How to combine the molecular profile with the clinicopathological profile of urothelial neoplastic lesions.

The current World Health Organization (WHO) 2004 classification of urothelial neoplasms was based on an attempt to reconcile molecular-genetic and pathology findings. This article provides an overview of the more recent molecular-genetic findings in the field and critically appraises their relationship with each of the WHO 2004 disease categories. Most of the WHO 2004 categories were successfully distinguished by means of expression and genome profiling and by distinct genetic alterations. Regarding urothelial papilloma, clinical and limited molecular-genetic data seem to suggest that they may not represent a precursor lesion for bladder cancer. It is more likely that urothelial papilloma is a benign neoplasm sharing mutations in the fibroblast growth factor-3 gene with seborrhoeic keratosis, allegedly its epidermal counterpart. Genetic alterations in papillary urothelial neoplasia of low malignant potential are identical to those found in non-invasive low-grade papillary urothelial carcinoma, implying that they are within a spectrum of the same neoplasm. Expression profiling data corroborate the view that (secondary) carcinoma in situ may act not only as a precursor lesion for invasive non-papillary urothelial carcinoma, but also as a precursor for non-muscle-invasive papillary urothelial carcinoma. Given the significant molecular genetic differences between non-invasive and invasive papillary urothelial carcinomas and their analogy with exophytic neoplastic precursor lesions in other organ systems, an alternative nomenclature is proposed, replacing papillary urothelial carcinoma with papillary intraurothelial neoplasm for the non-invasive (pTa) papillary carcinomas.

Features of prostate cancers detected during a prevalence screening round. The Rotterdam experience.

INTRODUCTION: Prostate-specific antigen (PSA) testing of asymptomatic men may lead to the detection of "minimal" prostate cancers that are less likely to be associated with morbidity or mortality. OBJECTIVE: To examine the significance of various diagnostic outcomes from needle biopsies of the prostate in an asymptomatic population of men. METHODS: Prostatic needle biopsy findings were matched with those from radical prostatectomy specimens using data from the Rotterdam section of the European Randomized study of Screening for Prostate Cancer (ERSPC). Men, aged between 55 and 75 years, with elevated PSA levels underwent lateralized sextant needle biopsies. In corresponding radical prostatectomy specimens, the tumor categories (minimal, moderate, or advanced) were determined. RESULTS: Prostate cancer was diagnosed in 5.1% of 19,970 screened men, and 31.6 % of the men had cancers that were categorized as "minimal." Repeat biopsies performed after initial diagnoses of either isolated prostatic intra-epithelial neoplasia (PIN) or "suspicious for malignancy," detected adenocarcinoma in 12.1%and 36.5 % of the men, respectively. In a substudy of 510 men with a benign biopsy outcome 12 months previously, repeat biopsies detected adenocarcinoma in 12.4 of the men. Of men who were subsequently treated with radical prostatectomy, the cancers were classified as "minimal" in 27.8% of the men with previously benign biopsies and in 47.4% of the men with previously suspicious lesions, CONCLUSIONS: The chance of finding a "minimal" prostate cancer in an asymptomatic population is substantial and increases when a repeat biopsy is performed following a biopsy with a suspicious outcome.

[Diagnosis based on prostate needle biopsy: inadequate correlation between pathologic results and clinical course for individual prognosis]. / Diagnostiek op prostaatbiopten: onvoldoende verband tussen pathologische uitslag en klinisch beloop voor een individuele prognose.

Since the introduction of serum testing for prostate-specific antigen (PSA) in 1990 for the early detection of prostate cancer, the number of men undergoing a prostate needle-biopsy procedure has increased dramatically. In order to highlight the significance of the various diagnostic outcomes of a prostate needle biopsy, the pathological findings from needle biopsies were compared with those from samples taken during radical prostatectomy and in follow-up biopsies, using data from the 'European randomised screening for prostate cancer' (ERSPC) trial. In men with an elevated PSA value and a benign or negative needle-biopsy result, 10-15% were found to have prostate cancer in follow-up biopsies. In men with a needle-biopsy diagnosis of adenocarcinoma, 29% were found to have questionable histopathological characteristics or minimal cancer that did not require therapy. The incidence of minimal cancer increased to 70% among men with a needle-biopsy diagnosis of focal carcinoma, i.e. a small focus (< 3 mm diameter) of well-differentiated adenocarcinoma, based on one biopsy from a series of six. In men with a needle-biopsy diagnosis of 'suspected malignancy' 36.5% were found to have prostate cancer in follow-up biopsies. In men with a needle-biopsy diagnosis of 'high grade prostatic intra-epithelial neoplasia' 13% were found to have prostate cancer in follow-up biopsies. This percentage was not significantly higher than the percentage of cancers detected after an initially benign biopsy outcome. To avoid over-treatment of a substantial number of men who lack symptoms of prostate cancer but are diagnosed on the basis of biopsy results, it is vital that clinical/pathologic parameters are developed and validated that can help in deciding whether to initiate curative treatment immediately.

Handling and pathology reporting of prostate biopsies.

