Papers by Theodorus Van Der Kwast
J Urol, 2010
INTRODUCTION AND OBJECTIVES: To evaluate the effects of focal laser ablation (FLA) on prostate ca... more INTRODUCTION AND OBJECTIVES: To evaluate the effects of focal laser ablation (FLA) on prostate cancer (PC) tissue, and to assess the accuracy of magnetic resonance imaging (MRI) in determining the ablated lesion volume by comparing to histology.
J Urol, 1999
Decreased expression of CD44 is an independent prognostic marker for surgically treated prostate ... more Decreased expression of CD44 is an independent prognostic marker for surgically treated prostate cancer. To investigate immunohistochemically defined CD44 expression in primary and metastatic prostate cancer, 2 groups of patients undergoing radical prostatectomy for clinically localized prostate cancer were studied. (1) pN 1 group: 23 patients, finally staged pN 1 , of whom the radical prostatectomy specimen and the lymph nodes were investigated to establish a correlation between CD44 expression in the concurrently resected primaries and metastases; (2) pN 0 group: 23 patients with pN 0 disease matched for pT stage and Gleason sum score with the pN 1 patients. Progression rates based on serum prostatespecific antigen (PSA) levels could be determined in 42 of these 46 patients. In addition, 28 distant metastases were studied. A CD44 score of F 10% was found in 22 of the 23 lymph node metastases (96%) and in 20 of the corresponding radical prostatectomies. In the pN 0 group this was observed in only 6 out of 23 specimens. In most of the distant metastases CD44 scores were F 10%. Patients with pN 0 disease and G 10% CD44-positive tumor cells had a significantly better prognosis than the other patients who were not significantly different from each other. CD44 expression is thus strongly reduced in prostate cancer metastases as well as in the corresponding primary tumors. This reduction may be used to predict the N stage clinically, provided that CD44 scores can be determined reliably on preoperative biopsy specimens.
World J Urol, 1997
In recent years the introduction of serum prostate-specific antigen (PSA) determination as a scre... more In recent years the introduction of serum prostate-specific antigen (PSA) determination as a screening tool for early detection of prostate cancer in asymptomatic men has led to a markedly increased detection of prostate cancers that are neither palpable nor visible with transrectal ultrasonography (stage T1c). In this preliminary study we assessed pathologic features and aspects that are indicative of clinical significance in T1c tumors and tumors with palpable or visible lesions (non-T1c tumors). Between June 1994 and December 1995, 51 consecutive radical prostatectomies were performed on screened participants in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC). After determination of pathologic stage and Gleason score, morphometric analysis was performed to determine tumor volume. Radical prostatectomy specimens were divided into three mutually exclusive subsets: T1c tumors, non-T1c tumors with preoperative PSA levels below 4 ng/ml, and non-T1c tumors with PSA levels equal to or greater than 4 ng/ml. These subsets were compared for differences in the distribution of tumor volume, pathologic stage, and Gleason score. An arbitrarily constructed categorization model was used to assess clinical significance. In all, 17 (33%) of the patients had clinical stage T1c disease. In our categorization mode, 88% of the T1c tumors fit the criteria for clinically significant tumors. T1c tumors, however, were significantly smaller (P < 0.01) and were more likely to be organ-confined (P = 0.01) as compared with non-T1c tumors in patients with an elevated preoperative serum PSA level. In contrast, tumors detected at preoperative PSA levels of < 4 ng/ml had comparably the lowest pathologic stages and tumor volumes in our series. In our categorization model, 42% of these tumors fit the criteria for minimal tumor. This group of radical prostatectomies was therefore most likely to harbor clinically insignificant cancer, a finding that was consistent in two other categorization models derived from earlier reports. T1c tumors comprise a large fraction of the tumors found in population-based screening. As judged by their pathologic characteristics. T1c tumors are clinically significant tumors. The overall low pathologic stage and Gleason score of these tumors make these patients excellent candidates for curative treatment by radical prostatectomy or radiotherapy. In contrast, some concern should be raised on the detection of tumors at low serum PSA levels by means of digital rectal examination and transrectal ultrasound alone, since a substantial proportion of these tumors could be considered clinically insignificant. Long-term follow-up, however, is necessary to substantiate this view.
