Publications by authors named "Achim Fleischmann"

50 Publications

Inter-observer reproducibility of classical lobular neoplasia (B3 lesions) in preoperative breast biopsies: a study of the Swiss Working Group of breast and gynecopathologists.

J Cancer Res Clin Oncol 2020 Jun 30;146(6):1473-1478. Epub 2020 Mar 30.

Institute of Pathology and Molecular Pathology, University Hospital Zurich, Schmelzbergstrasse 12, 8091, Zurich, Switzerland.

Purpose: Classical type of lobular neoplasia (LN) spans a spectrum of disease, including atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS), classical lobular neoplasia (LN), and the three-tiered classification of lobular intraepithelial neoplasia (LIN-1, -2, -3). This study addressed inter-observer variability of classical lobular neoplasias (LN) (B3 lesions) in preoperative breast biopsies among breast and gynecopathologists METHODS: A retrospective, observational, cross-sectional study was conducted. 40 preoperative digital images of breast core/vacuum biopsies were analyzed by eight experienced breast- and gynecopathologists. Evaluation criteria were ALH, LCIS, LN classic, LIN-1, LIN-2, LIN-3, focal B3 (one focus), extensive B3 (> one focus). Kappa-index and Chi-square tests were used for statistics. Digital scanned slides were provided to each participant. Agreement between the categories was defined as at least six of eight (cut-off 75%) concordant diagnoses.

Results: The highest agreement between eight pathologists was reached using the category lobular neoplasia (LN, classical), 26/40 (65%) cases were diagnosed as such. Agreements in other categories was low or poor: 12/40 (30%) (ALH), 9/40 (22%) (LCIS), 8/40 (20%) (LIN-1), 8/40 (20%) (focal B3), 3/40 (7.5%) (LIN-2), and 2/40 (5%) (extensive B3). Chi-square-test (classical LN versus the other nomenclatures) was significant (p = 0.001137).

Conclusion: Our data suggest that among Swiss breast pathologists, the most reproducible diagnosis for B3 lobular lesions is the category of classical LN. These data further support lack of consistent data in retrospective studies using different terminologies. Validation of reproducible nomenclature is warranted in further studies. This information is useful especially in view of retro- and prospective data analysis with different diagnostic categories.
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http://dx.doi.org/10.1007/s00432-020-03195-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230045PMC
June 2020

PD-L1 testing of non-small cell lung cancer using different antibodies and platforms: a Swiss cross-validation study.

Virchows Arch 2019 Jul 24;475(1):67-76. Epub 2019 May 24.

Institute of Medical Genetics and Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031, Basel, Switzerland.

With the approval of pembrolizumab for first- and second-line treatment of PD-L1+ non-small cell lung cancer (NSCLC), PD-L1 testing by immunohistochemistry (IHC) has become a necessity. However, the DAKO autostainer ASL48 for the FDA approved DAKO 22C3 pharmDx assay is not broadly available in Switzerland and other parts of Europe. The primary goal of this study was to cross-validate the 22C3 anti-PD-L1 antibody on Benchmark Ultra (VBMU) and Leica Bond (LBO) immunostainers. IHC protocols were developed for 22C3 on both platforms with the 22C3phDx using ASL48 as reference. A tissue microarray (TMA) was constructed from 23 NSCLC specimens with a range of PD-L1 staining results. Empty TMA sections and the 22C3 antibody were distributed to 16 participants for staining on VBMU (8 centers) and/or LBO (12 centers) using the centrally developed protocols. Additionally the performance of the Ventana SP263 assay was tested in five centers. IHC scoring was performed centrally. Categorical PD-L1 staining (0-49% vs. 50-100%) did not significantly differ between centers using VBMU, whereas data from LBO were highly variable (p < 0.001). The SP263 assay was well concordant with 22C3 on VBMU and with 22C3 pharmDx. PD-L1 IHC using a standardized 22C3 protocol on VBMU provides satisfactory results in most centers. The SP263 assay is confirmed as a valid alternative to 22C3 pharmDx. 22C3 PD-L1 IHC on LBO shows major staining variability between centers, highlighting the need for local validation and adjustment of protocols.
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http://dx.doi.org/10.1007/s00428-019-02582-0DOI Listing
July 2019

Neuroendocrine Differentiation in Metastatic Conventional Prostate Cancer Is Significantly Increased in Lymph Node Metastases Compared to the Primary Tumors.

Int J Mol Sci 2017 Jul 28;18(8). Epub 2017 Jul 28.

