A retrospective analysis of 111 canine prostatic samples: histopathological findings and classification.

The purpose of this retrospective study is to evaluate the frequency and further characterize the pathological features of common and uncommon histological lesions in 111 canine prostatic samples. Benign prostatic hyperplasia, suppurative and non-suppurative prostatitis, and prostate cancer were observed individually or in combination in 45, 11, 68 and 50 samples, respectively. Six growth patterns of prostatic carcinoma were differentiated: papillary, cribriform, solid, small acinar/ductal, signet ring, mucinous. In a few cases, perineurial invasion and collagenous micronodules were observed. Lesions considered preneoplastic in men, such as high-grade prostatic intraepithelial neoplasia (HGPIN) and prostatic inflammatory atrophy (PIA), were observed in 27 and 21 histological samples, respectively. This study represents a detailed characterization of the different histological subtypes of canine prostate cancer. The awareness of the unusual patterns might be critical in avoiding diagnostic misinterpretation. The high prevalence of PIA and HGPIN underlines the reasonable chance of their detection in routine biopsy specimens.

Cascaded discrimination of normal, abnormal, and confounder classes in histopathology: Gleason grading of prostate cancer.

BACKGROUND: Automated classification of histopathology involves identification of multiple classes, including benign, cancerous, and confounder categories. The confounder tissue classes can often mimic and share attributes with both the diseased and normal tissue classes, and can be particularly difficult to identify, both manually and by automated classifiers. In the case of prostate cancer, they may be several confounding tissue types present in a biopsy sample, posing as major sources of diagnostic error for pathologists. Two common multi-class approaches are one-shot classification (OSC), where all classes are identified simultaneously, and one-versus-all (OVA), where a "target" class is distinguished from all "non-target" classes. OSC is typically unable to handle discrimination of classes of varying similarity (e.g. with images of prostate atrophy and high grade cancer), while OVA forces several heterogeneous classes into a single "non-target" class. In this work, we present a cascaded (CAS) approach to classifying prostate biopsy tissue samples, where images from different classes are grouped to maximize intra-group homogeneity while maximizing inter-group heterogeneity. RESULTS: We apply the CAS approach to categorize 2000 tissue samples taken from 214 patient studies into seven classes: epithelium, stroma, atrophy, prostatic intraepithelial neoplasia (PIN), and prostate cancer Gleason grades 3, 4, and 5. A series of increasingly granular binary classifiers are used to split the different tissue classes until the images have been categorized into a single unique class. Our automatically-extracted image feature set includes architectural features based on location of the nuclei within the tissue sample as well as texture features extracted on a per-pixel level. The CAS strategy yields a positive predictive value (PPV) of 0.86 in classifying the 2000 tissue images into one of 7 classes, compared with the OVA (0.77 PPV) and OSC approaches (0.76 PPV). CONCLUSIONS: Use of the CAS strategy increases the PPV for a multi-category classification system over two common alternative strategies. In classification problems such as histopathology, where multiple class groups exist with varying degrees of heterogeneity, the CAS system can intelligently assign class labels to objects by performing multiple binary classifications according to domain knowledge.

Prostatic intraepithelial neoplasia: recent advances.

CONTEXT: There have been 2 putative prostatic cancer precursors, prostatic intraepithelial neoplasia (PIN) and atypical adenomatous hyperplasia (adenosis), but PIN remains as a well-known precancerous condition. OBJECTIVE: To describe recent advances in knowledge of PIN and to better define the diagnostic criteria and differential diagnosis of PIN. DATA SOURCES: Review of the pertinent literature and our experience. CONCLUSIONS: The presence of ductal/acinar epithelial changes including nuclear enlargement, prominent nucleoli, chromatin alterations, and luminal complexity is an easy way to identify the disorder. Four main patterns of high-grade PIN (HGPIN) have been described: tufting, micropapillary, cribriform, and flat. In addition, variants of HGPIN have also been described. Both HGPIN and prostatic carcinoma share an increased incidence and severity with advancing age and with high rates of occurrence in the peripheral zone of the prostate. Furthermore, HGPIN and prostate cancer share genetic and molecular markers as well, with PIN representing an intermediate stage between benign epithelium and invasive carcinoma. The clinical significance of HGPIN is that it identifies patients at risk for prostatic carcinoma. With the increased use of extended biopsy protocols, clinicians are more likely to identify HGPIN and less likely to miss concurrent carcinoma.

