Intraductal carcinoma of the prostate: interobserver reproducibility survey of 39 urologic pathologists.

The diagnosis of intraductal carcinoma (IDC) of the prostate remains subjective because 3 sets of diagnostic criteria are in use. An internet survey was compiled from 38 photomicrographs showing duct proliferations: 14 signed out as high-grade prostatic intraepithelial neoplasia (HGPIN), 17 IDC, and 7 invasive cribriform/ductal carcinoma. Each image was assessed for the presence of 9 histologic criteria ascribed to IDC. Thirty-nine respondents were asked to rate images as (1) benign/reactive, (2) HGPIN, (3) borderline between HGPIN and IDC, (4) IDC, or (5) invasive cribriform/ductal carcinoma. Intraclass correlation coefficient was 0.68. There was 70% overall agreement with HGPIN, 43% with IDC, and 73% with invasive carcinoma (P < .001, χ(2)). Respondents considered 19 (50%) of 38 cases as IDC candidates, of which 5 (26%) had a two-thirds consensus for IDC; two-thirds consensus for either borderline or IDC was reached in 9 (47%). Two-thirds consensus other than IDC was reached in the remaining 19 of 38 cases, with 15 supporting HGPIN and 4 supporting invasive carcinoma. Findings that differed across diagnostic categories were lumen-spanning neoplastic cells (P < .001), 2× benign duct diameters (P < .001), duct space contours (round, irregular, and branched) (P < .001), papillary growth (P = .048), dense cribriform or solid growth (both P = .023), and comedonecrosis (P = .015). When the 19 of 38 images that attained consensus for HGPIN or invasive carcinoma were removed from consideration, lack of IDC consensus was most often attributable to only loose cribriform growth (5/19), central nuclear maturation (5/19), or comedonecrosis (3/19). Of the 9 histologic criteria, only 1 retained significant correlation with a consensus diagnosis of IDC: the presence of solid areas (P = .038). One case that attained IDC consensus had less than 2× duct enlargement yet still had severe nuclear atypia and nucleomegaly. Six fold nuclear enlargement was not significant (P = .083), although no image had both 6× nuclei and papillary or loose cribriform growth: a combination postulated as sufficient criteria for IDC. Finally, 20.5% of respondents agreed that an isolated diagnosis of IDC on needle biopsy warrants definitive therapy, 20.5% disagreed, and 59.0% considered the decision to depend upon clinicopathologic variables. Although IDC diagnosis remains challenging, we propose these criteria: a lumen-spanning proliferation of neoplastic cells in preexisting ducts with a dense cribriform or partial solid growth pattern. Solid growth, in any part of the duct space, emerges as the most reproducible finding to rule in a diagnosis of IDC. Comedonecrosis is a rarer finding, but in most cases, it should rule in IDC. Duct space enlargement to greater than 2× the diameter of the largest, adjacent benign spaces is usually present in IDC, although there may be rare exceptions.

Adequate histologic sectioning of prostate needle biopsies.

No standard method exists for sampling prostate needle biopsies, although most reports claim to embed 3 cores per block and obtain 3 slices from each block. This study was undertaken to determine the extent of histologic sectioning necessary for optimal examination of prostate biopsies. We prospectively compared the impact on cancer yield of submitting 1 biopsy core per cassette (biopsies from January 2010) with 3 cores per cassette (biopsies from August 2010) from a large national reference laboratory. Between 6 and 12 slices were obtained with the former 1-core method, resulting in 3 to 6 slices being placed on each of 2 slides; for the latter 3-core method, a limit of 6 slices was obtained, resulting in 3 slices being place on each of 2 slides. A total of 6708 sets of 12 to 18 core biopsies were studied, including 3509 biopsy sets from the 1-biopsy-core-per-cassette group (January 2010) and 3199 biopsy sets from the 3-biopsy-cores-percassette group (August 2010). The yield of diagnoses was classified as benign, atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, and cancer and was similar with the 2 methods: 46.2%, 8.2%, 4.5%, and 41.1% and 46.7%, 6.3%, 4.4%, and 42.6%, respectively (P = .02). Submission of 1 core or 3 cores per cassette had no effect on the yield of atypical small acinar proliferation, prostatic intraepithelial neoplasia, or cancer in prostate needle biopsies. Consequently, we recommend submission of 3 cores per cassette to minimize labor and cost of processing.

The Symphony protocol for H&E staining of prostatic adenocarcinoma on needle biopsy: a multicentre analysis of 120 cases.

AIMS: The diagnosis of prostate carcinoma is based on a constellation of architectural, nuclear, cytoplasmic, and ancillary features. The aim of this study was to determine if the Ventana Symphony H&E protocol can improve on the detection of prominent nucleoli in foci of prostate cancer. METHODS: One hundred and twenty cases of Gleason score 3 + 3 = 6 cancers involving 10-30% of one core were retrieved from four academic institutions and two large laboratories (20 cases per institution). The routine H&E and Symphony H&E protocol stained slides from the same case were reviewed centrally in a blinded fashion at the Johns Hopkins Hospital. The mean percentages of prominent nucleoli in malignant and benign glands by visual estimation were recorded for each case. After unblinding, the routine H&E slides were compared in a pair-wise t-test with the corresponding Symphony stained slide. RESULTS: Within all sites, the Symphony slides showed statistically significantly more prominent nucleoli in the malignant glands than the routine slides. CONCLUSIONS: The Symphony H&E staining protocol consistently highlights nucleoli in cancer to a greater extent than routine H&E stains and may increase the likelihood of making a diagnosis of limited adenocarcinoma of the prostate in challenging cases.