Institute of Pathology, University of Bern, Bern 3008, Switzerland.

Neuroendocrine serum markers released from prostate cancers have been proposed for monitoring disease and predicting survival. However, neuroendocrine differentiation (NED) in various tissue compartments of metastatic prostate cancer is poorly described and its correlation with specific tumor features is unclear. NED was determined by Chromogranin A expression on immunostains from a tissue microarray of 119 nodal positive, hormone treatment-naïve prostate cancer patients who underwent radical prostatectomy and extended lymphadenectomy. NED in the primary cancer and in the metastases was correlated with tumor features and survival. The mean percentage of NED cells increased significantly ( < 0.001) from normal prostate glands (0.4%), to primary prostate cancer (1.0%) and nodal metastases (2.6%). In primary tumors and nodal metastases, tumor areas with higher Gleason patterns tended to display a higher NED, although no significance was reached. The same was observed in patients with a larger primary tumor volume and higher total size and number of metastases. NED neither in the primary tumors nor in the metastases predicted outcome significantly. Our data suggest that (a) increasing levels of neuroendocrine serum markers in the course of prostate cancer might primarily derive from a poorly differentiated metastatic tumor component; and (b) NED in conventional hormone-naïve prostate cancers is not significantly linked to adverse tumor features.
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http://dx.doi.org/10.3390/ijms18081640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578030PMC
July 2017

Extranodal extension of lymph node metastasis influences recurrence in prostate cancer: a systematic review and meta-analysis.

Sci Rep 2017 05 24;7(1):2374. Epub 2017 May 24.

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

The extranodal extension (ENE) of nodal metastasis involves the extension of neoplastic cells through the lymph node capsule into the perinodal adipose tissue. This morphological feature has recently been indicated as an important prognostic factor in various cancer types, but its role in prostate cancer is still unclear. We aimed to clarify it, performing the first meta-analysis on this issue, comparing prognostic parameters in surgically treated, node-positive prostate cancer patients with (ENE+) vs. without (ENE-) ENE. Data were summarized using risk ratios (RRs) for number of deaths/recurrences and hazard ratios (HRs), with 95% confidence intervals (CI), for the time-dependent risk related to ENE positivity. Six studies followed-up 1,113 patients with N1 prostate cancer (658 ENE+ vs. 455 ENE-) for a median of 83 months. The presence of ENE was associated with a significantly higher risk of biochemical recurrence (RR = 1.15; 95%CI: 1.03-1.28; I = 0%; HR = 1.40, 95%CI: 1.12-1.74; I = 0%) and "global" (biochemical recurrence and distant metastasis) recurrence (RR = 1.15; 95%CI: 1.04-1.28; I = 0%; HR = 1.41, 95%CI: 1.14-1.74; I = 0%). ENE emerged as a potential prognostic moderator, earmarking a subgroup of patients at higher risk of recurrence. It may be considered for the prognostic stratification of metastatic patients. New possible therapeutic approaches may explore more in depth this prognostic parameter.
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http://dx.doi.org/10.1038/s41598-017-02577-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443831PMC
May 2017

Her2 alterations in muscle-invasive bladder cancer: Patient selection beyond protein expression for targeted therapy.

Sci Rep 2017 02 16;7:42713. Epub 2017 Feb 16.

Department of Urology, University of Bern, Bern, Switzerland.

Although the introduction of novel targeted agents has improved patient outcomes in several human cancers, no such advance has been achieved in muscle-invasive bladder cancer (MIBC). However, recent sequencing efforts have begun to dissect the complex genomic landscape of MIBC, revealing distinct molecular subtypes and offering hope for implementation of targeted therapies. Her2 (ERBB2) is one of the most established therapeutic targets in breast and gastric cancer but agents targeting Her2 have not yet demonstrated anti-tumor activity in MIBC. Through an integrated analysis of 127 patients from three centers, we identified alterations of Her2 at the DNA, RNA and protein level, and demonstrate that Her2 relevance as a tumor driver likely may vary even within ERBB2 amplified cases. Importantly, tumors with a luminal molecular subtype have a significantly higher rate of Her2 alterations than those of the basal subtype, suggesting that Her2 activity is also associated with subtype status. Although some of our findings present rare events in bladder cancer, our study suggests that comprehensively assessing Her2 status in the context of tumor molecular subtype may help select MIBC patients most likely to respond to Her2 targeted therapy.
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http://dx.doi.org/10.1038/srep42713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5311866PMC
February 2017

Bladder cancer cells secrete while normal bladder cells express but do not secrete AGR2.