Current prostate biopsy interpretation: criteria for cancer, atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, and use of immunostains.

CONTEXT: The past decade has brought major changes in prostate biopsy sampling, interpretation, and reporting. OBJECTIVE: To summarize current information on diagnostic decision making, Gleason grading, "atypical" diagnoses, and use of immunostaining. DATA SOURCES: Pertinent literature from 1985 to 2005 is reviewed, emphasizing recent findings. CONCLUSIONS: Diagnosis begins by evaluating a focus of atypical single-cell layer lined acini according to the 3 minimal diagnostic criteria for cancer: an infiltrative pattern, nuclear enlargement and hyperchromasia, and prominent nucleoli. The Gleason score and linear extent or percent of each core containing cancer should be reported. Atypical small acinar proliferation suspicious for malignancy designates foci that have either qualitative or quantitative limitations in atypia precluding a definite cancer diagnosis. It has about a 3% incidence as an isolated finding. Contemporary studies indicate a 39% predictive value for cancer on repeat biopsy. Isolated high-grade prostatic intraepithelial neoplasia has a 3% to 14% incidence and predicts cancer on repeat biopsy in 23% of cases. Immunostaining for a marker of benign prostate (cytoplasmic keratin 34betaE12 or nuclear p63) and a marker of cancer (alpha-methylacyl coA racemase, clone P504S) may or may not resolve atypical small acinar proliferation diagnoses. Performance of 34betaE12 and P504S immunostains resolved 76% of atypical small acinar proliferation diagnoses per consensus of 3 urologic pathologists studied; a technical limitation is preservation of the focus in question on the levels used for immunostaining.

Histopathology reporting of prostate needle biopsies. 2005 update.

This report reviews the diagnostic and prognostic importance of the pathologic findings in prostate needle biopsies. The morphological findings of the needle biopsy may be placed into one of the following five categories: prostate cancer, atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, inflammation, and benign prostatic tissue. While the prime goal of the biopsy is to diagnose prostatic adenocarcinoma, once carcinoma is detected, further descriptive information regarding the type, amount of cancer, and grade forms the cornerstone for contemporary management of the patient and for assessment of the potential for local cure and the risk for distant metastasis. The information provided in the needle biopsy report regarding the attributes of carcinoma is used depending on the individual patient's medical condition and preference and on the treating physician's evaluation to determine whether any form of treatment is indicated and, if so, the type of therapy.

High-grade prostatic intraepithelial neoplasia on needle biopsy: risk of cancer on repeat biopsy related to number of involved cores and morphologic pattern.

The importance of isolated high-grade prostatic intraepithelial neoplasia (HGPIN) on needle biopsy is its association with synchronous invasive carcinoma. The relevance of this relationship has been called into question in recent years. In our study, we examined whether the histologic subtype of HGPIN (ie, tufting, micropapillary, cribriform, flat) and/or the number of core biopsies involved by HGPIN was predictive of a subset of men who were at higher risk of having invasive carcinoma on follow-up biopsies. We examined 200 sets of needle biopsies with a diagnosis of isolated HGPIN. Patient age ranged from 46 to 90 years (mean 66.4 years). The breakdown of the histologic subtypes of HGPIN is as follows: tufting 59%, micropapillary 34.3%, cribriform 6.2%, and flat 0.5%. A total of 132 patients (66%) had follow-up biopsies. Prostatic adenocarcinoma was identified in 28.8% of patients with 89.5% of cancers identified on the first two follow-up biopsies. For men that had two or more cores with HGPIN on the initial biopsy, 35.9% eventually had cancer on follow-up whereas men with only single core involvement had cancer in 22% of cases. Men with tufting/flat HGPIN on the initial biopsy had cancer on follow-up in 31.9% of cases, whereas the micropapillary/cribriform subtype was associated with cancer in 22% of follow-up biopsies. The histologic findings on the first repeat biopsy can be quite informative as to the risk of synchronous invasive carcinoma. Of the men with HGPIN on the first repeat biopsy, 32% eventually had cancer on follow-up. Additionally, if multiple cores were involved by HGPIN on the first repeat biopsy, the risk of finding cancer was 50%, regardless of single or multiple core involvement on the initial biopsy. Men with a benign diagnosis on the first repeat biopsy had a 14% risk of having cancer on follow-up. These data indicate that the multiple core involvement by HGPIN, both on initial and first repeat biopsy, defines a subset of men that are at increased risk of harboring synchronous invasive carcinoma. The histologic subtype of PIN does not appear to be as informative.