Can basal cells be seen in adenocarcinoma of the prostate?: an immunohistochemical study using high molecular weight cytokeratin (clone 34betaE12) antibody.

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.

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

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.

Risk of prostate cancer on first re-biopsy within 1 year following a diagnosis of high grade prostatic intraepithelial neoplasia is related to the number of cores sampled.

PURPOSE: We determined the influence of the extent of needle biopsy sampling on the detection rate of cancer on first biopsy within 1 year following a diagnosis of HGPIN. MATERIALS AND METHODS: We identified 791 patients with HGPIN on the initial biopsy who had a followup biopsy within 1 year of their diagnosis. The mean interval from diagnosis of HGPIN to re-biopsy was 4.6 months. In the initial biopsy with HGPIN, 323 men had 8 or more cores (median 10, range 8 to 26) and 332 men had 6 core biopsies. RESULTS: In the 6 core initial sampling group, the risk of cancer on re-biopsy was 20.8% compared to only 13.3% following an initial 8 core or more sampling (p = 0.011). With 6 core biopsies for both the initial and re-biopsy the risk of cancer was 14.1% (group 1). With an initial 6 core biopsy and 8 core or more biopsy on followup, the risk of cancer was 31.9% (group 2). With 8 core or more biopsy sampling for both initial and repeat biopsies, the risk for cancer was 14.6% (group 3). The differences between groups 1 and 3 as compared to group 2 were statistically significant (p = 0.001 and p <0.0001, respectively). CONCLUSIONS: With relatively poor sampling (6 cores) on the initial biopsy, associated cancers are missed resulting in only HGPIN on the initial biopsy, and with relatively poor sampling on re-biopsy there is also a relatively low risk of finding cancer on re-biopsy (group 1). With poor sampling on the initial biopsy and better sampling on re-biopsy, some of these initially missed cancers are detected on re-biopsy yielding a higher detection of cancer (group 2). Sampling more extensively on the initial biopsy detects many associated cancers, such that when only HGPIN is found they often represent isolated HGPIN. Therefore, re-biopsy even with good sampling does not detect many additional cancers (group 3). Our study demonstrates that the risk of cancer on biopsy within 1 year following a diagnosis of HGPIN (13.3%) is not that predictive of cancer on re-biopsy if good sampling (8 or more cores) is initially performed. For patients diagnosed with HGPIN on extended initial core sampling, a repeat biopsy within the first year is unnecessary in the absence of other clinical indicators of cancer.

Evidence suggesting PSA cutpoint of 2.5 ng/mL for prompting prostate biopsy: review of 36,316 biopsies.

OBJECTIVES: To determine whether a prostate-specific antigen (PSA) level of 2.0, 2.5, or 4.0 ng/mL is the most appropriate cutpoint for determining the need for prostate biopsy. It has been suggested that the PSA cutpoint of 4.0 ng/mL is inappropriate because the rate of prostate cancer detection is similar in patients with lower PSA values. Some investigators have recommended a 2.6-ng/mL cutpoint. Others have recommended a cutpoint of 2.0 ng/mL. METHODS: A total of 36,316 prostate biopsies submitted to DIANON Systems from January 1, 1997 through December 31, 2001 were reviewed. These biopsy specimens also had DIANON PSA test results available that had been performed within 6 months of the biopsy date. These biopsies were stratified according to the PSA level within the 6 months before the time of biopsy, and the prostate cancer detection rate was determined for the stratified PSA levels. RESULTS: The detection rate of prostate cancer varied according to the PSA level. The incidence of prostate cancer was similar for the groups with less than 2.0 ng/mL and 2.0 to 2.5 ng/mL (18.67% and 21.89%, respectively). Also, the groups with 2.5 to 4.0 ng/mL and 4.0 to 10.0 ng/mL had similar cancer detection rates (27.48% and 30.08%, respectively). CONCLUSIONS: The prostate cancer detection rate for a PSA level between 2.5 and 4.0 ng/mL was similar (27.48%) to that for the PSA range of 4.0 to 10.0 ng/mL (30.08%). The absolute cutpoint used to determine the need to evaluate a patient for prostate cancer by biopsy is not clear; however, many studies have suggested that 2.5 ng/mL may be a more appropriate cutpoint than 4.0 ng/mL.

Evidence of increased prostate cancer detection in men aged 50 to 59: a review of 324,684 biopsies performed between 1995 and 2002.

OBJECTIVES: To analyze the age-specific detection rate of prostate cancer diagnosed from 324,684 biopsies submitted to a single laboratory and to assess the degree of prostate cancer in younger men. The advent of prostate-specific antigen (PSA) testing and increased prostate cancer screening has led to increased evaluations for prostate cancer. The initial stage and age at presentation in prostate cancer has shifted. METHODS: From 1995 through 2001, all prostate biopsies submitted to the laboratory were reviewed and analyzed for the diagnosis of prostate cancer, cancer detection rate, and age at diagnosis. RESULTS: The overall detection rate of prostate cancer increased by 15% from 29% to 34% for all biopsies submitted during the study period. For the age group 50 to 59 years, a 45% increase occurred in the detection of prostate cancer from a baseline of approximately 11% in 1995 to greater than 16% in 2001. For the age group 70 to 79 years, the detection of prostate cancer decreased from a baseline of 41% in 1995 to 36% in 2001. CONCLUSIONS: The increase in prostate cancer diagnosis among younger men in the United States has been significant. The increase is likely multifactorial and may be attributable to the impact of PSA and prostate cancer screening efforts. This has led to a greater number of younger men undergoing evaluation for prostate cancer. Thus, a heightened awareness regarding the diagnosis of prostate cancer among younger men is needed.