen in 8 cases. Prognosis: approximately half of all patients developed metastatic disease either at time of presentation or subsequently. Of patients with meaningful follow-up, 6/7 died within 1 year of the diagnosis of sarcomatoid carcinoma; 20 were alive yet with very short follow-up (median 1 y; mean 2.3 y). Kaplan-Meier analysis revealed that the actuarial risk of death at 1 year after diagnosis of sarcomatoid carcinoma was 20%. No correlation was identified between patient survival and morphologic features, before radiation or hormone therapy, or concurrent high-grade prostate cancer. Sarcomatoid carcinoma demonstrates diverse spindle and epithelial cell morphologies. The sarcomatoid component often has heterologous elements and, in 1 case, no epithelial component was seen on hematoxylin and eosin-stained sections. The epithelial component is typically high-grade acinar adenocarcinoma, yet other aggressive tumor subtypes such as ductal adenocarcinoma and small cell carcinoma may also be seen.

Sarcomatoid carcinoma is an aggressive form of prostate cancer, the prognosis of which is dismal regardless of other histologic or clinical findings.
Anatomic distribution and pathologic characterization of small-volume prostate cancer (<0.5 ml) in whole-mount prostatectomy specimens.

Cheng L, Jones TD, Pan CX, Barbarin A, Eble JN, Koch MO.

[1] 1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA [2] 2Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA.
Mod Pathol. 2005 Aug;18(8):1022-6. Abstract quote  

Some investigators consider small-volume prostate cancer (0.5 ml or less) without Gleason pattern 4/5 elements as clinically insignificant.

The objective of this study was to characterize the anatomic distribution and pathologic features of small tumors (aggregate volume of 0.5 ml or less) in whole-mount prostatectomy specimens. Between 1999 and 2003, 371 consecutive patients underwent radical prostatectomy at the Indiana University Hospitals for localized prostate cancer. Patients who received hormonal or radiation therapy prior to the surgery were excluded from the study. A total of 62 specimens with total tumor volume of 0.5 ml or less were identified and included in this study. All specimens were embedded and whole-mounted. Tumor volume was measured using the grid method.

The mean age at the time of surgery was 59 years (median, 61 years; range, 37-72 years). The mean preoperative prostate-specific antigen (PSA) was 6.5 ng/ml (range: 0.3-18 ng/ml). The mean prostate weight was 53 g (range: 16-132 g). The mean tumor volume was 0.29 ml (median, 0.35 ml; range, 0.02-0.48 ml). Tumor multifocality and bilaterality were present in 69 and 37% of cases, respectively. Three (5%) had positive surgical margins. The largest tumor was located in the peripheral zone, transitional zone, and central zone in 79, 16, and 5% of cases, respectively. The largest tumor was located in the anterior prostate in 10 cases (16%) and in the posterior prostate in 52 cases (84%). The distribution of Gleason scores was 5 (12 cases, 19 %), 6 (40 cases, 65 %), and 7 (10 cases, 16 %). One case had a primary Gleason pattern 4. None had extraprostatic extension, seminal vesicle invasion, or lymph node metastasis.

Small-volume prostate cancers are often multifocal and bilateral, with predilection for the peripheral zone. Of these small-volume cases, 16% had Gleason pattern 4 and might, therefore, be clinically significant.
Stratified epithelium in prostatic adenocarcinoma: a mimic of high-grade prostatic intraepithelial neoplasia.

Hameed O, Humphrey PA.

1Department of Pathology and Immunology, Washington University Medical Center, St Louis, MO, USA.

Mod Pathol. 2006 Jul;19(7):899-906. Epub 2006 Apr 7. Abstract quote  

Typically glands of prostatic adenocarcinoma have a single cell lining, although stratification can be seen in invasive carcinomas with a cribriform architecture, including ductal carcinoma. The presence and diagnostic significance of stratified cells within non-cribriform carcinomatous prostatic glands has not been well addressed.

The histomorphological features and immunohistochemical profile of cases of non-cribriform prostatic adenocarcinoma with stratified malignant glandular epithelium were analyzed. These cases were identified from needle biopsy cases from the consultation files of one of the authors and from a review of 150 consecutive in-house needle biopsy cases of prostatic adenocarcinoma.

Immunohistochemistry was performed utilizing antibodies reactive against high molecular weight cytokeratin (34betaE12), p63 and alpha-methylacyl-coenzyme-A racemase (AMACR). A total of 8 cases were identified, including 2 from the 150 consecutive in-house cases (1.3%). In 4 cases, the focus with glands having stratified epithelium was the sole carcinomatous component in the biopsy, while such a component represented 5-30% of the invasive carcinoma seen elsewhere in the remaining cases. The main attribute in all these foci was the presence of glandular profiles lined by several layers of epithelial cells with cytological and architectural features resembling flat or tufted high-grade prostatic intraepithelial neoplasia, but lacking basal cells as confirmed by negative 34betaE12 and/or p63 immunostains in all cases. The AMACR staining profile of the stratified foci was variable, with 4 foci showing positivity, and 3 foci being negative, including two cases that displayed AMACR positivity in adjacent non-stratified prostatic adenocarcinoma.

Prostatic adenocarcinoma with stratified malignant glandular epithelium can be identified in prostate needle biopsy samples harboring non-cribriform prostatic adenocarcinoma and resembles glands with high-grade prostatic intraepithelial neoplasia. These 'PIN-like' carcinomas can present in pure form. Recognition of this pattern of prostatic adenocarcinoma is necessary to correctly diagnose such cases as invasive carcinoma.

Prostate Carcinoma With Squamous Differentiation: An Analysis of 33 Cases.

Parwani AV, Kronz JD, Genega EM, Gaudin P, Chang S, Epstein JI.

*Departments of Pathology and Urology, Johns Hopkins Hospital, Baltimore, MD; and Memorial-Sloan Kettering Cancer Center, New York, NY
Am J Surg Pathol. 2004 May;28(5):651-657. Abstract quote  

BACKGROUND:: Only sporadic cases of prostate carcinomas with squamous differentiation have been reported.

DESIGN:: The files of two institutions were reviewed for prostate cancers with squamous differentiation.

RESULTS:: A total of 33 cases were studied. The average age at diagnosis was 68 years (range 49-86 years). The most common presenting symptoms included bladder outlet obstruction and dysuria. Thirteen men had a positive digital rectal examination. Diagnosis was made by needle biopsy (n = 23); transurethral resection of the prostate (n = 5); needle and transurethral resection of the prostate (n = 1); transurethral resection of the bladder (n = 1); or biopsy of metastases (n = 3). In 21 of 33 cases, there was a prior diagnosis of adenocarcinoma of the prostate; 8 patients were treated with hormones, 4 were treated with radiation, and 1 received both radiation and hormone therapy. Of the 12 men without a prior diagnosis of adenocarcinoma, 2 patients had received hormonal therapy for benign prostatic hyperplasia. Eight of 33 cases were pure squamous carcinomas. The remaining cases were adenosquamous carcinoma (n = 16), adenosquamous and urothelial carcinoma (n = 3), and adenosquamous carcinoma and sarcoma (n = 6). The squamous carcinoma component of these mixed cases averaged 40% of the tumor volume (range 5%-95%) and had a range of cytologic atypia (mild [n = 6], moderate [n = 17], severe [n = 10]). In the 25 cases with adenocarcinoma, the glandular component tended to be high-grade (Gleason grade >6 in 19 cases). Immunohistochemistry for prostate specific acid phosphatase and prostate specific antigen was positive in a large percentage of the adenocarcinomas (85% and 75%, respectively) and only very focally positive in 12% of the squamous carcinomas. 34betaE12 was diffusely positive in >95% of the squamous carcinomas and only focally positive in <10% of the adenocarcinomas. Cytokeratins 7 and 20 did not differentiate the squamous and adenocarcinoma components. Follow-up was available on 25 of 33 cases, with the average survival being 24 months (range 0-63 months).

CONCLUSION:: Squamous differentiation in prostate cancer is uncommon, often but not necessarily arising in the setting of prior hormone or radiation therapy, and is associated with a poor prognosis. In addition to pure squamous cell carcinoma and adenosquamous cancer, other patterns may be seen. Whereas the adenocarcinoma component is typically high grade, the squamous component has a wide range of differentiation.
Amplifications of EGFR gene and protein expression of EGFR, Her-2/neu, c-kit, and androgen receptor in phyllodes tumor of the prostate.

1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.


Mod Pathol. 2006 Dec 22; Abstract quote

Phyllodes tumor of the prostate is a rare neoplasm with an unpredictable clinical behavior. It may undergo early recurrence with sarcomatous transformation or may even metastasize. Because targeted therapies have shown great success against several malignancies, there is hope that these same therapies may show similar promise in the treatment of other neoplasms.

This study was undertaken to investigate both amplification of the epidermal growth factor receptor (EGFR) gene by fluorescence in situ hybridization and the overexpression of EGFR, Her-2/neu, CD117 (c-kit), and androgen receptor by immunohistochemical staining in a series of 11 phyllodes tumors of the prostate. In the stromal elements, EGFR gene amplification was present in four of 11 tumors and polysomy chromosome 7 was present in two of 11 tumors. No amplification was present in the epithelial components. Only one of 11 tumors had polysomy of chromosome 7 in the epithelial components. Immunohistochemically, in the stromal components, EGFR expression was demonstrable in four of 11 tumors and androgen receptor was demonstrated in six of 10 tumors. Neither Her-2/neu nor c-kit expression was seen in the stromal components of any of the 11 tumors.

In the epithelial components, EGFR expression was present in all 11 tumors with strong staining in the basal cell layers and weak or no staining in luminal epithelium; androgen receptor expression was seen in seven of 10 tumors; Her-2/neu was weakly positive in four of 11 tumors; and c-kit expression was present focally and weakly in two of 11 cases with only 2-5% of cells staining. The highest staining intensity and the highest percentage of positively staining cells were seen with EGFR immunostaining in both the stromal and epithelial (mainly basal cells) components. Androgen receptor staining showed the next highest staining intensity and percentage of positive cells in both components. Her-2/neu and c-kit were only weakly or infrequently expressed in the epithelial components of prostatic phyllodes tumors.

Our data indicate that EGFR and androgen receptor are frequently and strongly expressed in both epithelial and stromal components of prostatic phyllodes tumors. EGFR gene amplification is frequently present in prostatic phyllodes tumors and may account for one of the mechanisms leading to protein overexpression in some but not all cases. Anti-EGFR and/or antiandrogen agents may be potentially useful for management of patients with tumors expressing EGFR and/or androgen receptor.
Specialized Stromal Tumors of the Prostate: A Clinicopathologic Study of 50 Cases.

Herawi M, Epstein JI.

Departments of *Pathology daggerUrology double daggerOncology, The Johns Hopkins Medical Institutions, Baltimore, MD.

Am J Surg Pathol. 2006 Jun;30(6):694-704. Abstract quote  

Specialized stromal tumors of the prostate encompass stromal sarcoma and stromal tumors of uncertain malignant potential (STUMP). As a result of their relative rarity and lack of long-term follow-up, the prognosis of STUMP is unclear.

We studied 50 cases of STUMP and stromal sarcoma with regard to their clinical presentation and follow-up. Patients ranged in age from 27 to 83 years (mean 58 years). The major presenting signs and symptoms were urinary obstructive symptoms (n=25), abnormal digital rectal exam (n=15), hematuria (n=7), hematospermia (n=1), and rectal dysfunction/fullness (n=3). An elevated prostate-specific antigen was either the sole or a compounding rationale for initial urologic examination and prostate biopsy in a subgroup of patients (n=11).

The histology in the 36 cases of STUMP not associated with sarcoma were as follows: 25 composed of stroma with scattered cytologically atypical cells associated with benign glands; 8 resembling glandular-stromal hyperplasia but with hypercellular stroma; 6 with extensive myxoid stroma; and 1 with phyllodes pattern. Four of these cases had mixed patterns. Seven cases of STUMP were associated with sarcoma, either concurrently or subsequently. In another 7 cases, pure sarcomas were encountered: 3 low grade (LG) and 4 high grade (HG). In 19 STUMPs, the location of the lesion was determinable: 10 cases arose in the peripheral zone, 7 cases were located in the transition zone, and 2 cases seemed to involve both zones. In 3 of these cases, tumors were adherent to the rectum at the time of resection. There was no evidence of progression of disease for 14 STUMPs after biopsy, TUR, or enucleation where follow-up ranged from 0.3 to 14 years (mean 4.9 years). Five cases of STUMP showed local tumor growth: 1 case increased in size from 6 to 7.5 cm in 3 years and 4 cases recurred frequently necessitating multiple TURs of the prostate (n=2, n=3, n=3, n=3) over 1.1, 2, 7, and 8 years, respectively. Fourteen patients with STUMP underwent radical prostatectomy (RP) soon after diagnosis; of these, 12 were organ confined where the tumor size ranged from 0.7 to 7.5 cm (mean 2.7 cm); 2 cases with a history of a 28 g TUR and a 275 g enucleation showed no residual tumor in the RP specimen. Three cases were lost to follow-up. The histologic subtypes of STUMP did not correlate with the clinical behavior or likelihood of being associated with sarcoma. Two of the LG sarcomas locally invaded around the seminal vesicle, yet all of the LG sarcomas with follow-up were free of disease at 3, 13, 24, 25, 30, and 36 months. Of the 6 HG sarcomas with follow-up, 3 were free of disease at 3, 17, and 72 months. One man was alive with metastasis to the lung 10 months after RP, 1 man was alive at 280 months with multiple metastases, and another died of disease at 115 months.

STUMPs can recur frequently, occur at a young age, often involve the peripheral zone where they can be adherent to the rectum requiring its removal, and can be associated with stromal sarcoma.

Although STUMPs can be histologically misdiagnosed as nodular hyperplasia, it is important to recognize that these are neoplasms with unique local morbidity and malignant potential. Whereas LG stromal sarcomas can locally invade, HG sarcomas can metastasize and lead to death.

Tubulocystic Clear Cell Adenocarcinoma Arising Within the Prostate

Chin-Chen Pan, M.D.; Hung Chiang, M.D.; Yen-Hwa Chang, M.D., Ph.D.; Jonathan I. Epstein, M.D.

From the Department of Pathology (C.-C.P., H.C.), the Division of Urology (Y.-H.C.), National Yang-Ming University and Veterans General Hospital-Taipei, Taiwan, R.O.C.; and the Department of Pathology and the James Buchanan Brady Urological Institute (J.I.E.), The Johns Hopkins Medical Institutions, Baltimore, Maryland, U.S.A.

Am J Surg Pathol 2000;24:1433-1436 Abstract quote

Neoplasms resembling ovarian common epithelial-type tumors, including clear cell adenocarcinomas, rarely occur in the lower urinary tract of men. When they do, they develop in the urethra or urinary bladder.

We report a case of such a tumor arising within the prostate of a 47-year-old man.

The tumor was a cystic mass in the left posterolateral region of the prostate. Histologically, the tumor was chiefly composed of tubulocystic and papillary glands lined by glycogen-rich, cuboidal or hobnail cells with clear to eosinophilic cytoplasm. The tumor cells were strongly positive for pan-cytokeratin, low molecular weight cytokeratin, and epithelial membrane antigen, and focally positive for high molecular weight keratin. The tumor did not immunohistochemically express prostate-specific antigen (PSA) and prostatic acid phosphatase. Serologically, the patient had increased levels of CA125 instead of PSA.

The clinical as well as the pathologic features are consistent with a clear cell adenocarcinoma as seen in the female genital tract rather than a typical prostatic adenocarcinoma.

Little or No Residual Prostate Cancer at Radical Prostatectomy: Vanishing Cancer or Switched Specimen?: A Microsatellite Analysis of Specimen Identity.

Cao D, Hafez M, Berg K, Murphy K, Epstein JI.

From the Departments of *Pathology and daggerUrology and Oncology, Johns Hopkins Medical Institutions, Baltimore, MD; and double daggerLaboratory Corporation of American, Research Triangle, NC.

Am J Surg Pathol. 2005 Apr;29(4):467-473. Abstract quote  

With more vigilant screening for prostate cancer, there has been an associated increase in patients with little or no residual cancer at radical prostatectomy after an initial diagnosis of minute cancer on needle biopsy. This raises a critical question as to whether the biopsy and subsequent radical prostatectomy in these patients are from the same patient.

We used PCR-based microsatellite marker analysis to perform identity test in 46 men (35 with minute cancer and 11 with no residual cancer). Of them, 41 were interpretable, including 31 with minute cancer and 10 with no residual cancer. All 31 interpretable cases with minute cancer showed match between the initial biopsy and radical prostatectomy specimens. Nine of the 10 interpretable cases with no residual cancer showed match and 1 showed mismatch. The remaining 5 cases (4 with minute cancer and 1 with no residual cancer) were considered uninterpretable due to technical problems. The initial biopsy of the mismatched case had high-grade cancer (Gleason score 4 + 4 = 8) measuring 9.6 mm in length with perineural invasion.

Our results confirm that, in most cases of "vanishing cancer" in radical prostatectomy specimens, it reflects a chance sampling of a minute cancer and not a switch in specimens. However, specimen switch can rarely occur, and if there is high grade or a lot of cancer on the biopsy with no or very minimal cancer in the radical prostatectomy specimen, one should evaluate for patient identity.

Minimal or no cancer in radical prostatectomy specimens. Report of 13 cases of the "vanishing cancer phenomenon".

Goldstein NS, Begin LR, Grody WW, Novak JM, Qian J, Bostwick DG.

Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California, USA.

Am J Surg Pathol 1995 Sep;19(9):1002-9 Abstract quote

Early detection efforts identify prostate cancer at lower clinical and pathologic stages, often resulting in smaller volumes of tumor in radical prostatectomy specimens. In some cases, complete sampling of the radical prostatectomy specimen for biopsy-proven adenocarcinoma reveals minimal or no residual cancer.

We evaluated the clinical and pathologic findings in 13 such cases in an effort to document this finding, which we refer to as the "vanishing cancer phenomenon." The mean number of prostate slides examined per case was 79 (range, 34-248). Carcinoma was absent in two cases, present in a single focus in eight cases, and present in two foci in three cases. Mean cancer volume in the 10 cases with residual tumor was 0.019 cc (range, 0.003-0.038); the largest single dimension of any tumor focus was 3 mm. All cancers were well differentiated or moderately differentiated in the biopsy and prostatectomy.

Our results indicate that in some cases cancer may be extremely difficult or impossible to find in the prostatectomy specimen despite exhaustive sampling. The incidence of this "vanishing cancer phenomenon" is probably increasing because more low-stage cancers are being treated by prostatectomy. The inability to identify cancer in a prostate removed for needle biopsy-proven carcinoma may not indicate technical failure.



Mucin expression in atypical adenomatous hyperplasia of the prostate.

Goldstein NS, Qian J, Bostwick DG.

Department of Pathology, William Beaumont Hospital, Royal Oak, MI 48073-6769, USA.

Hum Pathol 1995 Aug;26(8):887-91 Abstract quote

Prostatic atypical adenomatous hyperplasia (AAH) is a small glandular proliferation that has histological similarities with well-differentiated adenocarcinoma.

To determine the histochemical profile of AAH, we assessed the production of total neutral mucin, total acidic mucin, and sulfated acidic mucin in 24 cases of AAH, five cases of Gleason primary pattern 1 and 2 adenocarcinoma, and 29 cases of adjacent benign and hyperplastic prostatic tissue.

All specimens were formalin-fixed transurethral resections, and the diagnosis in each was confirmed by evaluation of the keratin 34B-E12 immunoreactive basal cell layer (intact in benign and hyperplastic epithelium, fragmented in AAH, and absent in cancer). The extent of mucin staining was measured semiquantitatively in 10% increments according to the number of stained glands. Neutral mucin was found in all but two cases, and there was no apparent difference in the amount of staining in benign glands, AAH, and cancer (mean number of stained glands, 43%). Total acidic mucin was more common in AAH (63% of cases; mean, 11% of glands) and adenocarcinoma (60% of cases; mean, 30% of glands) than in benign glands (0% of cases). Similarly, nonsulfated acidic mucin was more common in AAH (63% of cases; mean, 12% glands) and adenocarcinoma (60% of cases; mean, 8% of glands) than in benign glands (0% of cases); the pattern and intensity of staining for nonsulfated acidic mucin appeared to be similar to that for total acidic mucin in AAH and cancer.

These findings indicate that there is a close relationship in mucin expression between AAH and well-differentiated adenocarcinoma. Identification of acidic mucin should be used cautiously as an adjunct in the diagnosis of adenocarcinoma but is useful in separating some cases of AAH and adenocarcinoma from benign prostatic epithelium.

Is triple immunostaining with 34betaE12, p63, and racemase in prostate cancer advantageous? A tissue microarray study.

Department of Pathology, Singapore General Hospital, Singapore.

Am J Clin Pathol. 2007 Feb;127(2):248-53. Abstract quote

This study aimed to determine the usefulness of a combination of 3 immunohistochemical markers, 34/betaE12, p63 and alpha-methylacyl coenzyme A racemase (AMACR), for the diagnosis of prostate cancer using tissue microarrays (TMAs) constructed from 91 archival radical prostatectomy specimens derived from the Pathology Department files of Singapore General Hospital, Singapore. Triple immunostaining using a cocktail of these 3 antibodies was performed on TMA sections using the streptavidin-biotin method.

When compared with immunohistochemical staining using the individual antibodies, we found that the triple cocktail allowed improved evaluation of basal cells in benign glands, and AMACR allowed simultaneous corroboration of malignant prostatic glands in the same section.

We achieved a specificity of 100% with the triple cocktail, and sensitivity was acceptable, at 93.8%. In comparison, specificity and sensitivity of the individual antibodies were 95.5% and 97.3%, 93.3% and 93.8%, 97.0% and 95.6% for p63, 34betaE12, and AMACR, respectively.

The triple cocktail offers a cost-effective way of evaluating abnormal prostatic glandular foci, in addition to maximizing the use of small tissue samples from prostatic needle biopsies.
p63/AMACR antibody cocktail restaining of prostate needle biopsy tissues after transfer to charged slides: a viable approach in the diagnosis of small atypical foci that are lost on block sectioning.

Hameed O, Humphrey PA.

Department of Pathology and Immunology, Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University Medical Center, St Louis, MO 63110, USA.

Am J Clin Pathol. 2005 Nov;124(5):708-15. Abstract quote  

We assessed the utility of using a p63/a-methylacyl-coenzyme-A racemase (AMACR) antibody cocktail on destained H&E-stained sections.

We transferred 61 stored (7-11 months old) and 10 recent (<1 month old) H&E-stained sections of prostate needle biopsy tissues to charged slides and subsequently stained them with a p63/AMACR immunohistochemical antibody cocktail. The AMACR and p63 staining intensities were compared with those obtained with the same antibody cocktail performed on sections recut directly from the paraffin block.

Transfer of sections and subsequent immunohistochemical staining was successful in 69 (97%) of 71 cases. For stored cases, there were similar AMACR and p63 staining intensities in destained and recut sections in 55 (90%) and 11 (18%) of 61 cases, respectively. In recent sections, AMACR and p63 staining intensities were almost identical by both methods.

We conclude that p63/AMACR cocktail immunostaining of destained H&E-stained sections is a viable approach in the workup of small "suspicious" foci in recently sectioned prostate needle biopsy tissues. This approach is best used when 2 or more H&E-stained sections harbor the suspicious focus, as we always recommended preservation of at least 1 H&E-stained section.
Immunohistochemical Stains for p63 and alpha-Methylacyl-CoA Racemase, Versus a Cocktail Comprising Both, in the Diagnosis of Prostatic Carcinoma: A Comparison of the Immunohistochemical Staining of 430 Foci in Radical Prostatectomy and Needle Biopsy Tissues.

Hameed O, Sublett J, Humphrey PA.

From the Lauren V. Ackerman Laboratory of Surgical Pathology, Department of Pathology and Immunology, Washington University Medical Center, St. Louis, MO.
Am J Surg Pathol. 2005 May;29(5):579-87. Abstract quote  

The diagnosis of prostatic carcinoma and especially minimal prostatic carcinoma can sometimes be challenging on needle core biopsy and occasionally immunohistochemistry is an aid in the diagnosis. Immunostains, such as those directed against the basal cell marker p63 and, more recently, employing antibodies reactive with alpha-methylacyl-CoA racemase (AMACR), can be useful in this situation.

The aim of this investigation was to assess the diagnostic utility of a p63/AMACR antibody cocktail and compare the staining pattern it produces with that using the individual antibodies alone. A retrospective review of 31 consecutive radical prostatectomy specimens and 150 prostate needle biopsy samples was performed to select histologic sections showing foci of prostatic carcinoma and/or minimal prostatic carcinoma, high-grade prostatic intraepithelial neoplasia (HGPIN), as well as common benign mimickers of prostatic carcinoma, to include atrophy and basal cell hyperplasia, especially with prominent nucleoli. Serial histologic sections from the corresponding paraffin blocks were stained with hematoxylin and eosin and by immunostains for p63, AMACR, and a prediluted antibody cocktail comprising both. The diagnostic utility of the cocktail was assessed, and the staining characteristics it produced were compared with those using the individual immunostains.

In 430 foci, the cocktail produced a p63 staining profile identical to that using the single p63 antibody. Distinction of the nuclear p63 signal from the cytoplasmic AMACR localization was readily accomplished. There was an excellent agreement (kappa = 0.91; P < 0.0001) between the AMACR staining profile using the cocktail and the single AMACR antibody alone. The cocktail was very useful in highlighting prostatic carcinoma associated with HGPIN, flat and cribriform HGPIN, and distorted foci of minimal prostatic carcinoma. These data indicate that use of a p63/AMACR cocktail is essentially equivalent to use of each antibody separately for immunohistochemical confirmation of a diagnosis of prostatic carcinoma in needle biopsy.

This cocktail would be of diagnostic utility when only limited tissue is available for immunohistochemical evaluation of small, diagnostically difficult foci in prostate needle biopsy tissue.
Using an AMACR (P504S)/34bE12/p63 Cocktail for the Detection of Small Focal Prostate Carcinoma in Needle Biopsy Specimens

Zhong Jiang, MD, Cuizhen Li, MD, PhD, Andrew Fischer, MD, Karen Dresser, and Bruce A. Woda, MD
Am J Clin Pathol 2005;123:231-236 Abstract quote

We assessed the usefulness of immunohistochemical analysis with a 3-antibody cocktail (a-methylacyl coenzyme A racemase [AMACR, or P504S], 34bE12, 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 (34bE12) 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.
An Analysis of the p63/ a -Methylacyl Coenzyme A Racemase Immunohistochemical Cocktail Stain in Prostate Needle Biopsy Specimens and Tissue Microarrays

Schuyler O. Sanderson, MD, Thomas J. Sebo, MD, PhD, Linda M. Murphy, MT(ASCP), Roxann Neumann, RN, Jeff Slezak, MS, and John C. Cheville, MD
Am J Clin Pathol 2004;121:220-225 Abstract quote

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.

Tissue Protection Immunohistochemistry A Useful Adjunct in the Interpretation of Prostate Biopsy Specimens and Other Selected Cases in Which Immunostains Are Needed on Minute Lesions

Patty Kubier, HT(ASCP), AAS, QIHC, and Rodney T. Miller, MD

Am J Clin Pathol 2002;117:194-198 Abstract quote

Performing immunohistochemical analysis on minute lesions is a challenging task, primarily because they frequently disappear when the paraffin block is recut for immunostaining purposes. This is a particularly common occurrence with prostate biopsy specimens, in which immunostains for high-molecular-weight cytokeratin commonly are used as an adjunct to H&E examination for aiding in the interpretation of minute "suspicious" lesions.

We describe an original method designated tissue protection immunohisto-chemistry, that allows the performance of high-molecular-weight cytokeratin immunostains (or other immunostains) on previously stained H&E slides. The method described does not require destaining of H&E-stained sections, and it allows the preservation of the H&E stain on adjacent levels that may be present on the same slide.

The method described requires that the original H&E-stained sections be placed on adhesive slides, but it has the advantages of eliminating the requirement of a paraffin block for immunostaining and eliminating the need for saving intervening unstained sections for possible immunohistochemical analysis.

Immunophenotypic characterization of 225 prostate adenocarcinomas with intermediate or high Gleason scores.

Goldstein NS.

Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.

Am J Clin Pathol 2002 Mar;117(3):471-7 Abstract quote

This study provides detailed staining results for 225 prostate adenocarcinomas, including 150 Gleason score 8, 9, and 10 adenocarcinomas with cytokeratins (CKs) 7, 20, 5/6, and 17, prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), carcinoembryonic antigen (CEA), WT1, thyroid transcription factor-1 (TTF-1), and villin.

CK7 was reactive in 112 adenocarcinomas (49.8%). The percentage of CK7-reactive adenocarcinomas and the percentage of CK7-stained cells increased in higher Gleason score adenocarcinomas; most reactive neoplasms had CK7 staining of fewer than 25% of cells. CK20 had similar results. The percentage of PSA- and PAP-reactive adenocarcinomas and the percentage of stained cells in reactive neoplasms decreased in higher Gleason score adenocarcinomas. CK5/6 and CK17, WT1, CA-125, TTF-1, and villin were nonreactive. The prostate can be the primary site of metastatic adenocarcinoma that is nonreactive for PAP and PSA and has CK7 or CK20 reactivity in fewer than 50% of the cells.

The likelihood that a metastatic adenocarcinoma is from the prostate is low if reactivity with any of the cytokeratin antibodies, CEA, TTF-1, CA-125, WT1, or villin is extensive.

AMACR (P504S, Alpha-Methylacyl-CoA-Racemase, AMACR)  
Age-Associated Changes in Alpha-Methyl CoA Racemase (AMACR) Expression in Nonneoplastic Prostatic Tissues.

Gologan A, Bastacky S, McHale T, Yu J, Cai C, Monzon-Bordonaba F, Dhir R.

From the Department of Pathology, University of Pittsburgh, Pittsburgh, PA.

Am J Surg Pathol. 2005 Nov;29(11):1435-41. Abstract quote  

Alpha-methyl CoA racemase (AMACR) is overexpressed in several human cancers, most notably colon and prostate. AMACR expression in the prostate has been investigated primarily in patients, in an older age group, treated for prostatic carcinoma and benign prostatic hypertrophy. No studies have assessed the age distribution of AMACR expression in normal men.

Archival paraffin-embedded prostate tissue from 41 organ donor men (age range, 13-63 years) with no evidence of prostate neoplasia was stained with a monoclonal antibody for AMACR. Intensity was graded on a scale of 0 to 3. Semi-quantitative analysis of staining in acinar cells was used to generate a composite score (CS) [Sigma(% area x intensity)] for each case. Nondonor cases with foci of prostate cancer and high-grade prostatic intraepithelial neoplasia (PIN) were used as external positive controls for AMACR. These sections were also stained for Ki-67, to assess proliferative index. The 41 cases encompassed different age groups (13-20 years, N = 11; 20-45 years, N = 17; >45 years, N = 13). Acinar cells showed granular cytoplasmic staining. Focal positive staining was also seen in the prostatic urethra and the periurethral glands.

There was wide variation in the level of expression within each age group. The level of expression seen in subjects younger than 45 years was higher (mean CS = 41.3; median CS = 22.5) than that seen in subjects older than 45 years (mean CS = 8.8; median CS = 9.0) with a P value of 0.01. Most cases in the control set of prostatic adenocarcinoma cases showed moderate to strong staining. A negative correlation was seen evaluating CS and age in subjects 20 years of age and older (r = -0.47). Ki-67 staining was variable.

1) AMACR expression can be seen in benign prostatic glandular epithelium, across all age groups. However, it is age-related, with significantly lower expression in subjects younger than 45 years. This could account for the negative staining reported in benign glands, due to biased sampling of the older population. 2) Focal positive staining is seen in the prostatic urethra and periurethral glands in 71% of the cases, with no age correlation. This is of concern because this epithelium could potentially be misinterpreted as foci of PIN. 3) The low expression of AMACR in benign glands in the older age group makes this marker useful in detecting malignancy. However, AMACR staining should be interpreted with caution and the diagnosis of PIN or prostate cancer should be rendered only with convincing histologic evidence. 4) Ki-67 staining was very variable and showed no correlation with age and AMACR expression levels. AMACR expression had no correlation with proliferative index.
Altered Expression of a-Methylacyl-Coenzyme A Racemase in Prostatic Adenocarcinoma Following Hormone Therapy

Kimiko Suzue, MD, PhD, etal.
Am J Clin Pathol 2005;123:553-561 Abstract quote

a-Methylacyl-coenzyme A racemase (AMACR) is a sensitive and specific tissue marker for the diagnosis of prostatic carcinoma. However, limited data are available on AMACR expression in residual prostatic carcinoma following hormone therapy.

We analyzed 64 residual or recurrent prostatic adenocarcinomas following hormonal therapy for the expression of AMACR using a monoclonal antibody (P504S) to AMACR. In 20 localized cases, AMACR staining was absent in 11 (55%), 1+ in 6 (30%), and 2+ or 3+ in 3 (15%). However, in 15 metastatic cases, AMACR was absent in 1 (7%), 1+ in 3 (20%), and 2+ or 3+ in 11 (73%). None of the 29 postradiotherapy cases showed complete absence of AMACR staining: 2 (7%) were 1+, and 27 (93%) were 2+ or 3+. AMACR expression was reduced significantly in the majority of posthormonal residual carcinomas, whereas in postradiotherapy and in hormone-refractory metastatic prostatic adenocarcinoma, AMACR expression was retained.

Therefore, the diagnosis of residual prostatic carcinoma after hormonal therapy using AMACR immunostaining must be interpreted with caution. Furthermore, AMACR might have a role in the recurrence of prostatic adenocarcinoma after medical therapy.
Prospective evaluation of AMACR (P504S) and basal cell markers in the assessment of routine prostate needle biopsy specimens.

Browne TJ, Hirsch MS, Brodsky G, Welch WR, Loda MF, Rubin MA.
Hum Pathol. 2004 Dec;35(12):1462-8 Abstract quote.  

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.
Utility of immunohistochemistry for alpha-methylacyl-CoA racemase in distinguishing atrophic prostate cancer from benign atrophy.

Farinola MA, Epstein JI.

Hum Pathol. 2004 Oct;35(10):1272-8. Abstract quote  

Small atrophic prostate cancers on needle biopsy are rare and difficult to distinguish from benign atrophy on needle biopsy.