Oncotarget 2016 Mar;7(13):15747-56

Department of Urology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.

Anterior gradient 2 (AGR2) is a cancer-associated secreted protein found predominantly in adenocarcinomas. Given its ubiquity in solid tumors, cancer-secreted AGR2 could be a useful biomarker in urine or blood for early detection. However, normal organs express and might also secrete AGR2, which would impact its utility as a cancer biomarker. Uniform AGR2 expression is found in the normal bladder urothelium. Little AGR2 is secreted by the urothelial cells as no measurable amounts could be detected in urine. The urinary proteomes of healthy people contain no listing for AGR2. Likewise, the blood proteomes of healthy people also contain no significant peptide counts for AGR2 suggesting little urothelial secretion into capillaries of the lamina propria. Expression of AGR2 is lost in urothelial carcinoma, with only 25% of primary tumors observed to retain AGR2 expression in a cohort of lymph node-positive cases. AGR2 is secreted by the urothelial carcinoma cells as urinary AGR2 was measured in the voided urine of 25% of the cases analyzed in a cohort of cancer vs. non-cancer patients. The fraction of AGR2-positive urine samples was consistent with the fraction of urothelial carcinoma that stained positive for AGR2. Since cancer cells secrete AGR2 while normal cells do not, its measurement in body fluids could be used to indicate tumor presence. Furthermore, AGR2 has also been found on the cell surface of cancer cells. Taken together, secretion and cell surface localization of AGR2 are characteristic of cancer, while expression of AGR2 by itself is not.
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http://dx.doi.org/10.18632/oncotarget.7400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4941274PMC
March 2016

Bcl-2 predicts response to neoadjuvant chemotherapy and is overexpressed in lymph node metastases of urothelial cancer of the bladder.

Urol Oncol 2015 Apr 14;33(4):166.e1-8. Epub 2015 Jan 14.

Department of Urology, University of Bern, Bern, Switzerland; Department of Urologic Sciences, University of British Columbia, Vancouver, Canada. Electronic address:

Purpose: To assess whether Bcl-2, an inhibitor of the apoptotic cascade, can predict response to neoadjuvant chemotherapy in patients with urothelial cancer of the bladder (UCB).

Methods: Bcl-2 expression was analyzed in 2 different tissue microarrays (TMAs). One TMA was constructed of primary tumors and their corresponding lymph node (LN) metastases from 152 patients with chemotherapy-naive UCB treated by cystectomy and pelvic lymphadenectomy (chemotherapy-naive TMA cohort). The other TMA was constructed of tumor samples obtained from 55 patients with UCB before neoadjuvant chemotherapy (transurethral resection of the bladder cancer) and after cystectomy with pelvic lymphadenectomy (residual primary tumor [ypT+], n = 38); residual LN metastases [ypN+], n = 24) (prechemotherapy/postchemotherapy TMA cohort). Bcl-2 overexpression was defined as 10% or more cancer cells showing cytoplasmic immunoreactivity.

Results: In both TMA cohorts, Bcl-2 overexpression was significantly (P<0.05) more frequent in LN metastases than in primary tumors (chemotherapy-naive TMA group: 18/148 [12%] in primary tumors vs. 39/143 [27%] in metastases; postchemotherapy TMA: ypT+7/35 [20%] vs. ypN+11/19 [58%]). In the neoadjuvant setting, patients with Bcl-2 overexpression in transurethral resection of the bladder cancer specimens showed significantly (P = 0.04) higher ypT stages and less regression in their cystectomy specimens than did the control group, and only one-eighth (13%) had complete tumor regression (ypT0 ypN0). In survival analyses, only histopathological parameters added significant prognostic information.

Conclusions: Bcl-2 overexpression in chemotherapy-naive primary bladder cancer is related to poor chemotherapy response and might help to select likely nonresponders.
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http://dx.doi.org/10.1016/j.urolonc.2014.12.005DOI Listing
April 2015

The molecular signature of the stroma response in prostate cancer-induced osteoblastic bone metastasis highlights expansion of hematopoietic and prostate epithelial stem cell niches.

PLoS One 2014 8;9(12):e114530. Epub 2014 Dec 8.

Urology Research Laboratory, Department of Urology and Department of Clinical Research, University of Bern, Bern, Switzerland.