Inverted (Hobnail) high-grade prostatic intraepithelial neoplasia (PIN): report of 15 cases of a previously undescribed pattern of high-grade PIN.

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.

High-grade prostatic intraepithelial neoplasia with adjacent atypia is associated with a higher incidence of cancer on subsequent needle biopsy than high-grade prostatic intraepithelial neoplasia alone.

OBJECTIVES: High-grade prostatic intraepithelial neoplasia (HGPIN) is often considered a premalignant lesion of the prostate. Its incidence ranges from 0.7% to 20% in all prostate biopsies, and patients with HGPIN on initial biopsy are reportedly found to have a higher risk of cancer on subsequent biopsy. The purpose of our study was to determine the incidence of HGPIN in our patients who underwent prostate biopsy and to determine whether a further pathologic subclassification of HGPIN between HGPIN alone and HGPIN with adjacent atypical glands has any prognostic value in predicting the rate of prostate cancer on subsequent prostate biopsy. METHODS: A total of 485 patients who underwent prostate biopsy between January 1998 and October 1999 were included in the study. Each set of slides was reviewed by a single urologic pathologist to determine the presence of HGPIN alone or HGPIN with adjacent atypical glands. If any HGPIN was identified, a repeat biopsy was performed, and the presence of cancer was recorded. RESULTS: The overall incidence of HGPIN alone and HGPIN with adjacent atypical glands on initial biopsy was 33 (6.8%) of 485. Of these 33 patients, 21 (64%) had HGPIN alone and 12 (36%) had HGPIN with adjacent atypical glands. Three (14%) of 21 patients with HGPIN alone were found to have cancer on subsequent biopsy compared to 9 (75%) of 12 patients with HGPIN with adjacent atypia on initial biopsy. This difference is statistically significant (P <0.005). CONCLUSIONS: The incidence of HGPIN alone in our experience is 4.3% (21 of 485). Patients with HGPIN with adjacent atypical glands suspicious for cancer have a significantly higher incidence of cancer on subsequent biopsy than patients with HGPIN alone.

Morphological identification of the patterns of prostatic intraepithelial neoplasia and their importance.

High grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostatic carcinoma. PIN has a high predictive value as a marker for carcinoma, and its identification in biopsy specimens warrants repeat biopsy for concurrent or subsequent carcinoma. The only methods of detection are biopsy and transurethral resection; PIN does not greatly raise the concentration of serum prostate specific antigen (PSA) or its derivatives, does not induce a palpable mass, and cannot be detected by ultrasound. Androgen deprivation decreases the prevalence and extent of PIN, suggesting that this form of treatment might play a role in chemoprevention. Radiotherapy is also associated with a decreased incidence of PIN.

Data representation and reduction for chromatin texture in nuclei from premalignant prostatic, esophageal, and colonic lesions.

BACKGROUND: To identify nuclei and lesions with great specificity, a large set of karyometric features is arranged in the form of a linear profile, called a nuclear signature. The karyometric feature values are normalized as z-values. Their ordering along the profile axis is arbitrary but consistent. The profile of the nuclear signature is distinctive; it can be characterized by a new set of variables called contour features. A number of data reduction methods are introduced and their performance is compared with that of the karyometric features in the classification of prostatic, colonic, and esophageal lesions. METHODS: Contour characteristics were reduced to descriptive statistics of the set of z-values in the nuclear signature and to sequence information. The contour features derived were (1) relative frequencies of occurrence of z-values and of their differences and (2) co-occurrence statistics, run lengths of z-values, and statistics of higher-order dependencies. Performance was evaluated by comparing classification scores of diagnostic groups. RESULTS: Rates for correct classification by karyometric features alone and contour features alone indicate equivalent performance. Classification by a combined set of features led to an increase in correct classification. CONCLUSIONS: Image analysis and subsequent data reduction of nuclear signatures of contour features is a novel method, providing quantitative information that may lead to an effective identification of nuclei and lesions.