European Urology Supplements, 2009
European Urology Supplements, 2010
Radiology, Apr 8, 2010
To investigate relationships between magnetic resonance (MR) imaging measurements and the underly... more To investigate relationships between magnetic resonance (MR) imaging measurements and the underlying composition of normal and malignant prostate tissue. Twenty-four patients (median age, 63 years; age range, 44-72 years) gave informed consent to be examined for this research ethics board-approved study. Before undergoing prostatectomy, patients were examined with T2-weighted, diffusion-weighted, T2 mapping, and dynamic contrast material-enhanced MR imaging at 1.5 T. Maps of apparent diffusion coefficient (ADC), T2, volume transfer constant (K(trans)), and extravascular extracellular space (v(e)) were calculated. Whole-mount hematoxylin-eosin-stained sections were generated and digitized at histologic resolution. Percentage areas of tissue components (nuclei, cytoplasm, stroma, luminal space) were measured by using image segmentation. Corresponding regions on MR images and histologic specimens were defined by using anatomically defined segments in peripheral zone (PZ) and central gland tissue. Cancer and normal PZ regions were identified at histopathologic analysis. Each MR parameter-histologic tissue component pair was assessed by using linear mixed-effects models, and cancer versus normal PZ values were compared by using nonparametric tests. ADC and T2 were inversely related to percentage area of nuclei and percentage area of cytoplasm and positively related to percentage area of luminal space (P < or = .01). These trends were reversed for K(trans) (P < .001). K(trans) had a significantly negative (P = .01) slope versus percentage area of stroma, and v(e) had a positive (P = .008) slope versus percentage area of stroma. The v(e) was inversely proportional to the percentage area of nuclei (P = .05). All MR imaging parameters (P < or = .05) and the percentage areas of all tissue components (P < or = .001) except stroma (P > .48) were significantly different between cancer and normal PZ tissue. MR imaging-derived parameters measured in the prostate were significantly related to the proportion of specific histologic components that differ between normal and malignant PZ tissue. These relationships may help define imaging-related histologic prognostic parameters for prostate cancer.
The Journal of Pathology, May 1, 2009
Non-muscle invasive bladder cancers (NMI-BCs) represent 75% of bladder cancers upon presentation.... more Non-muscle invasive bladder cancers (NMI-BCs) represent 75% of bladder cancers upon presentation. After removal of the primary tumour by transurethral resection, multiple recurrences continue to develop in 70% of patients. Consequently, prolonged and costly surveillance by cystoscopy is required. Mutations in the FGFR3 oncogene are common in NMI-BCs and are associated with a lower chance of progression to muscle-invasive disease. Here we analysed the consistency of FGFR3 mutations in primary and recurrent tumours. This knowledge is of crucial importance if FGFR3 mutation analysis on urinary cells is to be used as an alternative for cystoscopical surveillance. To this end, we monitored the disease process and FGFR3 mutation status of primary and recurrent tumours in 118 patients with NMI-BC. During median follow-up of 8.8 years, these patients underwent 2133 cystoscopies and 80 patients developed 414 recurrences. FGFR3 mutations were equally prevalent in primary and recurrent tumours (63%). Patients can have different types of FGFR3 mutations in different tumours. Recurrence risk was not significantly different for patients with a mutant or wild-type primary tumour. Recurrence rates varied widely between patients but were constant for a patient and were unrelated to FGFR3 status. In the mutant patient group, in contrast to the wild-type group, recurrences continued to develop after 10 years. In 81% of the recurrences of patients with a mutant primary tumour, a mutation was found. Moreover, recurrences in this patient group were of lower stage and grade than those of patients with a wild-type primary tumour (p < 0.001). These results suggest that surveillance by FGFR3 mutation analysis on voided urine in combination with a reduced cystoscopy frequency of patients presenting with an FGFR3 mutant tumour is worth investigating.
The Journal of Urology
The feasibility of using the monoclonal antibody Ki-67 as a proliferation marker in human prostat... more The feasibility of using the monoclonal antibody Ki-67 as a proliferation marker in human prostatic carcinoma was studied on aspiration and core biopsy specimens obtained from 50 patients suspected of having prostate cancer. In 32 prostatic adenocarcinomas the Ki-67 index varied from 0.3 to 13.3% (mean 4.3) in cytological smears and from 0.8 to 17.8% (mean 5.1) in frozen sections from histological core biopsies. No significant correlation between the percentage of cells positive for Ki-67 and the histological tumor differentiation could be established. In 18 patients with benign prostatic hyperplasia the Ki-67 index varied from 0 to 3.0% (mean 1.2) and from 0 to 3.8% (mean 1.4) in cytological and histological material, respectively. The differences in the observed Ki-67 index between benign and malignant prostatic tissues are of statistical (p less than 0.001) and of clinical significance. Nine patients who underwent endocrine treatment or radiotherapy entered a followup protocol in which the Ki-67 staining procedure was applied to periodically obtained cytological aspiration biopsies. During month 1 after the start of therapy a statistically significant (p less than 0.05) decrease in the Ki-67 index to 58% of the initial values was found, while at 2 and 3 months the proliferative fraction showed a further decrease to 27 and 7%, respectively. As a marker, the monoclonal antibody Ki-67 was shown to provide a reliable method to estimate the proliferative cell fraction of human prostate cancer.