The reciprocal interaction between cancer cells and the tissue-specific stroma is critical for primary and metastatic tumor growth progression. Prostate cancer cells colonize preferentially bone (osteotropism), where they alter the physiological balance between osteoblast-mediated bone formation and osteoclast-mediated bone resorption, and elicit prevalently an osteoblastic response (osteoinduction). The molecular cues provided by osteoblasts for the survival and growth of bone metastatic prostate cancer cells are largely unknown. We exploited the sufficient divergence between human and mouse RNA sequences together with redefinition of highly species-specific gene arrays by computer-aided and experimental exclusion of cross-hybridizing oligonucleotide probes. This strategy allowed the dissection of the stroma (mouse) from the cancer cell (human) transcriptome in bone metastasis xenograft models of human osteoinductive prostate cancer cells (VCaP and C4-2B). As a result, we generated the osteoblastic bone metastasis-associated stroma transcriptome (OB-BMST). Subtraction of genes shared by inflammation, wound healing and desmoplastic responses, and by the tissue type-independent stroma responses to a variety of non-osteotropic and osteotropic primary cancers generated a curated gene signature ("Core" OB-BMST) putatively representing the bone marrow/bone-specific stroma response to prostate cancer-induced, osteoblastic bone metastasis. The expression pattern of three representative Core OB-BMST genes (PTN, EPHA3 and FSCN1) seems to confirm the bone specificity of this response. A robust induction of genes involved in osteogenesis and angiogenesis dominates both the OB-BMST and Core OB-BMST. This translates in an amplification of hematopoietic and, remarkably, prostate epithelial stem cell niche components that may function as a self-reinforcing bone metastatic niche providing a growth support specific for osteoinductive prostate cancer cells. The induction of this combinatorial stem cell niche is a novel mechanism that may also explain cancer cell osteotropism and local interference with hematopoiesis (myelophthisis). Accordingly, these stem cell niche components may represent innovative therapeutic targets and/or serum biomarkers in osteoblastic bone metastasis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114530PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4259356PMC
January 2016

Prevalence and prognostic significance of TMPRSS2-ERG gene fusion in lymph node positive prostate cancers.

Prostate 2014 Dec 22;74(16):1647-54. Epub 2014 Sep 22.

Institute of Pathology, University of Bern, Switzerland.

Background: TMPRSS2-ERG gene fusion is the most frequent genetic alteration in prostate cancer. However, information about its distribution in lymph node positive prostate cancers and the prognostic significance in these advanced tumors is unknown.

Methods: Gene fusion status was determined by fluorescence in situ hybridization on a tissue-microarray constructed from 119 hormone-naïve nodal positive, surgically treated prostate cancers containing samples from the primary tumors and corresponding lymph node metastases. Data were correlated with various tumor features (Gleason score, stage, cancer volume, nodal tumor burden) and biochemical recurrence-free, disease-specific, and overall survival.

Results: TMPRSS2-ERG fusion was detected in 43.5% of the primary tumors. Conversely, only 29.9% of the metastasizing components showed the fusion. Concordance in TMPRSS2-ERG status between primary tumors and metastases was 70.9% (Kappa 0.39); 20.9% and 8.1% of the patients showed the mutation solely in their primary tumors and metastases, respectively. TMPRSS2-ERG fusion was not correlated with specific histopathological tumor features but predicted favorable biochemical recurrence-free, disease-specific and overall survival independently when present in the primary tumor (P < 0.05 each).

Conclusion: TMPRSS2-ERG fusion is more frequent in primary prostate cancer than in corresponding metastases suggesting no selection of fusion-positive cells in the metastatic process. The gene fusion in primary tumors independently predicts favorable outcome.
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http://dx.doi.org/10.1002/pros.22882DOI Listing
December 2014

FGFR3 expression in primary invasive bladder cancers and matched lymph node metastases.

J Urol 2015 Jan 13;193(1):325-30. Epub 2014 Jun 13.

Leeds Institute of Cancer and Pathology, St. James's University Hospital, Leeds, United Kingdom. Electronic address:

Purpose: FGFR3 is considered a good therapeutic target for bladder cancer. However, to our knowledge it is unknown whether the FGFR3 status of primary tumors is a surrogate for related metastases, which must be targeted by FGFR targeted systemic therapies. We assessed FGFR3 protein expression in primary bladder tumors and matched nodal metastases.

Materials And Methods: We examined matched primary tumor and nodal metastases from 150 patients with bladder cancer clinically staged as N0M0. Four samples per patient were incorporated into a tissue microarray and FGFR3 expression was assessed by immunohistochemistry. FGFR3 expression was tested for an association with categorical clinical data using the Fisher exact test, and with overall and recurrence-free survival by Kaplan-Meier analysis.