Immunohistochemical staining for DNA topoisomerase II-alpha in benign, premalignant, and malignant lesions of the prostate.

BACKGROUND: The DNA topoisomerase II-alpha (topo II-alpha)-targeting drug etoposide was recently shown to be an active agent in the combined chemotherapy of hormone-insensitive prostatic carcinoma. Aside from being the molecular target of etoposide, topo II-alpha is also a cell proliferation marker. Much experimental data indicate that cells sensitive to topo II-targeting chemotherapeutic drugs are rapidly proliferating and show elevated topo II expression. There is little information concerning topo II expression in lesions of the prostate. METHODS: Paraffin blocks from cases of invasive prostatic carcinoma, prostatic intraepithelial neoplasia, and prostatic nodular hyperplasia were retrieved from the surgical pathology files at the University of Utah Health Sciences Center. Using a new immunohistochemical stain, specific for the alpha isoform of DNA topo II, enzyme expression was evaluated in 54 prostatic adenocarcinomas, 22 lesions of high-grade prostatic intraepithelial neoplasia (PIN), and 10 cases of benign prostatic nodular hyperplasia. Results were semiquantitated by determining for each case a topo II-alpha index, which represented the percent of positively staining cells. RESULTS: The average topo II-alpha index for well-differentiated prostatic adenocarcinomas (Gleason scores 2-4) was 1.5 +/- 0.9; for moderately differentiated tumors (Gleason scores 5-7), 3.1 +/- 2.4; and for poorly differentiated tumors (Gleason scores 8-10), 6.7 +/- 5.5. The average topo II-alpha index for all invasive prostatic adenocarcinomas was 4.0 (range, 0-19.0). Benign prostatic nodular hyperplasia had the lowest average topo II-alpha index, of 0.54 (range, 0.2-1.0). The average topo II-alpha index of 2.3 (range, 0-8.6) for high-grade prostatic intraepithelial neoplasia was intermediate between the invasive tumors and benign prostate. CONCLUSIONS: Topo II-alpha expression in carcinoma of the prostate correlates with Gleason score. The carcinomas with the highest expression of enzyme are more poorly differentiated and have the highest Gleason scores. Prostatic nodular hyperplasia shows little expression of topo II-alpha. Prostatic intraepithelial neoplasia has an average topo II-alpha index intermediate between nodular hyperplasia and carcinoma.

Statistical histometry of the basal cell/secretory cell bilayer in prostatic intraepithelial neoplasia.

OBJECTIVE: To delineate the sampling requirements for a histometric assessment of progression in low grade and high grade prostatic intraepithelial neoplasia (PIN) lesions. STUDY DESIGN: Images of whole glands from normal prostates, low grade PIN lesions and high grade PIN lesions were digitized. The images were processed by a machine vision system and automatically segmented, and a number of histometric characteristics descriptive of the disruption of the basal cell layer were extracted. Next, high-resolution images of secretory cell nuclei still facing or no longer facing intact segments of the basal cell layer were recorded and karyometrically analyzed. RESULTS: For the characterization of an individual lesion a minimum of 20-30 glands should be analyzed to provide an estimate of a progression index. Then, a change in progression, or due to regression, of approximately 16% can be documented. The disruption of the basal cell layer is accompanied by statistically highly significant changes in the chromatin texture and spatial distribution in secretory cell nuclei no longer facing an intact segment of that layer. CONCLUSION: Automated histometry by machine vision can provide valuable quantitative data for diagnostic assessment and for monitoring the efficacy of chemopreventive treatment.

Chromatin texture signatures in nuclei from prostate lesions.