European Urology
The effect of androgen deprivation therapy on the expression of androgen receptors (AR) and the p... more The effect of androgen deprivation therapy on the expression of androgen receptors (AR) and the proliferation-associated MIB-1 antigen in prostatic intraepithelial neoplasia (PIN) was investigated. Immunohistochemistry was performed on tissue sections of prostatectomy specimens of patients with prostate cancer who either were not treated prior to surgery or received androgen blockade therapy for 3 months. Immunohistochemistry on slides, selected for the presence of PIN was performed with an AR-specific monoclonal antibody and MIB-1 using a microwave antigen-retrieval method. AR expression was present in a majority of cells in PIN of both untreated and treated prostatectomy specimens. In addition, a proportion of normal prostatic glandular cells retained AR expression. The basal cells in both untreated and treated PIN did not express AR. MIB-1-positive cells were identified in PIN of untreated and treated cases. PIN lesions that persist after 3 months of androgen deprivation therapy continue to express AR and may therefore retain the potential to expand after cessation of this therapy.
International Journal of Cancer
ABSTRACT
Laboratory Investigation
Human prostate-specific transglutaminase (hTGp) is a cross-linking enzyme, the physiologic functi... more Human prostate-specific transglutaminase (hTGp) is a cross-linking enzyme, the physiologic function of which has not been established unequivocally yet. To gain insight into its distribution, we raised antisera against hTGp. By using Western blotting analysis, we found that these antisera specifically recognize a 77-kDa protein in prostatic fluids, seminal plasmas, and prostatic tissues. The concentrations of hTGp in these fluids and tissues were found to be highly variable among individuals. Immunohistochemical examination of several formalin-fixed paraffin-embedded human tissues revealed an exclusive expression in the prostate. The histologic localization and distribution of hTGp within the prostate was assessed by studying multiple sections from tumor-containing prostatectomy specimens and needle biopsies. hTGp expression was entirely restricted to luminal epithelial cells. No basal epithelial cells or stromal cells were stained. Within the prostate, large areas without any hTGp-positive cells were seen. Immunopositive cells were present either in a scattered pattern or concentrated in single or multiple glands in which all luminal epithelial cells expressed hTGp. The latter staining pattern occurred frequently, but not exclusively, in the peripheral zone, whereas scattered expression was most often observed in the transitional zone. Expression of the hTGp protein could occasionally be observed in high-grade prostatic intraepithelial neoplasia, but was not detected in prostate carcinoma cells. The expression pattern as observed for hTGp has not been found thus far for any other prostate-specific marker.
Nederlands tijdschrift voor geneeskunde
Since the introduction of serum testing for prostate-specific antigen (PSA) in 1990 for the early... more 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 &amp;amp;#39;European randomised screening for prostate cancer&amp;amp;#39; (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 (&amp;amp;lt; 3 mm diameter) of well-differentiated adenocarcinoma, based on one biopsy from a series of six. In men with a needle-biopsy diagnosis of &amp;amp;#39;suspected malignancy&amp;amp;#39; 36.5% were found to have prostate cancer in follow-up biopsies. In men with a needle-biopsy diagnosis of &amp;amp;#39;high grade prostatic intra-epithelial neoplasia&amp;amp;#39; 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.