We report on a study of 23 needle biopsy specimens with small foci of atrophic prostate cancer from the consult service of one of the authors. In 19 cancer cases the atrophic component was pure; in 4 cases it was dominant with a minor (<5%) nonatrophic cancer component. These atrophic cancers and 16 cases of florid benign atrophy on needle biopsy were examined by immunohistochemistry for alpha-methylacyl-CoA-racemase (AMACR). All cases of cancer and atrophy were verified immunohistochemically with antibodies to basal cells (34betaE12 and p63). AMACR staining were scored as 1+ (5% to 25% of glands expressing AMACR), 2+ (26% to 50% of glands expressing AMACR), or 3+ (>50% of glands expressing AMACR). Positive staining was defined as staining above that of surrounding benign glands. AMACR was expressed in 69.6% of atrophic prostate cancers (3+, 11 cases; 2+, 3 cases; 1+, 2 cases); 30.4% (7 cases) of atrophic prostate cancer exhibited no AMACR expression. In the 4 cases with a few glands of ordinary (nonatrophic) prostate cancer, the nonatrophic cancer demonstrated more intense and a greater extent of AMACR staining. Fourteen cases (87.5%) of benign atrophy showed no AMACR expression. In 2 cases (12.5%) of benign atrophy, background immunostaining made it difficult to assess AMACR expression.

We conclude that AMACR immunostaining alone is not sufficiently discriminatory in the differential diagnosis of atrophic prostate cancer versus benign atrophy. Atrophic prostate cancers are not as frequently or as strongly positive as ordinary prostate cancer.

Using a panel of immunostains including AMACR, 34betaE12 and p63 (positive AMACR immunostaining along with negative basal cell markers) is recommended in the differentiation of atrophic prostate cancer and benign atrophy.
Diagnostic utility of a p63/alpha-methyl-CoA-racemase (p504s) cocktail in atypical foci in the prostate.

Molinie V V, Fromont G, Sibony M, Vieillefond A, Vassiliu V, Cochand-Priollet B, Herve JM, Lebret T, Baglin AC.

1Service de Pathologie, Hopital Foch, Suresnes, France.
Mod Pathol. 2004 Oct;17(10):1180-1190 Abstract quote  

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

Wu CL, Yang XJ, Tretiakova M, Patton KT, Halpern EF, Woda BA, Young RH, Jiang Z.

Hum Pathol. 2004 Aug;35(8):1008-13. Abstract quote  

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 immunohistochemisty 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.
Discovery and Clinical Application of a Novel Prostate Cancer Marker
a-Methylacyl CoA Racemase (P504S)

Zhong Jiang, MD, etal.
Am J Clin Pathol 2004;122:275-289 Abstract quote

The recent discovery of the overexpression of P504S/a-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.

How Often Does Alpha-Methylacyl-CoA-Racemase Contribute to Resolving an Atypical Diagnosis on Prostate Needle Biopsy Beyond That Provided by Basal Cell Markers?

Zhou, Ming MD, PHD*; Aydin, Hakan MD*; Kanane, Hillel MD‡; Epstein, Jonathan I MD*†

From the Departments of *Pathology and †Urology, Johns Hopkins Medical Institutions, Baltimore, MD; and ‡Dianon Systems, Stratford, CT.


The American Journal of Surgical Pathology : Volume 28(2) February 2004 pp 239-243 Abstract quote

Background: Alpha-methylacyl-CoA-racemase (AMACR), a recently discovered tumor marker for prostate cancer, is being used increasingly in conjunction with hematoxylin and eosin (H&E) histology and basal cell markers in the workup of difficult prostate needle biopsies. However, it is not known how often a positive AMACR staining is used merely to support a malignant diagnosis that could otherwise be established based on routine H&E histology and negative basal cell staining.

Methods: This study included 307 prostate needle biopsies that were sent to us for consultation diagnosed as atypical by contributing pathologists. Immunohistochemistry for AMACR, high molecular weight cytokeratin, and p63 was performed. AMACR staining intensity was graded as negative, weak, moderate, and strong. Only staining that was significantly stronger than that of background benign glands was considered positive. An expert review diagnosis was first rendered as benign, atypical, or cancer based on the H&E-stained section and basal cell marker stains without the knowledge of AMACR expression. The AMACR stains were then reviewed and a final diagnosis was rendered.

Results: A total of 215 cases had a final diagnosis of cancer following evaluation of the H&E-stained section, basal cell markers, and AMACR. Of these 215 cases, 176 (81.9%) were positive and 39 (18.1%) were negative for AMACR staining. Of 81 cases with a final diagnosis of atypical following review of all material, 42 (51.9%) were positive and 39 (48.1%) were negative for AMACR staining. When AMACR staining was negative, in no case was the initial cancer, atypical, or benign diagnosis (based on routine histology and negative basal cell markers) changed based on AMACR stain results. Of 115 cases called atypical after expert review, 76 were positive for AMACR; of these 76 cases, 34 (44.7%) were changed to a final diagnosis of cancer. AMACR expression was positive, with moderate and strong staining in 30 of the 34 cases (88.2%), for which the immunohistochemical result converted the expert review atypical diagnosis to a final cancer diagnosis. Of these 34 cases, 11 underwent radical prostatectomy, and cancer was found in all cases. Three additional patients underwent repeat biopsy, and cancer was present in the repeat biopsy in 2 patients. The cases whose diagnosis was changed from atypical on expert review to cancer were all highly suspicious for cancer based on H&E histology and negative basal cell markers, yet a definitive cancer diagnosis could not be established because of small size, insufficient cytologic atypia, or biopsy artifact.

Conclusion: Interpretation and use of AMACR staining should be executed with caution. A negative AMACR stain can be seen in approximately 18% of cases considered to be cancer based on H&E stain combined with negative basal cell markers. A positive AMACR staining converted an atypical diagnosis, based on suspicious histology and negative basal cell marker stains, to cancer in approximately 10% (34 of 307) of cases thought to be atypical by contributing pathologists and in approximately 50% (34 of 76) of cases thought be atypical on expert review by a specialist in genitourinary pathology.

P504S Immunostaining Boosts Diagnostic Resolution of "Suspicious" Foci in Prostatic Needle Biopsy Specimens

Zhong Jiang, MD, Kenneth A. Iczkowski, MD, Bruce A. Woda, MD, Maria Tretiakova, MD, PhD, and Ximing J. Yang, MD, PhD
Am J Clin Pathol 2004;121:99-107 Abstract quote

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 b 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 b 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 b E12 staining; 18 (44%) were resolved by 1 or 2 evaluators and 29 (71%) by at least 1. According to whether post–keratin 34 b 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 b E12 immunostaining with P504S.
Diagnostic Usefulness of Monoclonal Antibody P504S in the Workup of Atypical Prostatic Glandular Proliferations

Lakshmi P. Kunju, MD, Mark A. Rubin, MD, Arul M. Chinnaiyan, MD, PhD, and Rajal B. Shah, MD
Am J Clin Pathol 2003;120:737-745 Abstract quote

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.

alpha-Methylacyl-CoA Racemase: A Variably Sensitive Immunohistochemical Marker for the Diagnosis of Small Prostate Cancer Foci on Needle Biopsy.

Magi-Galluzzi C, Luo J, Isaacs WB, Hicks JL, De Marzo AM, Epstein JI.

Am J Surg Pathol. 2003 Aug;27(8):1128-33 Abstract quote

Expression of the alpha-methylacyl-CoA racemase (AMACR) gene has recently been demonstrated by several groups to be markedly elevated in prostate cancer cells with little expression in benign prostate tissue and has been suggested as a molecular marker of prostate cancer on needle biopsy. There is scant data, however, as to the sensitivity and specificity of AMACR in the diagnosis of small foci of cancer on needle biopsy. A total of 209 needle biopsies of the prostate with small foci (<5% of a core) of prostatic adenocarcinoma were identified.

A total of 175 cases were received in consultation by one of the authors (140 from a single institution and 35 from different outside institutions) and 34 cases were from our hospital file. Immunohistochemistry for high molecular weight cytokeratin and p63 was performed in all cases to confirm the diagnosis of cancer. Only AMACR staining that was significantly stronger than that of background benign glands was considered positive; 88% of all cases of prostate cancer were positive for AMACR. The sensitivity varied among the different groups: 100% for the in house cases, 87.1% for the cases from a single institution, and 80% for cases from different outside institutions. The mean percentage of stained glands in positive cases was 95.9%, with 150 (71.8%) cases showing 100% of the glands positive and 25 (12.0%) cases showing no staining.

Because negative staining for basal cell markers, especially in a small focus of atypical glands, is not necessarily diagnostic of prostate cancer, positive staining for AMACR can increase the level of confidence in establishing a definitive malignant diagnosis.

However, the sensitivity of AMACR staining may vary in specimens from different pathology laboratories, possibly related to differences in fixation and processing. It is important to optimize the staining technique for each laboratory and recognize that some small cancers on needle biopsy may be AMACR negative.

Expression and Diagnostic Utility of Alpha-Methylacyl-CoA-Racemase (P504S) in Foamy Gland and Pseudohyperplastic Prostate Cancer.

Zhou M, Jiang Z, Epstein JI.

Am J Surg Pathol. 2003 Jun;27(6):772-8. Abstract quote

Foamy gland and pseudohyperplastic carcinomas are two uncommon variants of prostate cancer and often pose diagnostic challenges on needle biopsies. Alpha-methylacyl-CoA-racemase (AMACR) is a recently discovered tumor marker whose expression is significantly upregulated in prostate cancer. However, the original works only studied ordinary prostate cancer without reference to specific morphologic variants. Therefore, the expression and diagnostic utility of AMACR in specific variants of prostate cancer are unknown. In addition, two different antibodies, one monoclonal and one polyclonal, were used in the previous studies.

The goal of this study is to examine the expression pattern and diagnostic utility of AMACR in foamy gland and pseudohyperplastic prostate cancer and to compare the diagnostic utility of the two anti-AMACR antibodies in the same prostate needle biopsy series.

Prostate cancer with foamy gland or pseudohyperplastic features was retrieved from the Johns Hopkins Hospital Surgical Pathology file. Thirty needle biopsies harboring prostate cancer with foamy gland features and 17 needle biopsies harboring prostate cancer with pseudohyperplastic features were available for this study.

Immunohistochemistry for AMACR was performed with two antibodies, a monoclonal one (P504S) and a polyclonal one (AMACR-p), using previously published protocols. Immunohistochemistry for high molecular weight cytokeratin and p63 was performed to confirm the cancer diagnosis. The AMACR staining intensity was graded as negative, weak, moderate, and strong. Only the staining that was significantly stronger than that of background benign glands was considered positive. A total of 68% and 62% of foamy gland prostate cancer was positive for AMACR with P504S and AMACR-p antibodies, respectively. A total of 77% and 70% of pseudohyperplastic prostate cancer was positive for AMACR with P504S and AMACR-p antibodies, respectively. Staining was often heterogeneous with different staining intensities within the same lesion. The mean percentage of stained glands in positive cases was 74.4% (range 25-100%) with P504S and 78.9% (range 20-100%) with AMACR-p in foamy gland prostate cancer and 91% (range 10-100%) with P504S, and 86.7% (range 10-100%) with AMACR-p in pseudohyperplastic prostate cancer. Seven foci of high-grade prostatic intraepithelial neoplasia present in the study cases were all positive for AMACR. The two antibodies were not statistically different in their sensitivity and specificity.

In conclusion, AMACR is potentially a useful diagnostic marker for foamy gland and pseudohyperplastic prostate cancer in the following setting. When the pathologist favors the diagnosis of these variants of cancer on routine stained sections and stains for basal cells are negative, yet still a definitive diagnosis of cancer is difficult because of the cancers' deceptively benign appearance, positive staining for AMACR can provide the additional confidence to establish a definitive malignant diagnosis. The major caveat in the interpretation of positive staining is that high-grade prostatic intraepithelial neoplasia cannot be in the differential diagnosis.

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

Leav I, McNeal JE, Ho SM, Jiang Z.

Department of Pathology, Division of Urology, University of Massachusetts Medical School, Worcester, MA and the Division of Urology, Stanford Medical Center, Stanford, CA.

Hum Pathol 2003 Mar;34(3):228-33 Abstract quote

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 Coenzyme A Racemase as a Tissue Biomarker for Prostate Cancer

Mark A. Rubin, MD; Ming Zhou, MD, PhD; Saravana M. Dhanasekaran, PhD; Sooryanarayana Varambally, PhD; Terrence R. Barrette; Martin G. Sanda, MD; Kenneth J. Pienta, MD; Debashis Ghosh, PhD; Arul M. Chinnaiyan, MD, PhD

JAMA. 2002;287:1662-1670 Abstract quote

Molecular profiling of prostate cancer has led to the identification of candidate biomarkers and regulatory genes. Discoveries from these genome-scale approaches may have applicability in the analysis of diagnostic prostate specimens.

To determine the expression and clinical utility of -methylacyl coenzyme A racemase (AMACR), a gene identified as being overexpressed in prostate cancer by global profiling strategies.

Four gene expression data sets from independent DNA microarray analyses were examined to identify genes expressed in prostate cancer (n = 128 specimens). A lead candidate gene, AMACR, was validated at the transcript level by reverse transcriptase polymerase chain reaction (RT-PCR) and at the protein level by immunoblot and immunohistochemical analysis. AMACR levels were examined using prostate cancer tissue microarrays in 342 samples representing different stages of prostate cancer progression. Protein expression was characterized as negative (score = 1), weak (2), moderate (3), or strong (4). Clinical utility of AMACR was evaluated using 94 prostate needle biopsy specimens.

Main Outcome Measures
Messenger RNA transcript and protein levels of AMACR; sensitivity and specificity of AMACR as a tissue biomarker for prostate cancer in needle biopsy specimens.

Three of 4 independent DNA microarray analyses (n = 128 specimens) revealed significant overexpression of AMACR in prostate cancer (P<.001). AMACR up-regulation in prostate cancer was confirmed by both RT-PCR and immunoblot analysis. Immunohistochemical analysis demonstrated an increased expression of AMACR in malignant prostate epithelia relative to benign epithelia. Tissue microarrays to assess AMACR expression in specimens consisting of benign prostate (n = 108 samples), atrophic prostate (n = 26), prostatic intraepithelial neoplasia (n = 75), localized prostate cancer (n = 116), and metastatic prostate cancer (n = 17) demonstrated mean AMACR protein staining intensity of 1.31 (95% confidence interval, 1.23-1.40), 2.33 (95% CI, 2.13-2.52), 2.67 (95% CI, 2.52-2.81), 3.20 (95% CI, 3.10-3.28), and 2.50 (95% CI, 2.20-2.80), respectively (P<.001). Pairwise comparisons demonstrated significant differences in staining intensity between clinically localized prostate cancer compared with benign prostate tissue, with mean expression scores of 3.2 and 1.3, respectively (mean difference, 1.9; 95% CI, 1.7-2.1; P<.001). Using moderate or strong staining intensity as positive (score = 3 or 4), evaluation of AMACR protein expression in 94 prostate needle biopsy specimens demonstrated 97% sensitivity and 100% specificity for detecting prostate cancer.

AMACR was shown to be overexpressed in prostate cancer using independent experimental methods and prostate cancer specimens. AMACR may be useful in the interpretation of prostate needle biopsy specimens that are diagnostically challenging.

P504S A New Molecular Marker for the Detection of Prostate Carcinoma

Zhong Jiang, M.D. ; Bruce A. Woda, M.D. ; Kenneth L. Rock, M.D. ; Yingdan Xu, M.D. ; Lou Savas, B.S. ; Ashraf Khan, M.D. ; German Pihan, M.D. ; Feng Cai, Ph.D. ; John S. Babcook; Palaniswami Rathanaswami; Steven G. Reed, Ph.D. ; Jiangchun Xu, Ph.D. ; Gary R. Fanger, Ph.D.

From the Department of Pathology (Z.J., B.A.W., K.L.R., Y.X., L.S., A.K., G.P.), University of Massachusetts Medical School, Worcester, Massachusetts; Corixa Corporation (F.C., S.G.R., J.X., G.R.F.), Seattle, Washington; and Abgenix Biopharma Inc. (J.S.B., P.R.), Vancouver, British Columbia, Canada.

Am J Surg Pathol 2001;25:1397-1404 Abstract quote

The ability to diagnose prostate carcinoma would be improved by the detection of a tumor-associated antigen. P504S, a cytoplasmic protein, was recently identified by cDNA library subtraction in conjunction with high throughput microarray screening from prostate carcinoma.

The aim of this study was to establish the pattern of expression of P504S in prostate carcinoma and benign prostatic tissue. A total of 207 cases, including 137 cases of prostate carcinoma and 70 cases of benign prostate, from prostatectomies (n = 77), prostate needle biopsies (n = 112), and transurethral prostate resections (n = 18) were examined by immunocytochemistry for P504S. P504S showed strong cytoplasmic granular staining in 100% of prostate carcinomas regardless of Gleason scores and diffuse (>75% of tumor) staining in 92% of cases. In contrast, 171 of 194 (88%) of benign prostates, including 56 of 67 (84%) benign prostate cases and 115 of 127 (91%) cases of benign glands adjacent to cancers were negative for P504S. The remainders of benign prostates were focally and weakly positive for P504S. The staining pattern of these normal glands was different and easily distinguishable from that observed in prostate carcinoma. Expression of P504S was not found in basal cell hyperplasia, urothelial cells/metaplasia and small atrophic glands that may mimic prostate carcinoma.

Our findings indicate that P504S is a highly sensitive and specific positive marker for prostate carcinoma.

P504S/alpha-Methylacyl-CoA Racemase: A Useful Marker for Diagnosis of Small Foci of Prostatic Carcinoma on Needle Biopsy.

Jiang Z, Wu CL, Woda BA, Dresser K, Xu J, Fanger GR, Yang XJ.