Appropriate handling and processing of prostate needle biopsies is critical for an optimal examination by pathologists. Reporting by pathologists should be accurate, unequivocal and concise, giving the information needed for the urologist. Quality parameters need to be developed to survey the performance of pathology laboratories.

Guidelines for processing and reporting of prostatic needle biopsies.

The reported detection rate of prostate cancer, lesions suspicious for cancer, and prostatic intraepithelial neoplasia (PIN) in needle biopsies is highly variable. In part, technical factors, including the quality of the biopsies, the tissue processing, and histopathological reporting, may account for these differences. It has been thought that standardisation of tissue processing might reduce the observed variations in detection rate. Consensus among the members of the pathology committee of the European Randomised study of Screening for Prostate Cancer (ERSPC) concerning the optimal methodology of tissue embedding resulting in guidelines for prostatic needle biopsy processing was reached. The adoption of an unequivocal and uniform way of reporting lesions encountered in prostatic needle biopsies is considered helpful for decision taking by the clinician. The definition of parameters for quality control of prostatic needle biopsy diagnostics will further facilitate clinical epidemiological multicentre studies of prostate cancer.

Expression and prognostic relevance of vascular endothelial growth factor (VEGF) and its receptor (FLT-1) in nephroblastoma.

AIMS: To investigate the prognostic relevance of vascular endothelial growth factor (VEGF) and its receptor Flt-1 in nephroblastoma and whether tumour microvessel density (MVD) immunoreactivity, determined by the CD31 antigen, is related to the expression of VEGF and Flt-1. METHODS: The expression of VEGF and Flt-1 and MVD were investigated by means of immunohistochemical analysis in 62 Wilms's tumours. Patients were treated preoperatively with chemotherapy and had a mean follow up of 5.7 years. RESULTS: In general, VEGF and Flt-1 were expressed in normal kidney parenchyma and to a variable extent in the three main components of Wilms's tumour, namely: the blastemal, epithelial, and stromal cells. In tumour tissue, 52% and 47% of blastemal cells were positive for VEGF and Flt-1, respectively. A non-significant correlation was found between the expression of VEGF and Flt-1 in blastemal and epithelial cells and the clinicopathological stage. MVD was significantly higher in VEGF and Flt-1 positive tumours than in VEGF and Flt-1 negative tumours. Univariate analysis showed that the expression of VEGF and Flt-1 in blastemal cells was indicative of clinical progression and tumour specific survival. In addition, MVD expression was indicative of clinical progression. Epithelial staining was of no prognostic value. In a multivariate analysis, VEGF protein expression by blastemal cells was an independent prognostic marker for clinical progression. CONCLUSIONS: These results indicate that VEGF and Flt-1 protein expression are closely related to MVD and seem to be an important predictor for poor prognosis in treated patients with Wilms's tumour. Therefore, the expression of these molecules in primary Wilms's tumour may be useful in identifying those patients at high risk of tumour recurrence and in guiding antiangiogenic treatment.

Non-sentinel lymph node involvement in patients with breast cancer and sentinel node micrometastasis; too early to abandon axillary clearance.

AIMS: It has been suggested that patients with T1-2 breast tumours and sentinel node (SLN) micrometastases, defined as foci of tumour cells smaller than 2 mm, may be spared completion axillary lymph node dissection because of the low incidence of further metastatic disease. To gain insight into the extent of non-sentinel lymph node (n-SLN) involvement, SLNs and complementary axillary clearance specimens in patients with SLN micrometastases were examined. METHODS: A set of 32 patients with SLN micrometastases was selected on the basis of pathology reports and review of SLNs. Five hundred and thirteen n-SLNs from the axillary clearance specimens were serially sectioned and analysed by means of immunohistochemistry for metastatic disease. Lymph node metastases were grouped as macrometastases (> 2 mm), and micrometastases (< 2 mm), and further subdivided as isolated tumour cells (ITCs) or clusters. RESULTS: In 11 of 32 patients, one or more n-SLN was involved. Grade 3 tumours and tumours > 2 cm (T2-3 v T1) were significantly associated with n-SLN micrometastases as clusters (grade: odds ratio (OR), 8.3; 95% confidence interval (CI), 1.4 to 50.0; size: T2-3 tumours v T1: OR, 15; 95% CI, 2.18 to 103.0). However, no subgroup of tumours with regard to size and grade was identified that did not have n-SLN metastases. CONCLUSIONS: In patients with breast cancer and SLN micrometastases, n-SLN involvement is relatively common. The incidence of metastatic clusters in n-SLN is greatly increased in patients with T2-3 tumours and grade 3 tumours. Therefore, axillary lymph node dissection is especially warranted in these patients. However, because n-SLN metastases also occur in T1 and low grade tumours, even these should be subjected to routine axillary dissection to achieve local control.

Different PSA assays lead to detection of prostate cancers with identical histological features.