OBJECTIVE: To characterize nuclei from prostatic lesions in a highly specific manner by developing a nuclear chromatin texture signature and to characterize lesions by means of their composition of nuclei with diverse degrees of deviation from normal. STUDY DESIGN: High-resolution digitized imagery of nuclei from normal prostates, from prostatic neoplastic lesions of low and high grade and from histologically normal appearing regions of prostates with low and high grade prostatic intraepithelial neoplasia (PIN) lesions were recorded. A set of 65 features descriptive of the spatial and statistical distribution of nuclear chromatin was computed for each nucleus. These features were arranged and processed to form a distinctive signature. A distance metric from "normal" was defined and computed for each nucleus. RESULTS: Profiles of feature values can, after suitable scaling, be presented as distinctive feature value signatures. For many practical applications, profiles based on a standardized distance from normal nuclei may be more useful. Such profiles allow the derivation of a progression curve, showing increasing distances for diagnostic groups with increasing lesion progression up to high grade PIN lesions. Within each diagnostic group different cases show distinctive distributions of nuclei with differing degrees of deviation from normal, allowing the derivation of a lesion signature. CONCLUSION: Nuclear chromatin texture signatures may be of value for the characterization of both nuclei and lesions. They are based on a more comprehensive use of information offered by the nuclear chromatin pattern than that included in classification methods. While these signatures offer a more specific characterization of a clinical sample, they also are subject to more variability within a diagnostic category. This may not be due to randomness but may reflect some actual differences between lesions.

Case diagnosis as positive identification in prostatic neoplasia.

OBJECTIVE: To apply a distance measure and Bayesian belief network-based methodology to the positive identification of case diagnosis in prostatic neoplasia. STUDY DESIGN: Eight morphologic and cellular features were analyzed in 20 cases of normal prostate, 20 of low grade prostatic intraepithelial neoplasia (PIN), 20 of high grade PIN, 20 of prostatic adenocarcinoma with a cribriform pattern and 20 of prostatic adenocarcinoma with an acinar pattern. The diagnostic distance was evaluated to measure the "extent" to which the feature outcomes of the individual cases differed from the expected profile of outcomes in typical cases of normal prostate, low and high grade PIN, and cribriform and large acinar adenocarcinoma. Belief values were evaluated with a Bayesian belief network (BBN). RESULTS: A bivariate representation of the cumulative absolute diagnostic distances of all the cases from the prototypes of normal prostate and cribriform adenocarcinoma was made. Three separate groups of cases were observed, corresponding to normal prostate, low grade PIN and cribriform adenocarcinoma. An additional group was formed by the cases of high grade PIN and acinar adenocarcinoma--i.e., there was complete overlap between the diagnostic distance values of cases belonging to these two categories. However, these cases showed differences in clue outcomes. To explore the contribution of such observations to case identification, a bivariate representation of the diagnostic distances from high grade PIN and acinar adenocarcinoma was made. The cases then formed five separate groups corresponding to the five diagnostic categories. When the individual cases were considered, their shortest distance was from the prototype of the category into which they were originally diagnosed. The BBN gave these diagnostic categories the highest belief values. CONCLUSION: The combined evaluation of diagnostic distance and belief represents an identification procedure. The numeric value of certainty characterizes individual cases according to the level of progression from PIN toward cancer.

Knowledge-guided histometry of the basal cell layer in prostatic intraepithelial neoplasia.

OBJECTIVE: To define a procedure for the fully automated evaluation of histopathologic sections of prostatic intraepithelial neoplasia. STUDY DESIGN: The design is based on expert system-guided scene segmentation, the construction of a knowledge file and the defining of histometric measures for assessment of the basal cell layer. RESULTS: A knowledge file specifying a total of 263 entities was constructed. Of 73 multimegapixel-sized images of cribriform glands, 71 were correctly and completely processed. A histometric measure allowing precise indexing of the degree of lesion progression, based on the deterioration of the basal cell layer, was derived. CONCLUSION: The combination of image analytic and immunohistochemical procedures and fully automated processing provides a quantitative measure for evaluating prostatic intraepithelial neoplasia lesion progression and the effects of intervention.