Am J Surg Pathol 2002 Sep;26(9):1169-74 Abstract quote

Establishing a definitive diagnosis of malignancy in prostate needle biopsies with very small foci of adenocarcinoma is a major diagnostic challenge for surgical pathologists. A positive diagnostic marker specific for prostatic adenocarcinoma may enhance our ability to detect limited prostate cancer and reduce errors in diagnosis. P504S, also known as alpha-methylacyl-CoA racemase, recently identified by cDNA subtraction and microarray technology, might serve as such a specific marker because it has been demonstrated to be highly expressed in prostatic adenocarcinoma, but not in benign prostatic glands. However, whether small foci of carcinoma can be reliably detected by this marker is a crucial question for its clinical application.

The aim of this study was to assess the utility of P504S immunohistochemistry in detecting small amounts of prostate cancer in prostate needle biopsies. A total of 142 prostate needle biopsies, including 73 cases with a small focus of prostatic adenocarcinoma (</=1 mm) and 69 benign prostates, were examined by using immunohistochemistry for P504S and high molecular weight cytokeratin (34betaE12). P504S immunoreactivity was found in 69 of 73 cases (94.5%) of carcinoma but not in any benign prostates (0 of 69) or benign glands adjacent to malignant glands. The 34betaE12 immunostaining confirmed the absence of basal cells in the focus of carcinoma in all 73 cases.

The high specificity and sensitivity of P504S in the detection of minimal prostatic adenocarcinoma indicated its potential diagnostic value in clinical practice. Using a combination of P504S and 34betaE12 can help the diagnosis of limited prostatic adenocarcinoma on needle biopsy.

P504S Immunohistochemical Detection in 405 Prostatic Specimens Including 376 18-Gauge Needle Biopsies.

Beach R, Gown AM, De Peralta-Venturina MN, Folpe AL, Yaziji H, Salles PG, Grignon DJ, Fanger GR, Amin MB.

Am J Surg Pathol 2002 Dec;26(12):1588-96 Abstract quote

P504S is a recently described, prostate cancer-specific gene that encodes a protein involved in the beta-oxidation of branched chain fatty acids. A recent study has shown that immunohistochemical detection of P504S gene product is a sensitive and specific marker of prostatic carcinoma in formalin-fixed, paraffin-embedded tissues.

We performed a detailed analysis of P504S protein expression in a large series of prostate and bladder specimens with special emphasis on staining in specific morphologic patterns of prostatic adenocarcinoma, posthormonal and radiation therapy cases, and invasive urothelial carcinoma. A total of 366 prostate needle core biopsies from 124 patients with prostate cancer, 10 biopsies from 2 patients without prostate cancer, 28 prostatectomy specimens (16 with specific morphologic patterns, 7 posthormonal therapy and 5 postradiation therapy specimens), 5 bladder specimens with invasive urothelial carcinoma, and a single transurethral resection specimen from a patient with hormonally treated prostate cancer and invasive urothelial carcinoma were stained with P504S monoclonal antibody at a 1:250 dilution using standard heat-induced epitope retrieval and avidin-biotin technique. Extent (0, no staining; 1+, 1-10% staining; 2+, 11-50% staining; 3+, >/=51% staining) and location (luminal, subluminal, and diffuse cytoplasmic) of immunoreactivity in carcinoma and benign tissues were recorded. A total of 153 of 186 biopsies (82%) with prostatic adenocarcinoma stained for P504S. Pseudohyperplastic, atrophic, ductal, and mucinous prostatic carcinomas stained similarly, as did cases treated with hormone or radiotherapy. In 81 of 377 (21%) foci of benign prostatic tissue there was staining that was almost always focal, faint, and noncircumferential. Seminal vesicles did not stain for P504S. Five of six (83%) specimens with invasive urothelial carcinoma had 2+ staining and one case had focal staining.

We conclude that immunohistochemistry for P504S has potential utility in the diagnosis of prostate cancer, including those treated by hormones and radiation. Circumferential luminal to subluminal and diffuse cytoplasmic staining is the most specific staining pattern for prostatic carcinoma and is almost never associated with benign prostatic tissue.

However, a negative P504S immunostain does not automatically rule out prostate cancer, as 18% of cases were negative. Additionally, occasional benign glands, high-grade prostatic intraepithelial neoplasia, atypical adenomatous hyperplasia, and urothelial carcinoma may express P504S.

Therefore, we think that P504S is best used only in conjunction with strict light microscopic correlation and preferably with high molecular weight cytokeratin immunostaining.

Expression of b-Catenin in Prostatic Adenocarcinomas
A Comparison With Colorectal Adenocarcinomas

Tarek A. Bismar, MD, etal.
Am J Clin Pathol 2004;121:557-563 Abstract quote

We studied 101 prostatic adenocarcinomas (72 acinar, 29 ductal) and 16 cases with high-grade prostatic intraepithelial neoplasia (HPIN) immunohistochemically for the expression of b-catenin and compared the staining patterns with those of nonneoplastic prostatic epithelium and 24 colorectal adenocarcinomas. While nuclear staining for b-catenin was evident in 20 (83%) colorectal adenocarcinomas, predominantly membranous staining was observed in 89 prostatic adenocarcinomas (88%); the remaining 12 cases showed no immunoreactivity.

In prostatic tumors expressing b-catenin, staining intensity was comparable, increased, and decreased in 81, 4, and 4 cases, respectively, compared with adjacent nonneoplastic prostatic epithelium. No prostatic adenocarcinomas demonstrated nuclear staining. The b-catenin staining characteristics in HPIN were comparable to those in nonneoplastic prostatic epithelium. Negative staining for cytokeratins (CKs) 7 and 20, high-molecular-weight (HMW) CK, and villin and positive staining for prostate-specific antigen (PSA) were seen in 22 prostatic adenocarcinomas examined, in contrast with colorectal adenocarcinomas, which stained positively for CK20 and villin and negatively for CK7, HMWCK, and PSA.

These data suggest that the b-catenin signaling pathway acts differently in prostatic than in colorectal tumorigenesis. The immunophenotypes documented herein also might aid in the distinction between prostatic and colorectal origins when metastasis is encountered.

The pattern of CD10 expression in selected pathologic entities of the prostate gland.

Tawfic S, Niehans GA, Manivel JC.


Hum Pathol. 2003 May;34(5):450-6. Abstract quote

There is increasing evidence that neuropeptides, including bombesin, may influence growth, angiogenesis, invasiveness, and metastasis in prostate cancer. One of the molecules tightly involved in the regulation of neuropeptide activity is the integral membrane glycoprotein CD10, or neutral endopeptidase 24.11. The pattern of CD10 expression in hyperplastic and neoplastic conditions of the prostate gland has not been previously described.

Immunohistochemical staining for CD10 and high-molecular-weight cytokeratin was performed on 92 cases of paraffin-embedded tissue from needle-core biopsy specimens and prostatectomy specimens.

Normal and hyperplastic acini showed strong and distinct membrane (apical and intercellular) and cytoplasmic CD10 expression in basal and secretory cells.

In contrast, no intercellular membrane or cytoplasmic staining of secretory cells was seen in any cases of adenocarcinoma with Gleason patterns 2 or 3. A subset of high-Gleason grade adenocarcinoma (patterns 4 and 5) displayed CD10 expression in the secretory cells; those cases shared a distinct morphological pattern.

Prostatic intraepithelial neoplasia (PIN) showed consistent absence of intercellular membrane and cytoplasmic CD10 expression in the secretory cells, with preserved expression in basal cells. Interestingly, the basal cells in basal cell hyperplasia lacked CD10 expression, and no expression was noted in the secretory cells in all cases examined. Atrophic acini and those associated with acute and chronic inflammation retained CD10 expression.

In conclusion, a consistent differential pattern of CD10 expression was seen in basal cell hyperplasia, PIN, and adenocarcinoma, suggesting a role for CD10 in the pathobiology of the prostate gland.

Distinguishing Atrophy and High-Grade Prostatic Intraepithelial Neoplasia From Prostatic Adenocarcinoma With and Without Previous Adjuvant Hormone Therapy With the Aid of Cytokeratin 5/6

Neil A. Abrahams, MD, David G. Bostwick, MD, Adrian H. Ormsby, MBChB,1 Junqi Qian, MD, and Jennifer A. Brainard, MD
Am J Clin Pathol 2003;120:368-376 Abstract quote

We evaluated the sensitivity and specificity of cytokeratin (CK) 5/6 for distinguishing foci of atrophy from prostatic adenocarcinoma with and without previous hormonal adjuvant therapy and observed the intensity and pattern of staining in mimickers of prostatic adenocarcinoma (basal cell hyperplasia, atypical adenomatous hyperplasia, and tangentially cut high-grade prostatic intraepithelial neoplasia [PIN]).

We reviewed 146 acinar proliferations in 81 specimens (radical prostatectomy, previously untreated, 41; radical prostatectomy, following androgen-deprivation therapy, 11; transurethral resection, previously untreated, 29). All benign acinar proliferations stained positively for CK5/6, with immunoreactivity restricted to basal cells. Untreated and androgen-deprived prostatic adenocarcinomas were invariably negative. The pattern of staining was continuous in 79% of the atrophy cases (15/19), and all foci stained with CK5/6. Characteristic double-layer staining in basal cell hyperplasia was observed in 93% of cases (13/14), and foci of high-grade PIN had a characteristic "checkerboard" staining with areas of discontinuity.

Foci of atypical adenomatous hyperplasia showed continuous staining, including cauterized acini in 53% of cases (8/15), with a fragmented basal cell layer pattern in 47% of cases (7/15). CK5/6 staining of the basal cells in foci of atrophy is sensitive and specific for excluding prostatic adenocarcinoma with and without androgen-deprivation effect.
High moleculear weight Cytokeratin 34BetaE12 (CK903)

This antibody stain is helpful in identifying an intact basal cell layer, which is present in benign glands and lost in carcinoma

NOTE: Not all benign glands have basal cells. Indeed, even atrophic glands may have scattered negative glands in up to 11% of cases
Up to 12% of basal cell hyperplasia may fail to stain
Between 10-90% (average 50%) of glands in atypical adenomatous hyperplasia do not stain

Negative 34betaE12 staining in a small focus of atypical glands on prostate needle biopsy: A follow-up study of 332 cases.

Halushka MK, Kahane H, Epstein JI.

Hum Pathol. 2004 Jan;35(1):43-6 Abstract quote.  

Atypical glands on prostate needle biopsy with a negative 34betaE12 (cytokeratin 903; CK903) immunostain, indicating a lack of a basal cell layer, are typically diagnostic of prostate cancer. However, in certain cases a negative 34betaE12 immunostain in a small focus of atypical glands is still not convincing enough to make the diagnosis of cancer.

This study is the first report to evaluate the incidence of prostate cancer on follow-up biopsy in individuals with this diagnosis. A total of 543 men who had prostate core biopsy specimens diagnosed as a small focus of atypical-appearing glands with a negative 34betaE12 immunostain between January 1, 1997 and December 31, 2000 were selected for study. Some 61% of these 543 individuals (n = 332) had undergone at least one follow-up biopsy procedure. Of these, 43% of repeat biopsy cases (n = 142) were diagnostic of prostate cancer. A total of 46 individuals had at least 2 follow-up biopsy procedures, with 48% of these (n = 22) being diagnosed as cancer. The Gleason grades of the detected carcinomas were broken down as follows: Gleason grade 3 + 2 = 5, 6%; grade 3 + 3 = 6, 86%; grade 3 + 4 = 7, 1%; grade 4 + 3 = 7, 4%; and grade 4 + 4 = 8, 3%. The median amount of time to the first follow-up biopsy was 79 days, with 52% of follow-up biopsies performed within 90 days. A negative 34betaE12 immunohistochemical stain in a small focus of atypical glands is not associated with an increased prediction of prostate cancer on follow-up biopsy (43%), compared with previously published data for "small focus of atypical glands" alone (approximately 45%). Because 48% of men with an initial negative biopsy and multiple follow-up biopsy procedures were found to have cancer, more than one repeat biopsy session or more extensive sampling on the first repeat biopsy procedure may be necessary to maximize the identification of cancer. This finding is similar to that found in men with atypical diagnoses in general, without a negative 34betaE12 immunohistochemical stain. Only half of all individuals with a diagnosis of 34betaE12-negative focus of atypical glands underwent repeat biopsy within 3 months.

Urologists need to be educated as to the significance of an atypical diagnosis and the need for repeat biopsy. In a small focus of atypical glands on prostate biopsy, negative staining for 34betaE12 should not necessarily lead to a definitive malignant diagnosis in all cases, because almost half of these biopsies on follow-up sampling are benign.

Basal Cell Cocktail (34betaE12 + p63) Improves the Detection of Prostate Basal Cells.

Zhou M, Shah R, Shen R, Rubin MA.


Am J Surg Pathol 2003 Mar;27(3):365-71 Abstract quote

Antibodies against high molecular weight cytokeratin (34betaE12) and p63 are frequently used basal cell markers to aid in the diagnosis of prostate cancer (Pca). Absence of a basal cell marker in an atypical lesion histologically suspicious for cancer supports a diagnosis of Pca. However, absence of basal cells demonstrable by basal cell immunohistochemistry (IHC) is not always conclusive for PCa. Some benign prostatic lesions may have inconspicuous or even lack basal cell lining focally. Technical factors such as tissue fixation and antigen retrieval techniques may also make the detection of basal cells difficult. Improving the sensitivity of current basal cell markers is critical if these tests are being used to help make diagnostic decisions in conjunction with standard histology.

In this study, we test the hypothesis that that inclusion of both 34betaE12 and p63 in the same IHC reaction (basal cell cocktail) is advantageous over either marker used alone. One thousand three hundred fifty glands from 9 trans-urethral resectioned of prostate specimens with benign prostatic hypertrophy were used to study the immunostaining intensity and pattern for 34betaE12, p63, and the basal cell cocktail. Basal cell marker expression was scored as strong, moderate, weak, or negative. Basal cell staining was considered complete if 75% of the gland's circumference was positive for the basal cell marker and partial if <25% of the circumference was stained. The mean staining intensity and variance were calculated for 34betaE12, p63, and the basal cell cocktail. A paired test was used to evaluate whether the overall basal cell staining was significantly different between 34betaE12, p63, and the basal cell cocktail. F-test was used to assess the variances for 34betaE12, p63, and the basal cell cocktail.

A high-density tissue microarray (TMA) comprising prostate tissue from 103 tumors from men with clinically localized Pca and a separate TMA comprising metastatic hormone-refractory Pca samples from 23 rapid autopsy cases were used to study the aberrant expression of 34betaE12 and p63 in clinically localized and poorly differentiated Pca. The prostate glands in transition zone have variable basal cell staining intensity and pattern with 34betaE12, p63, or the cocktail.

Histologically, benign glands lack basal cell lining in 2%, 6%, and 2% of glands with cocktail, 34betaE12, and p63 staining, respectively. The staining variance for the cocktail is significantly smaller than that for 34betaE12 (0.0100 vs 0.1559, p = 0.0008). It is also smaller than that for p63, although a statistical significance has not been reached (0.0100 vs 0.0345, p = 0.099). The basal cell cocktail stains the basal cell layers more intensely than either 34betaE12 or p63 alone, with complete and partial strong basal cell staining in 93% and 1% of benign glands, compared with 55% and 4% with 34betaE12 and 81% and 1% with p63. Complete and partial weak staining is seen in 0% and 0% of benign glands with basal cell cocktail, compared with 8% and 7% with 34betaE12 and 4% and 1% with p63 (p = 0.007 and 0.014 for cocktail vs 34betaE12 and cocktail vs p63, respectively). A total of 2.8% clinically localized Pca had positive 34betaE12 staining and 0.3% had positive p63 staining. Five (22%) of the metastatic Pca is positive for 34betaE12. However, none had p63 expression.

The basal cell cocktail had a staining pattern identical to that of 34betaE12. IHC of the prostatic glands from the transition zone is subjected to staining variability that results in frequent variable and occasional negative basal cell staining in histologically benign glands; 34betaE12 is most susceptible, and basal cell cocktail is least susceptible to such variability.

Basal cell cocktail not only increases the sensitivity of the basal cell detection, but also reduces the staining variability and therefore renders the basal cell immunostaining more consistent. We recommend this basal cell cocktail for routine Pca diagnostic work-up.

Can Basal Cells Be Seen in Adenocarcinoma of the Prostate?: An Immunohistochemical Study Using High Molecular Weight Cytokeratin (Clone 34betaE12) Antibody.

Oliai BR, Kahane H, Epstein JI.

Am J Surg Pathol 2002 Sep;26(9):1151-60 Abstract quote

Rare reports describe high molecular weight cytokeratin (clone 34betaE12) antibody cross-reactivity in scattered prostate carcinoma (PCa) cells, yet most often not in a true basal cell distribution. There are no data specifically describing 34betaE12 reactivity in basal cells in PCa.