Results: Duplicate spots from primary tumors and lymph node metastases were highly concordant (OR 8.6 and 16.7, respectively, each p <0.001). Overall FGFR protein expression levels did not differ between primary and metastatic lesions (p = 0.78). Up-regulated expression was recorded in 53 of 106 evaluable primary tumor spots and 56 matched metastases. Concordance of FGFR3 expression levels in 79 matched primary tumor and metastasis specimens was high (OR 8.45, p <0.001). In 15 and 12 patients expression was up-regulated in only metastasis and in only the primary tumor, respectively. Overall and recurrence-free survival was not related to FGFR3 expression.

Conclusions: FGFR3 expression in matched primary and metastasized bladder cancer specimens showed good but not absolute concordance. Thus, in most patients primary tumor FGFR3 status can guide the selection of FGFR targeted therapy.
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http://dx.doi.org/10.1016/j.juro.2014.06.026DOI Listing
January 2015

Metastases in normal-sized pelvic lymph nodes: detection with diffusion-weighted MR imaging.

Radiology 2014 Oct 2;273(1):125-35. Epub 2014 Jun 2.

From the Department of Radiology, Neuroradiology and Nuclear Medicine (H.C.T., J.M.F., M.T., L.J.B., P.V.), Institute of Mathematical Statistics (J.H.), Department of Pathology (A.F.), and Department of Urology (U.E.S.), Inselspital, University of Bern, Freiburgstrasse 10, CH-3010 Bern, Switzerland.

Purpose: To prospectively assess the diagnostic performance of diffusion-weighted (DW) magnetic resonance (MR) imaging in the detection of pelvic lymph node metastases in patients with prostate and/or bladder cancer staged as N0 with preoperative cross-sectional imaging.

Materials And Methods: This study was approved by an independent ethics committee. Written informed consent was obtained from all patients. Patients with no enlarged lymph nodes on preoperative cross-sectional images who were scheduled for radical resection of the primary tumor and extended pelvic lymph node dissection were enrolled. All patients were examined with a 3-T MR unit, and examinations included conventional and DW MR imaging of the entire pelvis. Image analysis was performed by three independent readers blinded to any clinical information. Metastases were diagnosed on the basis of high signal intensity on high b value DW MR images and morphologic features (shape, border). Histopathologic examination served as the standard of reference. Sensitivity and specificity were calculated, and bias-corrected 95% confidence intervals (CIs) were obtained with the bootstrap method. The Fleiss and Cohen κ and median test were applied for statistical analyses.

Results: A total of 4846 lymph nodes were resected in 120 patients. Eighty-eight lymph node metastases were found in 33 of 120 patients (27.5%). Short-axis diameter of these metastases was less than or equal to 3 mm in 68, more than 3 mm to 5 mm in 13, more than 5 mm to 8 mm in five; and more than 8 mm in two. On a per-patient level, the three readers correctly detected metastases in 26 (79%; 95% CI: 64%, 91%), 21 (64%; 95% CI: 45%, 79%), and 25 (76%; 95% CI: 60%, 90%) of the 33 patients with metastases, with respective specificities of 85% (95% CI: 78%, 92%), 79% (95% CI: 70%, 88%), and 84% (95% CI: 76%, 92%). Analyzed according to hemipelvis, lymph node metastases were detected with histopathologic examination in 44 of 240 pelvic sides (18%); the three readers correctly detected these on DW MR images in 26 (59%; 95% CI: 45%, 73%), 19 (43%; 95% CI: 27%, 57%), and 28 (64%; 95% CI: 47%, 78%) of the 44 cases.

Conclusion: DW MR imaging enables noninvasive detection of small lymph node metastases in normal-sized nodes in a substantial percentage of patients with prostate and bladder cancer diagnosed as N0 with conventional cross-sectional imaging techniques.
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http://dx.doi.org/10.1148/radiol.14132921DOI Listing
October 2014

Diffusion-weighted magnetic resonance imaging detects significant prostate cancer with high probability.

J Urol 2014 Sep 15;192(3):737-42. Epub 2014 Mar 15.

Department of Radiology, Neuroradiology and Nuclear Medicine, Institute of Diagnostic, Interventional and Pediatric Radiology, University of Bern, Bern, Switzerland. Electronic address:

Purpose: We prospectively assessed the diagnostic accuracy of diffusion-weighted magnetic resonance imaging for detecting significant prostate cancer.