Journal of the National Cancer Institute
The interval cancer rate is an important parameter for determining the sensitivity of a screening... more The interval cancer rate is an important parameter for determining the sensitivity of a screening procedure and the screening interval. We evaluated the time and mechanism of detection and the stage distribution of interval prostate cancers diagnosed during a 4-year screening interval. We determined the rate of interval cancers and the sensitivity of the screening protocol (involving prostate-specific antigen, digital rectal and transrectal ultrasound examinations) in a cohort of 17 226 men (8350 on the screened arm, 8876 on the control arm) enrolled consecutively on the European Randomized Study of Screening for Prostate Cancer-Rotterdam. Men on the screened arm received a first screen between October 1993 and December 1996 and a scheduled second screen 4 years later. Prostate cancers detected in men enrolled on the control arm over the same 4-year period and, between screens, in men on the screened arm, were identified by linkage to the Dutch national cancer registry. During the first screen, 412 prostate cancers were detected. During the subsequent 4-year period, 135 cancers were diagnosed in men in the control arm and 25 cancers were diagnosed in men in the screened arm. Seven of the 25 cancers were diagnosed in men who had refused a recommended biopsy at their initial screen. Of the remaining 18 cancers, all were classified as stage T1A-C or T2A and none were poorly differentiated or metastatic. The rate of interval cancers relative to the number of cancers in the control group was 18.5% (25/135), or 13.3% (18/135), if the seven who refused an initial biopsy were excluded. The sensitivity of the screening protocol was 79.8% when considering all 25 interval cancers and 85.5% when considering 18 interval cancers. The interval cancer rate with a 4-year screening interval was low, confirming that the screening procedure has a high sensitivity and that the 4-year screening interval is reasonable.
JNCI Journal of the National Cancer Institute
The transplantable, hormone-dependent, human prostatic carcinoma PC-82 was used as an in vivo mod... more The transplantable, hormone-dependent, human prostatic carcinoma PC-82 was used as an in vivo model for monitoring the proliferative fraction of tumor cells under the influence of androgen withdrawal and resubstitution. The number of cycling cells was assessed by means of an immunoperoxidase method and monoclonal antibody Ki-67. The number of Ki-67-positive tumor cells dropped from an average of 17% in androgen-supplemented, tumor-bearing female BALB/c mice to approximately 1.0% within 10 days after removal of the testosterone (T) implant. A similar effect was noted after castration of tumor-bearing male BALB/c mice. Androgen resubstitution after a 10-day period of T deprivation resulted in a rise in the tumor cell proliferation index to 20% within 4 days. The same pattern of response to androgen depletion and resubstitution also was found when the number of cycling cells in S phase was assessed by the 5-bromo-2&amp;amp;#39;-deoxyuridine incorporation technique. Administration of supraphysiologic doses of T in intact male mice did not lead to an increase in the number of Ki-67-stained nuclei. Androgen manipulation did not influence the immunohistochemically assessed expression of prostatic acid phosphatase and prostate-specific antigen. The rapid effect of hormone deprivation and resubstitution in the tumor cell proliferation fraction suggests that monoclonal antibody Ki-67 can be used for monitoring the short-term effects of hormonal treatment of prostatic cancer.
The Journal of Urology
Growth fractions were assessed immunohistochemically in prostatic tissues with benign glandular h... more Growth fractions were assessed immunohistochemically in prostatic tissues with benign glandular hyperplasia (BPH) and in specimens of prostatic cancer using the monoclonal antibody Ki-67. This antibody is specific for a proliferation-associated nuclear antigen. In BPH tissues about 0.3% of nuclei of epithelial cells was reactive with Ki-67. The Ki-67 positive nuclei were distributed equally among the basal and luminal cells of the hyperplastic prostatic acini. In prostatic cancer the Ki-67 defined growth fraction ranged from 0.4% to 9.1% (mean value 2.9%). Cancers with a cribriform growth pattern and tumors composed of solid areas of undifferentiated cancer cells showed the highest growth fraction (average values 4.0%, respectively 7.6%). The investigated four tumors composed of undifferentiated solitary tumor cells with diffuse infiltration of the stroma demonstrated an unexpectedly low growth activity (average 1.2%). In cancers with a glandular growth pattern the Ki-67 defined growth fraction of tumor cells varied from 2.2% to 5%. Compared with other epithelial tumors these values are low, but they are in agreement with the earlier findings on prostatic cancer obtained with 3H-thymidine labeling and bromodeoxyuridine incorporation. The observed variation in the level of Ki-67 defined growth activity partly related to the histological tumor pattern suggests that Ki-67 labeling may serve as a prognostic factor additional to the current histopathological grading criteria of prostatic cancer.