From August 10, 1995 to May 1, 2000, a total of 3198 consult prostate needle biopsies with PCa and a 34betaE12 immunoperoxidase stain were reviewed at our institution. Thirty-six cases (1.1%), which on hematoxylin and eosin stain were unequivocal cancer, had at least focal 34betaE12 positivity in a basal cell distribution. Twenty-five had original diagnostic slides for review. All cancers were Gleason score 6. The mean number of cancer glands per case was 36.9 (10-108) with an average of 39% of glands (1-100%) showing 34betaE12 reactivity. Twenty-one cases had patchy staining in a basal cell distribution with one other case showing continuous staining. An additional case showed mainly tumor cell reactivity with rare basal cell staining. The final two cases showed a zonal staining pattern with small glands toward one side of the lesion showing basal cells [one with high grade prostatic intraepithelial neoplasia (HGPIN); one without HGPIN]. HGPIN was present in 16 of 25 (64%) cases adjacent to PCa. The mean number of HGPIN glands was 1.36 (1-6). In cases with HGPIN the mean ratio of cancer to HGPIN glands was 6.8 (0.5-13.0). In 12 cases in which the lesion was still present on deeper sectioning, we were able to confirm in nine cases the presence of basal cells using antibodies to p63, another marker for prostatic basal cells. Four of the 25 men underwent radical prostatectomy; all showed Gleason score 6 PCa.

Three radical prostatectomies demonstrated 34betaE12 reactivity: two with patchy staining in a basal cell distribution and one with mainly tumor cell staining. Adjacent HGPIN was present in all three radical prostatectomy specimens. Rare lesions with the appearance of PCa show 34betaE12 staining in a basal cell distribution either from retention of basal cells by early invasive cancer or from HGPIN outpouching. The lack of adjacent HGPIN in some cases and the large ratio of small atypical glands to HGPIN glands argue against HGPIN outpouching as the sole explanation.

In cases with adjacent HGPIN a comparison of the proximity and number of the small, atypical, infiltrative appearing glands to HGPIN is helpful. The diagnosis of PCa in the face of positive 34betaE12 basal cell staining should be made with extreme caution, only in the face of unequivocal cancer on the hematoxylin and eosin stain.

Comparison of the Basal Cell-Specific Markers, 34betaE12 and p63, in the Diagnosis of Prostate Cancer.

Shah RB, Zhou M, LeBlanc M, Snyder M, Rubin MA.

Am J Surg Pathol 2002 Sep;26(9):1161-8 Abstract quote

The basal cell-specific cytokeratin antibody (34betaE12) is widely used to aid in the diagnosis of cancer in challenging prostate needle biopsies (NBX) and transurethral resections of the prostate (TURP). Because prostate carcinoma (PCa) lacks basal cells, the absence of basal cell as determined by 34betaE12 can aid in the confirmation of a histologically suspicious lesion. However, false-negative staining occurs because of patchy cytoplasmic staining, making a definitive diagnosis difficult. A recently identified basal cell marker p63, a p53 homologue, stains basal cell nuclei but not secretory cells.

The aim of this study is to determine if the p63 antibody offers any clinically useful advantage over 34betaE12 in the diagnosis of challenging atypical prostate lesions. Ninety-four cases, comprised of 25 consecutive prostate NBX and 2 TURP with an atypical suspicious focus, 55 NBX cases of histologically unequivocal PCa and 12 TURP specimen removed for benign prostate hyperplasia, were stained with the monoclonal antibodies 34betaE12 and 4A4 anti-p63. Basal cell staining intensity, percentage basal cell-positive glands in benign, malignant, and atypical foci, and number of benign glands not staining were evaluated for 34betaE12 and p63 stains. A total of 67 prostate NBX cases, including one TURP, were diagnosed with PCa, 1 atypical small acinar proliferation, 10 benign, and 4 cases excluded because of lost tissue on step sections. None of the 67 PCa NBX cases demonstrated 34betaE12 or p63 immunoreactivity (100% specific).

Whereas 57 of 108 (53%) prostate NBX cores from 78 cases demonstrated a similar percentage of basal cell staining for both antibodies, 45 of 108 (41%) NBX cores demonstrated a higher percentage of p63 basal cell staining in benign glands. Only 6 of 108 NBX (6%) cores had a higher percentage of basal cell staining with 34betaE12 (Wilcoxon signed rank test, p <0.0001). Lack of basal cell staining in more than two benign glands occurred in 25 of 108 (23%) and 10 of 108 (9%) prostate NBX cores stained with 34betaE12 and p63, respectively. In the vast majority of atypical cases, both 34betaE12 and p63 staining differences were not clinically significant, except in 2 of 27 (7%) cases p63 offered diagnostic utility beyond the 34betaE12 immunostain. p63 in these cases demonstrated discontinuous but strong staining in atypical glands and adjacent benign glands, whereas 34betaE12 failed to stain optimally in this critical area. For 12 TURP cases the mean percentage basal cell positivity in benign glands was 75% and 95% for 34betaE12 and p63, respectively (p = 0.006). Lack of basal cell staining in more than two glands occurred in 12 of 12 (100%) and 2 of 12 (17%) TURP specimens stained with 34betaE12 and p63, respectively (p <0.0001).

In summary, 34betaE12 and p63 are highly specific for basal cells and therefore are negative in areas of PCa. p63 is more sensitive than 34betaE12 in staining benign basal cells, particularly for TURP specimens, offering slight advantage over 34betaE12 in diagnostically challenging cases. p63 may be used as an alternative to 34betaE12 stain for difficult prostate lesions.

Cytokeratin 34 beta E-12 immunoreactivity in benign prostatic acini. Quantitation, pattern assessment, and electron microscopic study.

Goldstein NS, Underhill J, Roszka J, Neill JS.

Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, MI 48073, USA.

Am J Clin Pathol 1999 Jul;112(1):69-74 Abstract quote

Because of the widespread use of keratin 34 beta E-12 to assist in the distinction between benign acini and malignant glands, the lack of immunoreactivity of benign prostatic acini are important issues.

We studied midprostate whole-mount sections from 21 low-volume adenocarcinoma radical prostatectomy specimens with keratin 34 beta E-12. We marked out benign 0.25-cm2 areas in the peripheral and transition zones and counted the number of small acini immunoreactive with keratin 34 beta E-12 to a total of 50 acini within each area. Small benign acini from nonatrophic peripheral zone lobules of 3 prostate specimens were examined by electron microscopy. The median number of immunoreactive acini in each region was 49.

The nonreactive 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. 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.

The basal cell layer becomes attenuated toward the periphery of some lobules and duct outpouchings, producing nonreactive acini adjacent to discontinuously reactive acini.


MUC6 Is a Marker of Seminal Vesicle-Ejaculatory Duct Epithelium and Is Useful for the Differential Diagnosis With Prostate Adenocarcinoma.

Leroy X, Ballereau C, Villers A, Saint F, Aubert S, Gosselin B, Porchet N, Copin MC.

Am J Surg Pathol 2003 Apr;27(4):519-21 Abstract quote

The diagnosis of prostate adenocarcinoma is usually made on needle biopsies. Numerous benign lesions may mimic malignancy, especially when the focus of carcinoma is limited. The presence of seminal vesicle-ejaculatory duct epithelium on prostate biopsy is not rare and could cause confusion with adenocarcinoma. Lipochrome pigments are frequently encountered in seminal vesicle-ejaculatory duct but may be also seen in prostate adenocarcinoma. Prostate specific antigen immunostaining in difficult cases is sometimes used, but high-grade adenocarcinomas may be negative. In one previous report, MUC6 was found to be expressed in seminal vesicle but not in normal prostate. MUC6 belongs to the family of human mucin genes.

So we investigated herein the immunohistochemical expression of MUC6 in prostate adenocarcinomas and seminal vesicle-ejaculatory duct.

We have tested 30 prostate adenocarcinomas of various grade, 10 normal seminal vesicles, and 10 prostate adenocarcinomas invading the seminal vesicles. The tissues were fixed in 1O% buffered formalin and embedded in paraffin. Immunohistochemistry was performed using the avidin-biotin-peroxidase complex technique. All adenocarcinomas and normal prostate structures tested were negative. In contrast, all seminal vesicles were diffusely immunostained with MUC6 antibody.

We concluded that MUC6 is a valuable marker of seminal vesicle-ejaculatory duct and is useful for the differential diagnosis with prostate adenocarcinoma.



Diagnostic Utility of Immunohistochemical Staining for p63, a Sensitive Marker of Prostatic Basal Cells

Michael H. Weinstein, M.D., Ph.D., Sabina Signoretti, M.D. and Massimo Loda, M.D.

Department of Pathology, Brigham and Women’s Hospital (MHW, ML) and the Dana Farber Cancer Institute (ML, SS), Boston, Massachusetts

Modern Pathology 2002;15:1302-1308 Abstract quote

Diagnostically reliable identification of prostatic basal cells has depended on staining for high molecular weight cytokeratin. The diagnosis of malignancy is often based on the absence of basal cells. False-negative staining is occasionally observed. Thus, a second method of identifying basal cells might prove useful. Selective expression of p63, a homologue of p53, has been demonstrated in prostatic basal cells.

We investigated the diagnostic utility of p63 staining in 70 consecutive specimens for which the differential diagnosis included prostatic adenocarcinoma: 68 needle biopsies and 2 transurethral resection blocks. High molecular weight cytokeratin staining was the gold standard when material was available. A total of 61 specimens were diagnosed as carcinoma, 4 as atrophy, 2 as high-grade prostatic intraepithelial neoplasia, 2 as unclassified collections of benign glands, and 1 as carcinoma versus high-grade prostatic intraepithelial neoplasia. Sections mounted on charged slides were used for p63 staining for 14 specimens. Sections previously hematoxylin and eosin stained on uncharged slides were used for 56 specimens.

In every case in which there was successful p63 staining (55 specimens), basal cells in benign lesions were properly marked and other cell types were not stained. Uninformative staining in the remaining 15 specimens was due to failure of tissue adherence in 14 specimens in which sections were on uncharged slides and, in 1 specimen, to poor positive internal control staining of benign glands. Thus, p63 staining was informative in 55 of 56 specimens (98%) for which there was material for examination. No case with satisfactory p63 and high molecular weight staining showed disagreement between the two stains. An additional group of 21 transurethral resection specimens was stained (p63 and high molecular weight cytokeratin). There was less false-negative staining for p63 compared with the case of high molecular weight cytokeratin. No false-positive staining was seen.

We conclude that p63 staining is at least as sensitive and specific for the identification of basal cells in diagnostic prostate specimens as is high molecular weight cytokeratin staining.

Polyclonal Anti-PSA Is More Sensitive but Less Specific Than Monoclonal Anti-PSA
Implications for Diagnostic Prostatic Pathology

Murali Varma, FRCPath
Meleri Morgan, MBBS
Bharat Jasani, FRCPath
Pheroze Tamboli, MD
Mahul B. Amin, MD

Am J Clin Pathol 2002:118:202-207 Abstract quote

Prostate-specific antigen (PSA) production by nonprostatic tissues has been reported, casting doubts on its specificity. The immunohistochemical relative specificity and sensitivity of PSA expression using monoclonal and polyclonal anti-PSA was analyzed on 60 prostate carcinomas, 40 normal seminal vesicles, and 310 nonprostatic tumors. All nonprostatic tumors proved negative with both antibodies.

However, 13 (32%) seminal vesicles showed immunoreactivity with polyclonal anti-PSA, but none showed immunoreactivity with the monoclonal antibody. The sensitivity of the 2 antibodies for prostate cancer varied with tumor grade. In Gleason pattern 3, both antibodies showed diffuse immunostaining in all cases. In Gleason pattern 5, polyclonal anti-PSA showed diffuse (>95%) tumor cell positivity in 18 cases (90%), while with the monoclonal antibody, 7 cases (35%) showed only focal (<10%) tumor cell immunoreactivity.

Thus, monoclonal anti-PSA seems to be useful in small gland proliferations in which the differential diagnosis includes seminal vesicle, while for poorly differentiated neoplasms, polyclonal anti-PSA is considered superior. Sections of high-grade prostate cancer should be included as positive controls for PSA immunostaining.

Immunohistochemical Staining of Precursor Forms of Prostate-specific Antigen (proPSA) in Metastatic Prostate Cancer.

*Univeristy of Pittsburgh Medical Center daggerJohns Hopkins Hospital, Baltimore, MD double daggerHybritech Incorporated, a subsidiary of Beckman Coulter, Inc, San Diego, CA.


Am J Surg Pathol. 2006 Oct;30(10):1231-1236 Abstract quote

Precursors of prostate-specific antigen (proPSA) have been previously shown to be more concentrated in prostate cancer tissue.

This study characterizes the immunohistochemical staining (IHS) of proPSA forms in metastatic prostate cancer compared with prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). A tissue microarray, consisting of 74 cases of metastatic prostate carcinoma and control tissues, was used. IHS, using monoclonal antibodies against proPSA with a truncated proleader peptide containing 2 amino acids ([-2]pPSA), native ([-5/-7]pPSA), PSA, and PAP, was analyzed. The monoclonal antibodies were specific for both benign and malignant prostatic glandular tissue. IHS with [-5/-7]pPSA showed the least number of cases with negative staining (3%), and the most number of cases with moderate or strong staining (76%).

In the 60 cases where all 4 stains could be evaluated, none of them were negative for proPSA and positive for PSA or PAP, and all 7 cases that were negative for both PSA and PAP showed IHS to proPSA. [-5/-7]pPSA (native proPSA) may be a better marker than PSA and PAP in characterizing metastatic prostate adenocarcinoma, with most of the cases showing positivity for the marker. Even cases that were negative for PSA and PAP, were reactive for proPSA. Such enhanced detection is particularly important in poorly differentiated carcinomas involving metastatic sites where prostate carcinoma is a consideration.

A panel of markers, including proPSA, should be performed when metastatic prostate carcinoma is in the differential diagnosis.


Distribution of peripheral nerves on needle biopsy

Am J Clin Pathol 2001;115:39-43
Nerves are distributed evenly from apex, mid-gland, and base and no difference between cancerous and benign specimens

Significant reduction in nerve density in cancerous vs. benign specimens

Small glandular proliferations on needle biopsies: most common benign mimickers of prostatic adenocarcinoma sent in for expert second opinion.

Herawi M, Parwani AV, Irie J, Epstein JI.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Am J Surg Pathol. 2005 Jul;29(7):874-80. Abstract quote  

The current study aimed to determine the incidence of various benign mimickers of prostatic adenocarcinoma most commonly encountered in a busy consultation practice. All prostate needle biopsies from the consult service of one of the authors were prospectively evaluated over a 7-month period. Only cases with foci where the contributor questioned malignancy and which upon expert review the entire case was determined to be benign were included in this study.

A total of 567 separate suspected atypical foci from 345 patients of a total of 4,046 patients (8.5%) received in consultation were identified. Of these, 281 foci (49.5%) had immunohistochemical (IHC) studies performed by the outside institution, which included high molecular weight cytokeratin (HMWCK) (n = 280), alpha-methylacyl-CoA racemase (AMACR) (P504s) (n = 45), and p63 (n = 34).

The most common mimicker was partial atrophy (203 of 567; 35.8%). Technically adequate IHC for basal cells was performed in 117 cases of partial atrophy with patchy or patchy/negative staining seen in 102 of 117 (87%), with the remaining 13% of cases completely negative. A total of 15 of 19 (79%) cases of partial atrophy were positive with AMACR. Crowded benign glands, insufficiently crowded or numerous to warrant a diagnosis of adenosis, was the second most common mimicker (146 of 567; 25.7%). Crowded benign glands had patchy or patchy/negative IHC for basal cells in 66 of 81 (81%) cases with the remaining 19% of cases completely negative. A total of 7 of 11 (64%) cases of crowded glands were positive for AMACR. In the past, complete atrophy, adenosis, seminal vesicle, and granulomatous prostatitis were considered common mimickers of prostate cancer on prostatic needle biopsies.

Our study shows that currently partial atrophy and crowded benign glands are the most common benign changes causing diagnostic difficulty and prompting consultation. Negative or patchy staining for basal cells and positive staining for AMACR may contribute to diagnostic difficulty in these entities.
Benign mimickers of prostatic adenocarcinoma.

Srigley JR.

1Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.
Mod Pathol 2004;17:328-348 Abstract quote

The diagnosis of prostatic adenocarcinoma, especially when present in small amounts, is often challenging. Before making a diagnosis of carcinoma, it is prudent for the pathologist to consider the various benign patterns and processes that can simulate prostatic adenocarcinoma. A useful method of classifying benign mimickers is in relationship to the major growth patterns depicted in the classical Gleason diagram.

The four major patterns are small gland, large gland, fused gland and solid. Most mimickers fit within the small gland category and the most common ones giving rise to false-positive cancer diagnosis are atrophy, post-atrophic hyperplasia, atypical adenomatous hyperplasia and seminal vesicle-type tissue. A number of other histoanatomic structures such as Cowper's gland, verumontanum mucosal glands, mesonephric glands and paraganglionic tissue may be confused with adenocarcinoma. Additionally, metaplastic and hyperplastic processes within the prostate may be confused with adenocarcinoma. Furthermore, inflammatory processes including granulomatous prostatitis, xanthogranulomatous prostatitis and malakoplakia may simulate high-grade adenocarcinoma. Atypical adenomatous hyperplasia (adenosis), a putative precursor of transition zone adenocarcinoma, has overlapping features with low-grade adenocarcinoma and may cause problems in differential diagnosis, especially in the needle biopsy setting.

The pathologist's awareness of the vast array of benign mimickers is important in the systematic approach to the diagnosis of prostatic adenocarcinoma. Knowledge of these patterns on routine microscopy coupled with the prudent use of immunohistochemistry will lead to a correct diagnosis and avert a false-positive cancer interpretation.
High-Grade Prostatic Intraepithelial Neoplasia and Atypical Small Acinar Proliferation: Predictive Value for Cancer in Current Practice.

Schlesinger C, Bostwick DG, Iczkowski KA.