Materials And Methods: We performed a prospective study of 111 consecutive men with prostate and/or bladder cancer who underwent 3 Tesla diffusion-weighted magnetic resonance imaging of the pelvis without an endorectal coil before radical prostatectomy (78) or cystoprostatectomy (33). Three independent readers blinded to clinical and pathological data assigned a prostate cancer suspicion grade based on qualitative imaging analysis. Final pathology results of prostates with and without cancer served as the reference standard. Primary outcomes were the sensitivity and specificity of diffusion-weighted magnetic resonance imaging for detecting significant prostate cancer with significance defined as a largest diameter of the index lesion of 1 cm or greater, extraprostatic extension, or Gleason score 7 or greater on final pathology assessment. Secondary outcomes were interreader agreement assessed by the Fleiss κ coefficient and image reading time.

Results: Of the 111 patients 93 had prostate cancer, which was significant in 80 and insignificant in 13, and 18 had no prostate cancer on final pathology results. The sensitivity and specificity of diffusion-weighted magnetic resonance imaging for detecting significant PCa was 89% to 91% and 77% to 81%, respectively, for the 3 readers. Interreader agreement was good (Fleiss κ 0.65 to 0.74). Median reading time was between 13 and 18 minutes.

Conclusions: Diffusion-weighted magnetic resonance imaging (3 Tesla) is a noninvasive technique that allows for the detection of significant prostate cancer with high probability without contrast medium or an endorectal coil, and with good interreader agreement and a short reading time. This technique should be further evaluated as a tool to stratify patients with prostate cancer for individualized treatment options.
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http://dx.doi.org/10.1016/j.juro.2014.03.039DOI Listing
September 2014

Tumor regression grade of urothelial bladder cancer after neoadjuvant chemotherapy: a novel and successful strategy to predict survival.

Am J Surg Pathol 2014 Mar;38(3):325-32

*Institute of Pathology †Department of Urology, University of Bern, Bern, Switzerland.

Histopathologic tumor regression grades (TRGs) after neoadjuvant chemotherapy predict survival in different cancers. In bladder cancer, corresponding studies have not been conducted. Fifty-six patients with advanced invasive urothelial bladder cancer received neoadjuvant chemotherapy before cystectomy and lymphadenectomy. TRGs were defined as follows: TRG1: complete tumor regression; TRG2: >50% tumor regression; TRG3: 50% or less tumor regression. Separate TRGs were assigned for primary tumors and corresponding lymph nodes. The prognostic impact of these 2 TRGs, the highest (dominant) TRG per patient, and competing tumor features reflecting tumor regression (ypT/ypN stage, maximum diameter of the residual tumor) were determined. Tumor characteristics in initial transurethral resection of the bladder specimens were tested for response prediction. The frequency of TRGs 1, 2, and 3 in the primary tumors were n=16, n=19, and n=21; corresponding data from the lymph nodes were n=31, n=9, and n=16. Interobserver agreement in determination of the TRG was strong (κ=0.8). Univariately, all evaluated parameters were significantly (P ≤ 0.001) related to overall survival; however, the segregation of the Kaplan-Meier curves was best for the dominant TRG. In multivariate analysis, only dominant TRG predicted overall survival independently (P=0.035). In transurethral resection specimens of the chemotherapy-naive bladder cancer, the only tumor feature with significant (P<0.03) predictive value for therapy response was a high proliferation rate. In conclusion, among all parameters reflecting tumor regression, the dominant TRG was the only independent risk factor. A favorable chemotherapy response is associated with a high proliferation rate in the initial chemotherapy-naive bladder cancer. This feature might help personalize neoadjuvant chemotherapy.
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http://dx.doi.org/10.1097/PAS.0000000000000142DOI Listing
March 2014

Combined ultrasmall superparamagnetic particles of iron oxide-enhanced and diffusion-weighted magnetic resonance imaging facilitates detection of metastases in normal-sized pelvic lymph nodes of patients with bladder and prostate cancer.

Eur Urol 2013 Dec 30;64(6):953-60. Epub 2013 Jul 30.

University Hospital of Bern, Department of Urology, Bern, Switzerland.

Background: Conventional cross-sectional imaging with computed tomography and magnetic resonance imaging (MRI) has limited accuracy for lymph node (LN) staging in bladder and prostate cancer patients.

Objective: To prospectively assess the diagnostic accuracy of combined ultrasmall superparamagnetic particles of iron oxide (USPIO) MRI and diffusion-weighted (DW) MRI in staging of normal-sized pelvic LNs in bladder and/or prostate cancer patients.