The Canadian Journal of Urology
Prostate-specific antigen (PSA) testing of asymptomatic men may lead to the detection of &amp... more Prostate-specific antigen (PSA) testing of asymptomatic men may lead to the detection of &amp;amp;quot;minimal&amp;amp;quot; prostate cancers that are less likely to be associated with morbidity or mortality. To examine the significance of various diagnostic outcomes from needle biopsies of the prostate in an asymptomatic population of men. 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. Prostate cancer was diagnosed in 5.1% of 19,970 screened men, and 31.6 % of the men had cancers that were categorized as &amp;amp;quot;minimal.&amp;amp;quot; Repeat biopsies performed after initial diagnoses of either isolated prostatic intra-epithelial neoplasia (PIN) or &amp;amp;quot;suspicious for malignancy,&amp;amp;quot; 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 &amp;amp;quot;minimal&amp;amp;quot; in 27.8% of the men with previously benign biopsies and in 47.4% of the men with previously suspicious lesions, The chance of finding a &amp;amp;quot;minimal&amp;amp;quot; prostate cancer in an asymptomatic population is substantial and increases when a repeat biopsy is performed following a biopsy with a suspicious outcome.
Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology
Since the introduction of the World Health Organization (WHO) 1973 terminology for bladder cancer... more Since the introduction of the World Health Organization (WHO) 1973 terminology for bladder cancer, noninvasive epithelial bladder tumors have consistently been labeled bladder carcinomas. In the WHO 2004 classification the removal of the &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;carcinoma&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; label from a small subset of noninvasive bladder carcinomas with indolent behavior created the entity of papillary urothelial neoplasms of low malignant potential, but the remaining noninvasive carcinomas of the urothelial tract retained this label. In this overview, we analyze clinical, pathologic and molecular-genomic findings to support a more evidence-based nomenclature of papillary neoplastic lesions of the urinary tract. In line with the tendency during the last few decades to label flat precancerous lesions of various organs intraepithelial neoplasms, we may now also refer to dysplasia and carcinoma in situ of the urinary tract as low and high grade intraurothelial neoplasia, respectively. To harmonize nomenclature, we now propose that the terms low and high grade papillary urothelial carcinoma be replaced by low and high grade papillary intraurothelial neoplasiafor all noninvasive urothelial cancers.
The Journal of Urology
We evaluated the influence of knowledge of urine test outcome on the accuracy of cystoscopy (diag... more We evaluated the influence of knowledge of urine test outcome on the accuracy of cystoscopy (diagnostic review bias) during surveillance in patients with low grade, nonmuscle invasive urothelial carcinoma. We performed a prospective, single-blind, randomized, multicenter clinical trial of surveillance by microsatellite analysis urine test in 448 patients with nonmuscle invasive (pTa, pT1, G1, G2) urothelial carcinoma. Positive or negative urine test results were only communicated to the urologist in the intervention arm of 226 patients, in which cystoscopy was done if the test was positive, and at 3, 12 and 24 months. Urine test results were not communicated in the control arm of 222 patients who underwent standard 3-month cystoscopy. The primary outcome measure was the number of histologically proven bladder cancer recurrences. At a median 34-month followup 218 recurrences were detected in the intervention arm compared to 163 in the control arm (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). Of 131 cystoscopies done with knowledge of a positive urine test 42 recurrences were detected. Only 6 recurrences were found in the 120 cystoscopies done without information on the positive test result (chi-square p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). There was no difference in recurrence detection when urine test results were negative in the intervention and control arms (18 of 260 patients or 7% and 18 of 326 or 6%, respectively, p = 0.45). Diagnostic review bias should be considered in the evaluation of point of care urine tests for bladder cancer monitoring. Awareness of a positive urine test result significantly improves the urothelial carcinoma detection rate using cystoscopy.
Cancer Research
The high recurrence rate of human bladder cancer can be attributed to intraepithelial expansion o... more The high recurrence rate of human bladder cancer can be attributed to intraepithelial expansion of tumor cells or shedding and subsequent implantation of tumor cells elsewhere in the bladder. E-Cadherin is a calcium-dependent cell-cell adhesion molecule, and loss of E-cadherin by tumor cells is associated with increased tumor aggressiveness. Here we demonstrate that E-cadherin is also an important determinant of the mechanisms which are involved in the recurrence rate of bladder cancer. In a recently developed in vitro cocultivation model, we studied the effect of E-cadherin expression on the intraepithelial expansion pattern of six different human bladder carcinoma cell lines into primary murine urothelium. Bladder carcinoma cells lacking E-cadherin infiltrate into the primary urothelium as individual cells (pagetoid pattern). In contrast, a sharp demarcation is observed between E-cadherin-positive bladder cancer cells and the primary urothelium (carcinoma in situ pattern). With the same model, we demonstrate that only E-cadherin-positive bladder carcinoma cell lines could attach to and colonize the intact primary urothelium. We hypothesize that it is the latter process that plays an important role in the high recurrence rate that is observed in some of the patients.
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Papers by Theodorus Van Der Kwast