From the *Bostwick Laboratories, Richmond VA; and daggerDepartments of Pathology, Immunology, and Laboratory Medicine, University of Florida; and Pathology and Laboratory Medicine, Veterans Affairs Medical Center, Gainesville, FL.

Am J Surg Pathol. 2005 Sep;29(9):1201-1207. Abstract quote  

In earlier studies, prostate cancer (PCa) has been reported to appear in 21% to 48% of subsequent biopsies for isolated high-grade prostatic intraepithelial neoplasia (PIN) and in 34% to 60% for isolated atypical small acinar proliferation suspicious for, but not diagnostic of, malignancy (ASAP).

We report results of follow-up biopsies in a recent cohort of community practice patients who underwent biopsy for PSA abnormalities. The study group consisted of 336 men with initial diagnoses of PIN (n = 204), ASAP (n = 78), or both lesions (n = 54) who underwent at least one repeat biopsy. Mean follow-up intervals in months were 6.0 for PIN, 3.8 for ASAP, and 4.9 for PIN/ASAP. Follow-up PCa detection rates were 23%, 37%, and 33%, respectively.

The predictive value of ASAP was significantly higher than that for PIN (P = 0.0188). In 23 PIN studies with chronologic midpoints in the early 1990s, follow-up PCa was detected in a mean of 36% of cases, whereas this value was 21% after the year 2000. In 13 ASAP studies, mean PCa detection on follow-up was 45% until 1996 and 39% from 1997 to present. PIN/ASAP predicted PCa in 33% of cases in our study, similar to ASAP alone (P = 0.65) and had a mean predictive value of 44% in the literature.

Factors that may account for the decline in PIN predictive values include: 1) extended biopsy techniques that yield higher rates of initial cancer detection, 2) lower detection rate for the remaining small cancers that may accompany PIN, and 3) remaining PIN cases may lack concomitant cancer.

Practice patterns of clinicians following isolated diagnoses of atypical small acinar proliferation on prostate biopsy specimens.

Fadare O, Wang S, Mariappan MR.

Department of Pathology, Yale University School of Medicine, and Yale-New Haven Hospital, New Haven, Conn 06504, USA.
Arch Pathol Lab Med. 2004 May;128(5):557-60. Abstract quote  

CONTEXT: The controversial diagnostic term atypical small acinar proliferation (ASAP) has gained some acceptance as a legitimate way for pathologists to describe minute foci of small prostatic acini that raise the suspicion of carcinoma but that fail to attain the requisite diagnostic threshold for carcinoma.

OBJECTIVE: To investigate the practice patterns of clinicians following this diagnosis and to identify clinicopathologic parameters that may be of influence.

DESIGN: All cases with a diagnosis of ASAP on a prostate biopsy specimen during a 7-year period were retrieved from our computerized database. Cases with concurrent diagnoses of adenocarcinoma and/or prostatic intraepithelial neoplasia were excluded. Medical and pathologic records for the remaining patients were reviewed and correlated with pathologic data.

RESULTS: Fifty-five (2.8%) of 1964 prostate biopsies performed during this period provided the diagnosis of ASAP, of which 36 met our study criteria. The average age of the patients was 65 years, and the mean total prostate-specific antigen (PSA) level was 6.41 ng/mL. The rate of biopsy subsequent to an ASAP diagnosis was 67% (24/36), and the mean duration to subsequent biopsy was 246 days (median, 182 days; range, 71-728 days). Adenocarcinoma was diagnosed in 9 (38%) of 24 specimens taken during the subsequent biopsy. Neither age nor PSA level significantly predicted a greater likelihood for subsequent biopsy. Additionally, among patients who received a subsequent biopsy, the aforementioned parameters were not predictive of carcinoma in the second biopsy. The average number of cores following an ASAP diagnosis (6 cores) did not differ significantly from the average at initial biopsy (7.18 cores, P =.64). Pathology report characteristics, such as inclusion of a descriptive note or explicit recommendation of a second biopsy, did not significantly increase the likelihood of a subsequent biopsy. Reasons for a delay in or lack of a subsequent biopsy following an ASAP diagnosis were miscellaneous and attributable to the patients in most cases.

CONCLUSION: The diagnosis of ASAP generates a subsequent biopsy in two thirds of cases after an average duration of 246 days. Although closer follow-up may be recommended based on the high rate of association with carcinoma on subsequent biopsy, we found no evidence that any delays in or lack of a subsequent biopsy is attributable to a lack of understanding on the part of urologists of the significance of the diagnosis.

Follow-up of atypical prostate needle biopsies suspicious for cancer.

Chan TY, Epstein JI.

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

Urology 1999 Feb;53(2):351-5 Abstract quote

OBJECTIVES: To determine both how the diagnosis of an atypical biopsy influences a urologist's decision to repeat the biopsy and the outcome of rebiopsy.

METHODS: Of 200 atypical biopsies that we confirmed from outside consultations to the Johns Hopkins Hospital from 1992 to 1993, we were able to retrieve follow-up information for 144 cases. Each atypical biopsy was evaluated for the reason for atypia (atrophic glands, rule out [r/o] adenosis, atypical not otherwise specified [NOS; insufficient cytologic and/or architectural atypia], r/o prostatic intraepithelial neoplasia [PIN], inflammation, crush artifact) and a favored diagnosis (cancerous, benign, and undetermined).

RESULTS: Of the 144 atypical biopsies, 92 were rebiopsied (63.9%). The time from the initial atypical biopsy to rebiopsy ranged from 0.5 months to 3 years (63% less than 6 months; 39% less than 3 months). Rebiopsy revealed carcinoma in 48.9%, benign in 38%, atypical in 8.7%, and PIN in 4.4%. The median prostate-specific antigen (PSA) value was lower in men who did not undergo a repeat biopsy (6 versus 7.8) (rank sum analysis, P = 0.04). No correlation was found between PSA level and results of the rebiopsy. Of the atypical biopsies in which cancer was favored, 61% were cancerous on rebiopsy versus 33% where a benign process was favored. The three reasons for atypical biopsies that seemed to correlate with outcome of rebiopsy were atypical NOS (68% cancer on rebiopsy); inflammation (63% cancer on rebiopsy); and r/o adenosis (36% cancer on rebiopsy).

CONCLUSIONS: Although 48.9% of the rebiopsied cases were cancerous, only 63% of men underwent rebiopsy, raising a concern that cancers are being missed in those cases not rebiopsied after an atypical diagnosis. Although there was a trend for serum PSA to correlate with outcome of rebiopsy, this correlation was not significant, and even men with serum PSA less than 4 ng/mL had a 33% risk of cancer on rebiopsy. Although histologic features of the atypical foci may be useful as factors in determining the urgency for rebiopsy, they also were not statistically significant in predicting outcome. Men with atypical diagnoses should undergo rebiopsy regardless of serum PSA levels and regardless of why the lesions were atypical.

Atypical small acinar proliferation suspicious for malignancy in prostate needle biopsies: clinical significance in 33 cases.

Iczkowski KA, MacLennan GT, Bostwick DG.

Department of Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.

Am J Surg Pathol 1997 Dec;21(12):1489-95 Abstract quote

Prostate needle biopsies occasionally contain an atypical small acinar proliferation (ASAP) that is suspicious for, but not diagnostic of, adenocarcinoma. The histologic features and clinical significance of this finding are unexplored.

We evaluated 33 cases of ASAP with at least one follow-up needle biopsy seen at Mayo Clinic from 1993 to 1996.

Numerous histologic and clinical features were assessed to determine their predictive value for adenocarcinoma on subsequent biopsy. Mean patient age was 61.6 years (range 45-72). Adenocarcinoma was identified on follow-up biopsy in 15 of 33 patients (45%), with a median follow-up of 9 months (range 1-27). Gleason score varied from 4 to 7 (mean 5.9). Two patients (6%) had subsequent diagnoses of ASAP after one and three repeat biopsies. Digital rectal examination, serum prostate-specific antigen, and a variety of histologic findings were not predictive of cancer on follow-up biopsy. These histologic findings included number of biopsy cores (mean 5.5), number of acini per focus of ASAP (mean 7.9), number of foci (mean one), variation in acinar size, nuclear enlargement (none, 12% of cases; mild, 45%; moderate, 33%; severe, 10%), nucleolar enlargement (none, 27%; mild, 46%; moderate, 27%), luminal mucin (39%), crystalloids (6%), focal chronic inflammation (64%), adjacent atrophy (100%), and adjacent high-grade prostatic intraepithelial neoplasia (PIN) (42%).

Stratification of suspicion in cases of ASAP without PIN into three categories ("favor benign, uncertain, and favor carcinoma") was somewhat predictive of subsequent cancer (20%, 25%, and 60% of cases with subsequent cancer, respectively), but the results were not significant. The high predictive value of ASAP for subsequent adenocarcinoma warrants repeat biopsy. No single clinical or pathologic feature appeared to increase the likelihood of subsequent cancer.

Differentiating between minimal prostatic adenocarcinoma and simulants Am J Clin Pathol 2000;114:896-909

Am J Surg Pathol 1994;18:863–870.
Am J Surg Pathol 1995;19:737–747.
Am J Surg Pathol 1995;19:506–518.
Pathol Res Pract 1995;191:860–867.
Cancer 1996;78:330–336

Lobular, relatively well-circumscribed, but sometimes focally infiltrative lesion consisting of closely packed, small acini with pale to clear cytoplasm and frequent intraluminal crystalloids and, less commonly, pale blue mucin

Almost exclusively of transition zone origin and has overlapping morphologic features with well-differentiated prostate cancer of transition zone origin

Some researchers have considered AAH to be a possible precursor to transition zone adenocarcinoma, but studies of the spatial association of the 2 lesions have been inconclusive

Expression of alpha-Methylacyl-CoA racemase (P504S) in atypical adenomatous hyperplasia of the prostate.

Yang XJ, Wu CL, Woda BA, Dresser K, Tretiakova M, Fanger GR, Jiang Z.

Department of Pathology, University of Chicago, Illinois, USA.

Am J Surg Pathol 2002 Jul;26(7):921-5 Abstract quote

Atypical adenomatous hyperplasia (AAH) of the prostate, also known as adenosis, is characterized by a proliferation of prostatic glands with abnormal architectural patterns, but without significant cytologic atypia. In some cases it may be difficult to distinguish AAH from prostatic carcinoma. Additionally, it is not clear whether AAH is a precursor lesion of prostatic adenocarcinoma. P504S, a protein highly expressed in prostatic adenocarcinoma, has been recently shown to be a marker of prostate cancer.

The goal of this study is to examine the expression of P504S in AAH by immunohistochemistry. A total of 80 prostate specimens, including 40 cases of AAH (prostatectomy N = 30, biopsy N = 6, transurethral resection N = 4), 20 cases of prostatic adenocarcinomas, and 20 cases of benign prostatic hyperplasia, were studied. Immunohistochemistry for a prostate cancer marker alpha-methylacyl-CoA racemase (P504S) and a basal cell-specific marker 34betaE12 was performed in all the cases. The 34betaE12 stain confirmed the presence of patchy basal cells in all 40 cases of AAH. P504S was undetectable in the majority of AAHs (33 of 40, 82.5%), focally expressed in four of 40 (10.0%), or diffusely positive only in three of 40 (7.5%) cases of AAH. Interestingly, two of seven P504S-positive AAHs were found adjacent to adenocarcinoma. In contrast, all benign prostatic hyperplasias (20 of 20, 100%) were negative for P504S, and all 20 cases of prostatic carcinomas (100%) showed a diffuse P504S staining pattern.

These findings suggest that AAH is a heterogenous entity. The biologic significance of P504S expression in a small subset of AAH remains to be determined. Because most cases of AAH are negative for P504S, immunostaining of P504S is also of diagnostic value in distinguishing the majority of AAHs from prostatic adenocarcinoma.

A working group classification of focal prostate atrophy lesions.

Johns Hopkins University School of Medicine.


Am J Surg Pathol. 2006 Oct;30(10):1281-91. Abstract quote

Focal atrophy is extremely common in prostate specimens. Although there are distinct histologic variants, the terminology is currently nonstandardized and no formal classification has been tested for interobserver reliability.

This lack of standardization hampers the ability to study the biologic and clinical significance of these lesions. After informal and formal meetings by a number of the authors, focal atrophy lesions were categorized into 4 distinct subtypes as follows: (i) simple atrophy, (ii) simple atrophy with cyst formation, (iii) postatrophic hyperplasia, and (iv) partial atrophy.

In phase 1 of the study, pathologists with varying levels of experience in prostate pathology were invited to view via the Internet a set of "training" images with associated descriptions of lesions considered typical of each subtype. In phase 2 of the study, each participant provided diagnoses on a series of 140 distinct "test" images that were viewed over the Internet. These test images consisted of the 4 subtypes of atrophy and images of normal epithelium, high grade prostatic intraepithelial neoplasia, and carcinoma. The diagnoses for each image from each pathologist were compared with a set of "standard" diagnoses and the kappa statistic was computed. Thirty-four pathologists completed both phases of the study. The interobserver reliability (median kappa) for classification of lesions as normal, cancer, prostatic intraepithelial neoplasia, or focal atrophy was 0.97. The median kappa for the classification of atrophy lesions into the 4 subtypes was 0.80. The median percent agreement with the standard diagnosis for the atrophy subtypes were: simple 60.6%, simple with cyst formation 100%; postatrophic hyperplasia 87.5%; partial atrophy 93.9%. The lower percentage for simple atrophy reflected a propensity to diagnose some of these as simple atrophy with cyst formation.

Seven pathologists completed the phase 2 analysis a second time, and their intraobserver reproducibility was excellent. Three of 4 pathologists with low agreement with the standard diagnosis for simple atrophy improved their scores after repeating the analysis after re-examination of the "training set" of images.

In conclusion, these criteria for variants of focal prostate atrophy may facilitate studies to examine the relation between various patterns of prostate atrophy and prostate cancer.

Inflammatory atrophy of the prostate. Prevalence and significance.

Billis A, Magna LA.

Department of Anatomic Pathology, School of Medicine, State University of Campinas (UNICAMP), Campinas, Brazil.

Arch Pathol Lab Med. 2003 Jul;127(7):840-4. Abstract quote

CONTEXT: Recently, prostatic atrophy associated with chronic inflammation has been linked to carcinoma either directly or indirectly by first developing into high-grade prostatic intraepithelial neoplasia.

OBJECTIVE: The purpose of our study was to test this hypothesis in autopsies.

DESIGN: A step section method was used to cut the posterior lobe in coronal planes at intervals of 0.3 to 0.5 cm in 100 consecutive autopsies of men older than 40 years. Prostatic atrophy was classified as simple, hyperplastic (or postatrophic hyperplasia), and sclerotic and was analyzed for the presence of chronic inflammation. Prostatic atrophy without (group A) and with inflammation (group B) was correlated with the following variables: age, race, histologic (incidental) carcinoma, high-grade prostatic intraepithelial neoplasia, and extent of both these lesions.

RESULTS: Of the 100 prostates examined, 12%, 22% and 66%, respectively, had no atrophy, atrophy without inflammation (group A), and atrophy with inflammation (group B). There was no statistically significant difference between groups A and B for age (P =.55), race (P =.89), presence of histologic (incidental) carcinoma (P =.89), extensive carcinoma (P =.43), presence of high-grade prostatic intraepithelial neoplasia (P =.65), extensive high-grade intraepithelial neoplasia (P =.30), or subtypes of prostatic atrophy. Neither a topographical relation nor a morphologic transition was seen between prostatic atrophy and histologic carcinoma or high-grade intraepithelial neoplasia. Sclerotic atrophy either alone or combined with other subtypes was more frequent in the group with inflammation. A striking morphologic finding was a topographical relation of focal inflammation with sclerotic atrophy in areas with erosion of the epithelium.

CONCLUSIONS: Inflammatory prostatic atrophy does not appear to be associated with histologic (incidental) carcinoma or high-grade intraepithelial neoplasia. One possible cause of inflammatory infiltrate associated with prostatic atrophy may be the extravasated prostatic secretions, which were noted in areas of eroded epithelium, a common finding in the sclerotic type of prostatic atrophy.

Prostatic adenocarcinoma with atrophic features: malignancy mimicking a benign process.

Egan AJ, Lopez-Beltran A, Bostwick DG.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.

Am J Surg Pathol 1997 Aug;21(8):931-5 Abstract quote

Acinar atrophy and postatrophic hyperplasia in the prostate are commonly confused with adenocarcinoma. The converse situation may also present a diagnostic dilemma.

We recently encountered a number of cases of adenocarcinoma with features that mimicked atrophy, raising the serious concern for the underdiagnosis of malignancy. To investigate the frequency of prostatic adenocarcinoma with atrophic features and the histologic criteria that allow its distinction from benign processes, we reviewed the histopathologic findings in 202 consecutive totally embedded whole-mount radical prostatectomy specimens with adenocarcinoma, 100 consecutive routine needle biopsy specimens, and five additional selected needle biopsy specimens.