Design, Setting, And Participants: Examinations with 3-Tesla MRI 24-36 h after administration of USPIO using conventional MRI sequences combined with DW-MRI (USPIO-DW-MRI) were performed in 75 patients with clinically localised bladder and/or prostate cancer staged previously as N0 by conventional cross-sectional imaging. Combined USPIO-DW-MRI findings were analysed by three independent readers and correlated with histopathologic LN findings after extended pelvic LN dissection (PLND) and resection of primary tumours.

Outcome Measurements And Statistical Analysis: Sensitivity and specificity for LN status of combined USPIO-DW-MRI versus histopathologic findings were evaluated per patient (primary end point) and per pelvic side (secondary end point). Time required for combined USPIO-DW-MRI reading was assessed.

Results And Limitations: At histopathologic analysis, 2993 LNs (median: 39 LNs; range: 17-68 LNs per patient) with 54 LN metastases (1.8%) were found in 20 of 75 (27%) patients. Per-patient sensitivity and specificity for detection of LN metastases by the three readers ranged from 65% to 75% and 93% to 96%, respectively; sensitivity and specificity per pelvic side ranged from 58% to 67% and 94% to 97%, respectively. Median reading time for the combined USPIO-DW-MRI images was 9 min (range: 3-26 min). A potential limitation is the absence of a node-to-node correlation of combined USPIO-DW-MRI and histopathologic analysis.

Conclusions: Combined USPIO-DW-MRI improves detection of metastases in normal-sized pelvic LNs of bladder and/or prostate cancer patients in a short reading time.
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http://dx.doi.org/10.1016/j.eururo.2013.07.032DOI Listing
December 2013

[Urothelial carcinoma - lymphatic vessels provide more accurate prognosis].

Aktuelle Urol 2013 Jul 31;44(4):258-9. Epub 2013 Jul 31.

Institut für Pathologie, Universität Bern.

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http://dx.doi.org/10.1055/s-0033-1351765DOI Listing
July 2013

CCND1/CyclinD1 status in metastasizing bladder cancer: a prognosticator and predictor of chemotherapeutic response.

Mod Pathol 2014 Jan 26;27(1):87-95. Epub 2013 Jul 26.

Institute of Pathology, University of Bern, Bern, Switzerland.

The CCND1 gene encodes the protein CyclinD1, which is an important promoter of the cell cycle and a prognostic and predictive factor in different cancers. CCND1 is amplified to a substantial proportion in various tumors, and this may contribute to CyclinD1 overexpression. In bladder cancer, information about the clinical relevance of CCND1/CyclinD1 alterations is limited. In the present study, amplification status of CCND1 and expression of CyclinD1 were evaluated by fluorescence in situ hybridization and immunohistochemistry on tissue microarrays from 152 lymph node-positive urothelial bladder cancers (one sample each from the center and invasion front of the primary tumors, two samples per corresponding lymph node metastasis) treated by cystectomy and lymphadenectomy. CCND1 amplification status and the percentage of immunostained cancer cells were correlated with histopathological tumor characteristics, cancer-specific survival and response to adjuvant chemotherapy. CCND1 amplification in primary tumors was homogeneous in 15% and heterogeneous in 6% (metastases: 22 and 2%). Median nuclear CyclinD1 expression in amplified samples was similar in all tumor compartments (60-70% immunostained tumor nuclei) and significantly higher than in non-amplified samples (5-20% immunostained tumor nuclei; P<0.05). CCND1 status and CyclinD1 expression were not associated with primary tumor stage or lymph node tumor burden. CCND1 amplification in primary tumors (P=0.001) and metastases (P=0.02) and high nuclear CyclinD1 in metastases (P=0.01) predicted early cancer-related death independently. Subgroup analyses showed that chemotherapy was particularly beneficial in patients with high nuclear CyclinD1 expression in the metastases, whereas expression in primary tumors and CCND1 status did not predict chemotherapeutic response. In conclusion, CCND1 amplification status and CyclinD1 expression are independent risk factors in metastasizing bladder cancer. High nuclear CyclinD1 expression in lymph node metastases predicts favorable response to chemotherapy. This information may help to personalize prognostication and administration of adjuvant chemotherapy.
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http://dx.doi.org/10.1038/modpathol.2013.125DOI Listing
January 2014

Targeting GRPR in urological cancers--from basic research to clinical application.

Nat Rev Urol 2013 Apr 19;10(4):235-44. Epub 2013 Mar 19.

Department of Nuclear Medicine, University Hospital Freiburg, Freiburg, Germany.