OBJECTIVE: Because different PSA assays still show a wide inter-assay variation, we wondered what influence these discrepancies could have on the individual tumour characteristics of the cancers that each of these assays detect in a critical low PSA range. We analysed five different PSA assays in a biopsy simulation with PSA cut-offs of 3.0 and 4.0 ng/ml. MATERIALS AND METHODS: Randomly taken samples of 360 men with prostate cancer and 96 with benign prostatic disease from a screened population with PSA range of 1.0-6.0 ng/ml (Tandem-E) were investigated. In all cases the diagnosis was confirmed by sextant biopsies. One hundred and thirty-seven men (38%) underwent radical prostatectomy. Variability amongst assays was illustrated in terms of missed cancers and unnecessary biopsies, and in terms of pathologic features of detected cancers at both PSA cut-offs. RESULTS: Compared to Tandem-E, all assays, except Access, showed significant differences in PSA measurements. Furthermore, none of the assays discriminated significantly between benign and malignant prostatic disease (p>0.05). Tandem-E and Elecsys lead significantly more frequently to the detection of cancers at the cost of more unnecessary biopsies compared to the other assays. Yet, at both PSA cut-offs the proportion of cancers with a certain pathologic grade or stage that were detected by each assay were approximately the same. CONCLUSIONS: Our study shows that the use of different PSA assays only have consequences for the number, and not for the tumour characteristics of the prostate cancers that are detected. Thus, different PSA assays detect prostate cancers with the same tumour features.

Value of tissue markers p27(kip1), MIB-1, and CD44s for the pre-operative prediction of tumour features in screen-detected prostate cancer.

The pre-operative prediction of prognostic tumour features in the radical prostatectomy specimen using routine clinicopathological variables remains limited. The present study evaluated the predictive value of the cell-cycle protein p27(kip1), the proliferation marker MIB-1, and the cell-adhesion protein CD44s, determined on the diagnostic needle biopsy of asymptomatic men screened for prostate cancer. Of 81 screen-detected prostate cancers, representative biopsy cores and matched radical prostatectomy specimens were immunohistochemically stained for these tissue markers. Conventional pre-operative and post-operative clinicopathological variables were assessed and cancers were divided according to a validated tumour classification model (potentially harmless, clinically significant). Low (<50%) p27(kip1) expression, high (> or = 10%) MIB-1 expression, and low (<25%) CD44s expression were considered adverse prognostic signs. Binary logistic regression analysis was performed to assess the most valuable predictors of clinically significant disease. An adverse prognostic immunostaining assessment on the biopsy was found in 10 (12.3%), 17 (21.0%), and 25 (30.9%) cases for p27(kip1), MIB-1, and CD44s, respectively. The concordance in tissue marker assessment between the biopsy specimen and matched radical prostatectomy specimens was low for all three. The positive predictive value (PPV) of p27(kip1) was 90.0%, remarkably higher than that of MIB-1 and CD44s (41.2% and 52.0%, respectively), indicating that a low radical prostatectomy p27(kip1) score is expected if the biopsy p27(kip1) score is low. Logistic regression analysis revealed that biopsy Gleason score (p<0.01) and p27(kip1) assessment (p<0.01) remained the only significant predictors of clinically significant disease. All cases with low p27(kip1) expression were found to have clinically significant disease after radical prostatectomy. The assessment of p27(kip1) in the biopsy specimen might thus assist in distinguishing between potentially aggressive and potentially non-aggressive disease in prostate cancer screening.

Serendipity in detecting disease in low prostate-specific antigen ranges.

OBJECTIVE: To assess the magnitude of prostate cancer detection by serendipity (the coincidental detection of prostate cancer during the evaluation of an abnormal screening test result) when a digital rectal examination (DRE) and transrectal ultrasonography (TRUS) are used as initial screening tests for prostate cancer in men with low levels of prostate-specific antigen (PSA; 0.0-3.9 ng/mL). PATIENTS AND METHODS: In all, 117 participants of a population-based screening study were diagnosed with prostate cancer after a standard evaluation of an abnormal screening test result; 49 underwent radical prostatectomy. Serendipity was defined as either: (i) the presence of prostate cancer opposite to the side that raised suspicion for cancer on DRE and/or TRUS; (ii) a negative lesion-directed biopsy while cancer was present in one or more of the cores of the sextant biopsy; (iii) a tumour volume of < 0.5 mL on radical prostatectomy. RESULTS: Depending on the definition, 27-63% of prostate cancers detected at low PSA values were detected coincidentally and not as a result of a true-positive test result. The proportion of cancers detected by serendipity was inversely correlated with serum PSA level. CONCLUSION: A relatively high proportion of prostate cancers diagnosed in men with low PSA levels, and in which a biopsy was prompted by a suspicious DRE and/or TRUS, are considered to be detected by chance only. As these cancers are mostly small (< 0.5 mL), with potentially low biological aggressiveness, relying on serendipity seems disadvantageous in prostate-cancer screening. The level of serendipity in prostate cancer detection, the poor performance of the screening test, and high inter-observer variability, casts further doubt on the utility of DRE (and TRUS) as initial screening tests for prostate cancer in population-based screening.