None of the patients had received androgen deprivation therapy before specimen acquisition. Prostatic adenocarcinoma with atrophic features was defined as a proliferation of malignant acini that architecturally resembled atrophy or postatrophic hyperplasia but retained the diagnostic cytologic features of cancer. The acini were round, often dilated and distorted, and lined by flattened attenuated epithelium with scant cytoplasm. All cases had cytologic evidence of malignancy, including nuclear enlargement and prominent nucleoli; these findings could not be attributed to inflammation or treatment effect. Atrophic features were identified in cancer in six radical prostatectomy specimens (3%) and two routine needle biopsy specimens (2%). The proportion of cancer with atrophic features comprised a mean of 27% of each tumor in the prostatectomy specimens (range 10-60%) and 24% in the needle biopsies (range 10-90%). In the prostatectomy cases, the Gleason score of the cancers was 7 (in five cases) and 5 (in one case); in the biopsy specimens the Gleason score was 6 (in five cases) and 7 (in two cases). In addition, atrophic cancer in the prostatectomy cases had luminal eosinophilic proteinaceous secretions (six cases), blue mucin (five cases), crystalloids (two cases), apocrine blebs (three cases), collagenous micronodules (one case), and high-grade prostatic intraepithelial neoplasia within two high-power fields (three cases); the histologic features were similar in the needle biopsy specimens.

We conclude that prostatic adenocarcinoma with atrophic features is an unusual finding that is easily confused with benign acinar atrophy. It is recognized by a combination of architectural and cytologic findings and usually coexists with typical Gleason score 5-7 acinar adenocarcinoma. This pattern is important to recognize to avoid the underdiagnosis of malignancy.

Basal cell hyperplasia: An unusual diagnostic dilemma on prostate needle biopsies.

Hosler GA, Epstein JI.
Hum Pathol. 2005 May;36(5):480-5. Abstract quote  

Summary Basal cell hyperplasia (BCH) is a well-recognized entity on transurethral resection specimens, but it is an uncommon finding on prostatic needle biopsies, and the diagnostic difficulties with it have not been fully defined on this material.

A 13-year (1991-2003) retrospective review of the consult files of one of the authors was performed. In all cases, the focus of BCH was referred for consultation to rule out adenocarcinoma.

Thirty-three cases of prominent BCH were identified. The dominant pattern of BCH consisted of either glands (26/33) or solid nests (7/33). Other minor patterns included cribriform (5), pseudocribriform (4), cords (1), and adenoid basal (1). Twelve of 33 cases showed an infiltrative pattern. Other features of BCH included prominent nucleoli (14/33), abnormal secretions (17/33 with dense pink and/or blue mucin), mitoses (6/33), altered stroma with increased cellularity (6/33), calcifications (6/33), intraluminal crystalloids (3/33) and perineural invasion (1/33). By immunohistochemistry, 7 (100%) out of 7 were positive for p63 and 14 (88%) of 16 were positive for high molecular weight cytokeratin. No cases (0/6) were positive for alpha-methylacyl-coenzyme A racemase.

Basal cell hyperplasia, as a mimicker of cancer, is an uncommon entity encountered on prostatic needle biopsies. Helpful features for its diagnosis include solid nests, pseudocribriform glands, multilayering of cells, calcifications, and cellular stroma. Immunohistochemistry can be useful for documenting the basal cell layer and demonstrating negative racemase staining.
Basal Cell Proliferations of the Prostate Other Than Usual Basal Cell Hyperplasia: A Clinicopathologic Study of 23 Cases, Including Four Carcinomas, With a Proposed Classification.

McKenney JK, Amin MB, Srigley JR, Jimenez RE, Ro JY, Grignon DJ, Young RH.

Departments of Pathology, *Emory University School of Medicine, Atlanta, Georgia; daggerCredit Valley Hospital, McMaster University, Mississauga, Ontario, Canada; double daggerM. D. Anderson Cancer Center, Houston, Texas; section signHarper Hospital, Wayne State University, Detroit, Michigan; and paragraph signMassachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Am J Surg Pathol. 2004 Oct;28(10):1289-1298. Abstract quote  

Basaloid proliferations of the prostate with morphologic patterns other than usual basal cell hyperplasia are rare, and the distinction between benign and malignant lesions has been difficult.

We describe 23 such lesions and classify them into two groups: adenoid cystic-like hyperplasia and adenoid cystic or basaloid carcinoma. Adenoid cystic-like hyperplasia (n = 19) was characterized by an older age at presentation (mean, 71.8 years), transition zone location with background of nodular hyperplasia, multifocality, lobulation, circumscription, and small acini with occasional hyalinization. A cribriform pattern limited to small- and medium-sized glands, squamous metaplasia, and hypercellular myxoid stroma were occasionally seen.

Adenoid cystic carcinoma (n = 3) was characterized by a younger age at presentation (mean, 46.0 years), peripheral zone involvement, and large acini that were often dilated and exhibited extensive interanastomoses, prominent intraglandular hyalinization, perineural invasion, and extraprostatic extension.

Basaloid carcinoma (n = 1) showed infiltration between normal glands, perineural invasion, and extraprostatic extension but lacked a cribriform architecture. The degree of cytologic atypia and mitotic rate overlapped between the hyperplasia and carcinoma cases. Both hyperplastic lesions and adenoid cystic carcinomas showed a basal cell phenotype with strong immunoreactivity to cytokeratins 14 and 34βE12, but the basaloid carcinoma was negative for these markers. In all cases, the proliferating basal cells were nonreactive for myoepithelial and prostatic secretory cell markers. The 8 patients with adenoid cystic-like hyperplasia with available follow-up information had no progression of disease (mean follow-up period, 8.6 years). One patient with adenoid cystic carcinoma died with widespread metastases, but the 3 other patients with carcinomas had no disease progression (mean follow-up period, 7.0 years).

In conclusion, most florid basaloid proliferations of the prostate fall into one of two categories. In the first, there is a clear association with nodular hyperplasia (adenoid cystic-like hyperplasia) and, although cytologic atypia and mitoses may be seen, they are present within a lesion that retains an orderly, vaguely nodular (noninfiltrative) pattern. The second group of cases (adenoid cystic and basaloid carcinoma) shows a widespread, haphazard infiltrative growth pattern. This study suggests that adenoid cystic carcinomas are biologically indolent following prostatectomy but have a low risk of distant metastasis.

Basal cell hyperplasia in the peripheral zone of the prostate.

Thorson P, Swanson PE, Vollmer RT, Humphrey PA.

Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University Medical Center, St. Louis, Missouri 63110, USA.

Mod Pathol. 2003 Jun;16(6):598-606. Abstract quote

Basal cell hyperplasia in the prostate is often viewed as a transition zone proliferation, related to usual, nodular glandular, and stromal hyperplasia. Basal cell hyperplasia in the prostatic peripheral zone, the most common site for development of prostatic intraepithelial neoplasia and carcinoma, has not been previously characterized.

We characterized the incidence and histomorphological attributes of basal cell hyperplasia in a series of 500 consecutive sextant needle core biopsy samples and in 26 completely embedded prostate glands from radical prostatectomy specimens. Comparative proliferation indices (by MIB-1 staining) and apoptotic indices (by TUNEL labeling) were quantitated for peripheral zone versus transition zone basal cell hyperplasia versus normal basal cells. The incidence of basal cell hyperplasia in prostate needle biopsy tissue was 10.2% (51 of 500 cases). Usual basal cell hyperplasia was detected in 8.2% of the 500 cases, and basal cell hyperplasia with prominent nucleoli, in 2.0% of cases. Basal cell hyperplasia in needle biopsy tissue was typically focal and associated with inflammation, which was usually lymphocytic, in 84% of cases. Peripheral zone basal cell hyperplasia was found in 23% of whole prostate glands. Peripheral zone basal cell hyperplasia was not observed to be in direct physical continuity with intraepithelial or invasive neoplasia. Peripheral zone and transition zone basal cell hyperplasia exhibited similar mean proliferation and apoptotic indices, at 1% and 0.07%, respectively. This proliferation index was elevated, and apoptotic index was decreased, relative to normal basal cells (P = 1 x 10(-7)).

Basal cell hyperplasia in the peripheral zone is present in a significant minority of prostate needle biopsy samples and whole prostate glands. The presence of prominent nucleoli in basal cell hyperplasia may cause diagnostic concern for a neoplastic proliferation. The increase in cell number in basal cell hyperplasia appears to be due to a coordinate increase in proliferation index coupled with a diminished apoptotic index. The presence of inflammation in the majority of basal cell hyperplasia foci suggests that peripheral zone basal cell hyperplasia in untreated patients may represent a stereotyped response to injury such as that sustained because of inflammation.

Florid basal cell hyperplasia of the prostate: A histological, ultrastructural, and immunohistochemical analysis.

Yang XJ, Tretiakova MS, Sengupta E, Gong C, Jiang Z.


Hum Pathol. 2003 May;34(5):462-70. Abstract quote

Basal cell proliferation is a common finding in a benign hyperplastic prostate gland. Occasionally, basal cell hyperplasia is so florid that it can be mistaken for prostatic adenocarcinoma.

We characterized histological, ultrastructural, and immunohistochemical features of florid basal cell hyperplasia from transurethral resections (n = 11) and prostatectomy specimens (n = 4). Fifteen cases of prostatic adenocarcinoma were used as comparison. Intraluminal calcification was present in 40% of florid basal cell hyperplasia cases (6 of 15) and a unique finding of intracytoplasmic hyaline globules was detected in 53.3% of florid basal cell hyperplasia cases (8 of 15).

Ultrastructural analysis revealed luminal calcification and intracytoplasmic electron-dense globules in foci of basal cell hyperplasia. Crystalloids, a frequent finding in low-grade prostate cancer, were absent in all 15 cases of florid basal cell hyperplasia. By immunohistochemistry, the basal cell-specific 34betaE12 and p63 as well as glutathione-s-transferase pi were positive in all basal cell hyperplasia cases but negative in all prostatic adenocarcinomas. These distinguishing features of florid basal cell hyperplasia are helpful in differential diagnosis from prostatic adenocarcinoma.

Cytokeratins 8 and 18 were both positive in basal cells, benign secretory cells, and carcinoma cells, failing to be of discrimatory value.

Immunostaining for alpha-methylacyl-coenzyme racemase, a new prostate cancer marker, was negative in hyperplastic basal cells but detected a distinct minor benign cell population in basal cell hyperplasia of possible neuroendocrine origin.

Unusual Morphologic Patterns of Basal Cell Hyperplasia of the Prostate

Nathalie C. Rioux-Leclercq, M.D. ; Jonathan I. Epstein, M.D.

From the Departments of Pathology and Urology, Johns Hopkins Medical Institutions, Baltimore, Maryland, U.S.A.

Am J Surg Pathol 2002;26:237-243 Abstract quote

The distinction of basal cell hyperplasia (BCH) from carcinoma or high-grade prostatic intraepithelial neoplasia may be difficult.

We reviewed 25 cases of BCH with unusual features and identified four distinct groups: BCH with intracytoplasmic globules (five cases); BCH with calcifications (eight cases), including one with globules; BCH with squamous features (three cases); and cribriform BCH (nine cases), including two cases with globules.

A total of five cases contained prominent nucleoli and/or cytologic atypia. Hyaline cytoplasmic globules have not been described in any other prostatic entity and appear diagnostic of BCH. Calcifications observed in BCH were psammomatous, differing from the fine stippled calcifications occasionally seen in areas of comedonecrosis within high-grade prostatic carcinoma. Basal cell hyperplasia with squamous features differed from squamous differentiation in carcinomas (adenosquamous carcinoma) and from benign foci of squamous differentiation seen associated with either prostatic infarcts or with hormonal therapy. Whereas cribriform prostatic intraepithelial neoplasia and cribriform cancer glands represent a single glandular unit with punched out lumina, many of the glands within a focus of cribriform BCH appeared as fused individual BCH glands. The use of cytokeratin 34E12 can help in difficult cases. In cribriform BCH high-molecular-weight cytokeratin shows multilayered staining of the basal cells in some of the glands and a continuous layer of immunoreactivity. Cribriform prostatic intraepithelial neoplasia demonstrates an interrupted immunoreactive single cell layer of basal cells.

Recognition of the architectural and cytologic features of unusual morphologies of BCH can be used to facilitate its diagnosis and differentiation from prostatic carcinoma and high-grade prostatic intraepithelial neoplasia.


Central zone histology of the prostate: a mimicker of high-grade prostatic intraepithelial neoplasia.

Srodon M, Epstein JI.

Department of Urology, The Johns Hopkins University Hospital, Baltimore, MD 21231, USA.

Hum Pathol 2002 May;33(5):518-23 Abstract quote

The central zone (CZ) is located at the base of the prostate adjacent to the seminal vesicles. Its histology as a potential mimicker of high-grade prostatic intraepithelial neoplasia (PIN) has not been formally studied.

Three groups were evaluated. Group 1 comprised 30 consecutive radical prostatectomy specimens assessed for the extent of CZ and of Roman arch and/or cribriform formation in the CZ. Group 2 comprised 100 consecutive cases of nonconsult prostate needle biopsies, screened in a random blinded fashion to identify CZ histology and the specificity of its identification on biopsy. Group 3 comprised 34 consult cases (1984 to the present) with CZ histology on needle biopsy. For group 1, the average maximum diameter of CZ histology was 5 mm. Two cases (6.7%) did not contain the classic features of CZ histology. The average amount of cribriform and/or Roman arch formation in the areas with CZ histology was 16.5%. In group 2, 10% of prostate needle biopsy cases had CZ histology. Of these, 80% were located on biopsy specimens designated as the base of the prostate, 10% were located in the base and midportion of the prostate, and 10% were located in the midportion of the prostate. For group 3, CZ histology occupied on average 32% of the involved core. The 2 most common histologic features were eosinophilic cytoplasm (97%) and location at the end of a core (97%). Other features were Roman arch formation (59%), a prominent basal cell layer (32%), cribriform formation (26%), and associated thick muscle bundles typical of bladder neck (24%). On average, cribriform and/or Roman arch formation occupied 22% of the CZ area seen on biopsy. Twenty-six of the consult cases were sent in with preliminary outside diagnoses. Of these, 21 (81%) were either PIN or atypical: 11 (42%) high-grade PIN, 7 (27%) PIN, and 3 (12%) atypical glands.

Our findings show that CZ histology is distinctive, as seen in radical prostatectomy specimens. Less frequently it is found on needle biopsy, where the presence of Roman arch and/or cribriform formation mimics PIN. Recognition of the distinctive features of CZ histology (i.e., tall columnar cells with eosinophilic cytoplasm, prominent basal cell layer, and lack of cytologic atypia) can help avoid a misdiagnosis of PIN or "atypia" on needle biopsy.

Span the spectrum from completely benign (clear cell cribriform hyperplasia, cribriform central zone glands, cribriform basal cell hyperplasia) to premalignant (cribriform high-grade prostatic intraepithelial neoplasia) to malignant (cribriform acinar and ductal adenocarcinoma)

Am J Surg Pathol 2001;25:147-155

Of 574 high-grade prostatic intraepithelial neoplasia (PIN) lesions on needle biopsy seen at Johns Hopkins over 75 months-identified 23 consult cases in which the differential diagnosis was cribriform high-grade PIN versus infiltrating cribriform carcinoma

Prebiopsy prostate-specific antigen (PSA) averaged 6.5 ng/mL (range, 0.3 to 37.3)
A positive digital rectal examination (DRE) was present in 12 of 22 (55%) patients for whom information was available
Ordinary high-grade PIN was present elsewhere in the biopsy specimens in 32% of cases.

Cellular maturation toward the center of the cribriform glands (45%)
Identifiable basal cells on hematoxylin and eosin sections (36%)
Marked nuclear atypia (9%)
Mitoses (23%)
Nucleoli were not visible in 18% of cases, small in 36%, and prominent in 45%.

With a mean follow-up of 13.8 months for those without progression (25.9 months' overall follow-up), a repeat biopsy diagnosis of cancer was seen in 10 of 22 men:
By report: Gleason score (Gs) 4 (n = 1); Gs 6 (n = 3); Gs 7 (n = 4); Gs 9 (n = 2); three biopsy specimens showed ductal features
An additional two men developed bone metastases without biopsy

Overall, 12 of 22 (55%) patients had cancer on follow-up
(one patient lost to follow-up)

Two histologic findings were statistically predictive of cancer on follow-up: Atypical cribriform glands in biopsy specimens from both sides of the prostate and the presence of detached cribriform glands

Four clinicopathologic findings predicted carcinoma on follow-up:
Positive DRE (p = 0.02)
Positive transrectal ultrasound (p = 0.02)
Bilateral atypical cribriform glands (p = 0.02)
Detached cribriform glands (p = 0.04)

Cribriform Hyperplasia

Am J Surg Pathol 1986;10:665–71

True cribriform hyperplasia occurs within the transition zone and hence is rarely seen on needle biopsy

Differs from both cribriform high-grade PIN and cribriform cancer by:
Lack of cytologic atypia
Clear cells
Obvious basal cell layer around some of the glands

Cribriform Central Zone Glands

Urology [Suppl] 1981;17:11–16.
Interpretation of prostate biopsies. 2nd ed. New York, NY, Raven, 1995:46, 211.

Cribriform Central Zone Glands which is a small area adjacent to seminal vesicles

Glands with predominant Roman bridge formation and focal cribriform gland formation
Lack cytologic atypia
Distinctive tall pseudostratified nuclei with eosinophilic cytoplasm

Cribriform basal cell hyperplasia

Am J Surg Pathol 1992;16:1205–14.

May contain nuclei with prominent nucleoli
Occurs predominantly within the transition zone and is rarely seen on needle biopsy
Cribriform glands are uncommon in basal cell hyperplasia and often appear more as fused individual glands of basal cell hyperplasia rather than true cribriform glands

Squamous metaplasia
Transitional cell metaplasia
Radiation atypia
Postoperative spindle cell nodule
Atypical stromal cells
Extramedullary hematopoiesis
Cowper glands
Paraganglia in prostate
Benign glands adjacent to nerves and skeletal muscle

Infarct of the Prostate Gland Experience on Needle Biopsy Specimens

Rolando A. Milord, M.D.; Hillel Kahane, M.D.; Jonathan I. Epstein, M.D.

From the Johns Hopkins Hospital, Baltimore, Maryland, U.S.A. (J.I.E., R.A.M.); and Dianon Systems, Stratford, Connecticut, U.S.A. (H.K.).

Am J Surg Pathol 2000;24:1378-1384 Abstract quote

Prostatic infarcts are uncommon and in the past have only been reported on transurethral resections of the prostate.

We reviewed 13 consults and 2 nonconsult cases of needle biopsies showing prostatic infarcts from two institutions.

The incidence of infarcts on biopsy were 2 in 2958 (0.07%) and 1 in 108,586 (0.0009%) in our nonconsult cases. Men averaged 71 years of age (range, 57–84 yrs). No relationship was seen with histories of hypertension, diabetes, atherosclerotic coronary vascular disease, recent surgery, and steroid use. Four of 12 men with available information had acute urinary retention, with markedly enlarged prostates in three (90 cc, 92 cc, 94 cc); two of these men had hematuria. An additional two men also had large glands (84 cc, 150 cc), one also with hematuria. Of eight men without acute urinary retention, three had sudden prostate-specific antigen (PSA) rises (increases of 199 ng/mL, 219 ng/mL, 287 ng/mL). Infarcts were usually an isolated focus on one core and varied from 1 mm to 11 mm (mean, 6.3 mm). Six cases showed earlier-aged infarcts with coagulative necrosis and recent hemorrhage and six showed intermediate-aged infarcts with reactive stroma and epithelium without necrosis. In the remaining three cases, there were remote infarcts characterized by replacement of the stroma by dense fibrosis with metaplastic glands. Adjacent tissue revealed reactive nests of immature squamous metaplasia in 14 of 15 cases with visible nucleoli (12 cases), squamous atypia (7 cases), and mitoses ranging from 1–10 (7 cases). Pathologists sent in 10 of 13 consult cases (77%) for problems with interpretation of the infarcts; remaining consults had other pathology of concern. One case was misdiagnosed as urothelial cancer. Features helpful in recognizing infarcts' benign nature were cyst formation containing cellular debris with or without neutrophils (73%), corpora amylacea (20%), and rings of collagen around squamous islands (40%). Infarcts are typically, although not exclusively, found in large prostates and may result in sudden rises in serum PSA.

Infarcts' distinctive histology must be recognized and distinguished from necrosis resulting from infection and prior cryotherapy, as we have seen such misdiagnoses. Pathologists' awareness of prostatic infarcts on needle biopsy and their potential for atypical histology can prevent the misdiagnosis of cancer.

Inverted Papillomas of the Prostatic Urethra.

Fine SW, Chan TY, Epstein JI.

Departments of *Pathology daggerUrology double daggerOncology, The Johns Hopkins Hospital, Baltimore, MD.


Am J Surg Pathol. 2006 Aug;30(8):975-979. Abstract quote

Inverted papillomas of the genitourinary tract are uncommon benign neoplasms usually occurring in the urinary bladder and less frequently in the upper urinary tract. To date, there are scant data and no comprehensive studies of inverted papilloma originating in the prostatic urethra.

We identified 21 cases and evaluated their demographic, clinical, and histopathologic features. Patients had a mean age of 65.1 years (range: 30 to 89 y), with 10/21 (47.6%) presenting with gross hematuria (n=8) or irritative symptoms (n=2) related to the inverted papilloma and 11/21 (52.4%) detected incidentally during work-up/treatment of prostate cancer (n=6) or benign prostatic hypertrophy (BPH) (n=5). Fourteen cystoscopically evaluated lesions measured 0.1 to 2.0 cm, and were described as polypoid (n=9), papillary (n=4), or an enlarged median lobe (n=1). Lesions were diagnosed on transurethral resection (n=8), biopsy/polypectomy targeted to the lesion (n=6), radical prostatectomy for prostate cancer (n=4), or biopsy unrelated to the lesion (n=3).

Histologically, 14/21 cases (67%) displayed classic inverted papilloma architecture. The remaining cases showed foci of squamous metaplasia with moderate atypia (n=4), rare true papillary fronds in a classic inverted papilloma background (n=2), or both (n=1). Eleven cases with prostatic tissue revealed adenocarcinoma of the prostate [n=6; Gleason score 6 (n=3) or 7 (n=3)], high-grade prostatic intraepithelial neoplasia (n=1), benign prostatic hypertrophy (n=3), or adenosis (n=1). No patients had a prior history of either inverted papilloma or urothelial carcinoma, whereas 2 patients were diagnosed with high-grade urothelial carcinoma of the bladder synchronous with their inverted papilloma diagnosis. Only 1 of the 18 patients with available follow-up had a recurrence of inverted papilloma in the prostatic urethra. None of the other patients had local recurrences or recurrences at other locations in the urinary tract (mean follow-up 39.9 mo; range: 3 to 120 mo). Inverted papillomas of the prostatic urethra are benign lesions that are commonly detected incidentally and are not associated with a history of urothelial malignancy.

Although urothelial carcinoma elsewhere in the genitourinary tract may occur simultaneously, malignant transformation or recurrence as a malignant lesion has not been identified in inverted papilloma of the prostatic urethra.
Perineural Involvement by Benign Prostatic Glands on Needle Biopsy.

Ali TZ, Epstein JI.

From the Departments of *Pathology, daggerUrology, and double daggerOncology, Johns Hopkins Hospital, Baltimore, MD.

Am J Surg Pathol. 2005 Sep;29(9):1159-1163. Abstract quote  

Uncommonly, benign prostatic glands can be seen in the perineural space, known as "benign perineural involvement." This phenomenon has not been specifically studied on needle biopsies; 27 needle biopsy cases with perineural involvement were evaluated; 22 (81.4%) were received in consultation, while 5 (18.5%) were in-house cases.

In 15 of 22 (68.2%) consult cases, a question was raised by the submitting pathologist regarding the focus. The following patterns of perineural involvement were observed: indentation 14 (51.8%) cases, by up to 3 glands; tracking 8 (29.6%) cases, by up to 6 glands; wrapping 7 (25.9%) from one half to three fourths around the nerve, by up to 3 glands, 1 case showed 95% wrapping; intraneural 4 (14.8%) cases by up to 3 glands; adjacent 2 (7.4%) cases by up to 2 glands. Partial atrophy in the involved glands was seen in 10 (38.4%) cases and complete atrophy in 6 (23%). Of 8 cases with the lesion still present on slides for immunohistochemistry, high molecular weight cytokeratin (HMWCK) and p63 were positive in 6 (75%) and negative in the 2 (25%) cases with partial atrophy. A total of 6 (27%) cases had more than one pattern of perineural involvement. On hematoxylin and eosin sections, basal cells were not identified in 12 (46%) cases, including 2 negative and 1 positive cases stained for HMWCK. Patterns most closely mimicking cancer included intraneural and incomplete perineural encirclement.

Perineural invasion by benign atrophic glands cause diagnostic difficulty, especially with negative HMWCK. Careful attention to hematoxylin and eosin morphology and comparison of perineural involvement to adjacent and distant benign glands are necessary.

Exaggerated Signet-Ring Cell Change in Stromal Nodule of Prostate: A Pseudoneoplastic Proliferation

Hanlin L. Wang, M.D., Ph.D.; Peter A. Humphrey, M.D., Ph.D.

Am J Surg Pathol 2002; 26(8):1066-1070 Abstract quote.

A stromal nodule of the prostate was incidentally identified in a simple prostatectomy specimen from a 66-year-old man with benign prostatic hyperplasia. Microscopically, the nodule consisted of short spindly cells with bland nuclear features. Many of the cells in the nodule, however, contained a large, clear cytoplasmic vacuole that displaced and indented the nucleus, generating signet-ring cell morphology.

Immunohistochemically, these cells were strongly positive for vimentin and weakly positive for desmin, suggesting a myofibroblastic nature. Further immunostains demonstrated the cells to be negative for cytokeratins and prostate-specific antigen, excluding the possibility of signet-ring cell carcinoma.

The cytoplasmic vacuoles also stained negative for mucin production. Electron microscopy revealed no intracytoplasmic lumina. Notably, thermal effect or other signs of cellular injury, frequently associated with signet-ring cell change seen in prostate specimens obtained by transurethral resection and needle biopsy, were not appreciated in this stromal nodule.

This case demonstrates that signet-ring cell change may occur in benign, hyperplastic, prostatic stromal cells in the absence of cellular damage.

Gastrointestinal Stromal Tumors (GISTs) on Prostate Needle Biopsy: A Clinicopathologic Study of 8 Cases.

Departments of *Pathology daggerUrology double daggerOncology, Johns Hopkins Hospital, Baltimore, MD.


Am J Surg Pathol. 2006 Nov;30(11):1389-1395 Abstract quote

Gastrointestinal stromal tumors (GISTs) are typically not included in the differential diagnosis of spindle cell tumors seen on prostate needle biopsy. However, their recognition is critical due to their unique clinical management.

We report the rare phenomenon of 8 cases of GISTs diagnosed on prostate needle biopsy. The mean patient age at diagnosis was 53.6 years (range: 42 to 65 years). Tumors variably presented with rectal fullness, urinary obstructive symptoms, and abnormal digital rectal examination. Four tumors were resected. One of these cases was shown to be primary in the rectum without prostatic involvement. The second case extensively involved the prostate but its epicenter was in the rectal muscularis propria. The third case was an encapsulated mass separated by a thin fibrous capsule from the prostate. The fourth case was a perirectal mass that underwent local excision. Four lesions have not been resected. On the basis of imaging studies, one seemed to be a prostatic mass, however, additional imaging investigations showed the mass to be separate from the prostate. Three cases have not yet been studied radiographically. Tumors measured 1.0, 1.7, 5.4, 7.0, 7.4, and 8.5 cm. The sizes of 2 recently diagnosed tumors remain undetermined. Histologically, all 8 GISTs showed spindled cells with a fascicular growth pattern. Additional histologic findings included focal epithelioid features (n=3), necrosis (n=3), mitotic rates of >5 per 50 high-power field (n=2), and cytologically malignant features (n=3). CD117/c-kit was diffusely positive in all 8 cases and CD34 in 7/8 cases. In all cases studied, stains for S100, desmin, and smooth muscle actin were negative. Two patients were treated with imatinib mesylate. One underwent radical prostatectomy after reduction in tumor size after imatinib administration. Another patient was treated with imatinib for several months with complete tumor response and no residual tumor seen in a subsequent local excision.Rectal or extraintestinal GIST can result in a clinical impression of a prostatic lesion.

One should consider CD117/c-kit in the immunohistochemical panel to exclude GIST before diagnosing a solitary fibrous tumor, leiomyosarcoma, or specialized prostatic stromal tumor on prostate needle biopsy.
Prostate-Specific Antigen, High-Molecular-Weight Cytokeratin (Clone 34bE12), and/or p63
An Optimal Immunohistochemical Panel to Distinguish Poorly Differentiated Prostate Adenocarcinoma From Urothelial Carcinoma

Lakshmi P. Kunju, MD, etal.
Am J Clin Pathol 2006;125:675-681
Abstract quote

An optimal immunohistochemical panel to distinguish poorly differentiated prostate (PCa) from urothelial (UCa) carcinoma was selected from a panel consisting of prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP), high-molecular-weight cytokeratin (HMWCK) (clone 34bE12), cytokeratin (CK) 7, CK20, p63, and a-methylacyl-coenzyme A racemase.

The pilot group was composed of poorly differentiated UCa (n = 36) and PCa (n = 42). PSA and PAP stained 95% of PCa vs 0% and 11% of UCa cases, respectively. HMWCK and p63 stained 97% and 92% of UCa vs 2% and 0% of PCa cases respectively. CK7/CK20 coexpression was noted in 50% of UCa cases, whereas 86% of PCa cases were negative with both. A panel of PSA, HMWCK, and p63 was optimal for separating 95% PCa (PSA+/HMWCK and/or p63–) vs 97% UCa (PSA–/HMWCK and/or p63+). This panel was used on 26 diagnostically challenging cases and resolved 81% of cases as UCa vs PCa. The majority of PCa cases retain PSA.

Negative PSA with positive HMWCK and/or p63 establishes a diagnosis of UCa.

A Clinicopathologic Analysis of Urothelial Carcinomas Diagnosed on Prostate Needle Biopsy

Bahram R. Oliai, M.D.; Hillel Kahane, M.D.; Jonathan I. Epstein, M.D.

Am J Surg Pathol 2001;25:794-801 Abstract quote

No data exist on urothelial carcinoma diagnosed on prostatic needle biopsy. We reviewed 21 cases (19 consultations) of urothelial carcinoma diagnosed on prostate needle biopsy from 1991 to 1998.

In 13 of 21 (62%) cases, urothelial carcinoma showed in situ urothelial carcinoma involving prostatic ducts and acini (DCIS) only; 6 of 21 (29%) cases showed both DCIS and invasive carcinoma and 2 of 21 (9%) cases showed widespread stromal invasion without DCIS. In contrast to prostatic adenocarcinoma, cases exhibited greater nuclear pleomorphism, variably prominent nucleoli, increased mitoses, and necrosis.

Immunostains for PSA and PSAP were negative in all 18 cases studied. CK7 was positive in 14 of 16 cases, CK20 was positive in 13 of 16 cases, and 34E12 was positive in 11 of 17 cases. A total of 7 of 17 (41%) men had no prior or subsequent history of urothelial carcinoma outside the prostate, 6 of 17 (35%) had concurrent urothelial cell carcinomas of the bladder (1 with extensive carcinoma in situ [CIS] at cystoprostatectomy), 2 of 17 (12%) had a prior urothelial cell carcinoma, and 2 of 17 (12%) developed urothelial cell carcinomas outside the prostate subsequent to the needle biopsy diagnosis. A total of 14 of 18 (78%) men had an elevated prostate specific antigen (PSA), abnormal digital rectal examination, or abnormal ultrasound suggestive of prostatic adenocarcinoma.

Follow-up information was available in 17 cases. Six of nine (67%) patients with DCIS eventually died of disease (DOD) (2 with prior urothelial cell carcinoma, 1 with no prior or subsequent history, 3 without information), and 3 of 9 (33%) patients with DCIS were alive with residual disease (AWD). Of the patients with invasive carcinomas, 4 of 8 (50%) were DOD, 2 of 8 (25%) were AWD, and 2 of 8 (25%) were alive without evidence of disease. All men who are alive were treated aggressively with surgery and often adjuvant chemotherapy–radiation. Overall, 10 of 17 (59%) men were DOD with a mean survival after diagnosis of 23.2 months (2–72 months).

The diagnosis of urothelial carcinoma on prostate needle biopsy is difficult because it is rare and clinically can mimic prostatic adenocarcinoma; often there is no history of urothelial carcinoma elsewhere. Although the prognosis is poor even with only apparent DCIS, histologic recognition is essential because the only opportunity for improved outcome is early and aggressive treatment.

Immunohistochemical profile of high-grade urothelial bladder carcinoma and prostate adenocarcinoma.

Mhawech P, Uchida T, Pelte MF.

Office of Biostatistics, The University of Texas Medical Branch at Galveston, Galveston, TX; and the Department of Pathology, Geneva University Hospital, Geneva, Switzerland.


Hum Pathol 2002 Nov;33(11):1136-40 Abstract quote

The differential diagnosis between poorly differentiated prostate adenocarcinoma (PAC) involving the bladder and high-grade urothelial bladder cancer (UC) with prostate extension can be very challenging.

The aim of this study is to evaluate the use of a panel of antibodies to distinguish the poorly differentiated forms of these two tumors. We evaluated a series of 40 PAC cases (Gleason's grade >/= 8) and 45 (G3) UC cases obtained from transurethral endoscopic resection material. Immunohistochemical analysis was performed using the following antibodies: prostate acid phosphatase (PAP), prostate-specific antigen (PSA), uroplakin III (UP), thrombomodulin (TM), cytokeratin (CK) 7, and CK20. PAC expressed PSA and PAP in 34 and 38 cases, respectively. The sensitivity and specificity of expressing at least 1 marker (PSA+ or PAP+) is 95% and 100%, respectively. All UC cases were negative for both markers. UC expressed UP and TM in 27 and 22 cases, respectively. In addition, 36 of 45 cases stained positively for at least 1 marker (UP + or TM +) with specificity and sensitivity of 80% and 100%, respectively. All cases of PAC were negative for both markers. Twenty-eight UC cases were CK7+/CK20 +, and 4 PAC cases stained positively for both markers. On the other hand, 29 PAC cases and 4 UC cases were CK7-/CK20-.

We concluded that PSA, PAP, UP, and TM are very useful markers in differentiating poorly differentiated UC from PAC. Finally, when all 4 markers (PAP, PSA, UP, and TM) were negative, CK7 and CK20 appeared of no major use in making the differential diagnosis.

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation

Commonly Used Terms
This is a glossary of terms often found in a pathology report.

Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscope

Surgical Pathology Report
Examine an actual biopsy report to understand what each section means

Special Stains
Understand the tools the pathologist utilizes to aid in the diagnosis

How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate

Got Path?
Recent teaching cases and lectures presented in conferences

Internet Links

Last Updated February 19, 2007

Send mail to The Doctor's Doctor with questions or comments about this web site.
Read the Medical Disclaimer.

Copyright © The Doctor's Doctor