Gastrin releasing peptide (GRP) is a regulatory peptide that acts through its receptor (GRPR) to regulate physiological functions in various organs. GRPR is overexpressed in neoplastic cells of most prostate cancers and some renal cell cancers and in the tumoral vessels of urinary tract cancers. Thus, targeting these tumours with specifically designed GRP analogues has potential clinical application. Potent and specific radioactive, cytotoxic or nonradioactive GRP analogues have been designed and tested in various animal tumour models with the aim of receptor targeting for tumour diagnosis or therapy. All three categories of compound were found suitable for tumour targeting in animal models. The cytotoxic and nonradioactive GRP analogues have not yet shown convincing tumour-reducing effects in human trials; however, the first clinical studies of radioactive GRP analogues--both agonists and antagonists--suggest promising opportunities for both diagnostic tumour imaging and radiotherapy of prostate and other GRPR-expressing cancers.
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http://dx.doi.org/10.1038/nrurol.2013.42DOI Listing
April 2013

Ultrasmall superparamagnetic particles of iron oxide allow for the detection of metastases in normal sized pelvic lymph nodes of patients with bladder and/or prostate cancer.

Eur J Cancer 2013 Feb 18;49(3):616-24. Epub 2012 Oct 18.

Department of Radiology, Institute for Diagnostic, Interventional, and Pediatric Radiology, Inselspital University Hospital Bern, Switzerland.

Aim: Lymph node metastases influence prognosis and outcome in patients with bladder and prostate cancer. Cross sectional imaging criteria are limited in detecting metastases in normal sized lymph nodes. This prospective study assessed the diagnostic accuracy of ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) for the detection of metastases in normal sized lymph nodes using extended pelvic lymph node dissection (ePLND) and histopathology as the reference standard.

Methods: Seventy-five patients (bladder cancer, n=19, prostate cancer n=48, both, n=8) were examined using 3T MR before and after USPIO-administration. A preoperative reading with two readers in consensus and a second postoperative reading with three independent blinded readers were performed. Results were correlated with histopathology and diagnostic accuracies were calculated for all readings.

Results: A total of 2993 lymph nodes were examined histopathologically. Fifty-four metastatic nodes were found in 20/75 patients (26.7%). The first reading had a sensitivity of 55.0%, specificity of 85.5%, positive predictive value (PPV) of 57.9%, negative predictive value (NPV) of 83.9%, and diagnostic accuracy (DA) of 77.3% on a per patient level. The second reading had a mean sensitivity of 58.3%, specificity of 83.0%, PPV of 58.0%, NPV of 84.4% and DA of 76.4% on a per patient level. The majority of missed metastases were smaller than 5mm in short axis diameter.

Conclusions: USPIO-enhanced MRI in bladder and prostate cancer patients allows detection of metastases in normal sized lymph nodes and might guide the surgeon to remove suspicious lymph nodes not included in standard PLND.
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http://dx.doi.org/10.1016/j.ejca.2012.09.034DOI Listing
February 2013

Does quantification of USPIO uptake-related signal loss allow differentiation of benign and malignant normal-sized pelvic lymph nodes?

Contrast Media Mol Imaging 2012 May-Jun;7(3):346-55

Department of Radiology, Neuroradiology and Nuclear Medicine, University Hospital and Inselspital, University of Bern, Bern, Switzerland.

Ultrasmall superparamagnetic iron oxide (USPIO) particles are promising contrast media, especially for molecular and cellular imaging besides lymph node staging owing to their superior NMR efficacy, macrophage uptake and lymphotropic properties. The goal of the present prospective clinical work was to validate quantification of signal decrease on high-resolution T(2)-weighted MR sequences before and 24-36 h after USPIO administration for accurate differentiation between benign and malignant normal-sized pelvic lymph nodes. Fifty-eight patients with bladder or prostate cancer were examined on a 3 T MR unit and their respective lymph node signal intensities (SI), signal-to-noise (SNR) and contrast-to-noise (CNR) were determined on pre- and post-contrast 3D T(2)-weighted turbo spin echo (TSE) images. Based on histology and/or localization, USPIO-uptake-related SI/SNR decrease of benign vs malignant and pelvic vs inguinal lymph nodes was compared. Out of 2182 resected lymph nodes 366 were selected for MRI post-processing. Benign pelvic lymph nodes showed a significantly higher SI/SNR decrease compared with malignant nodes (p < 0.0001). Inguinal lymph nodes in comparison to pelvic lymph nodes presented a reduced SI/SNR decrease (p < 0.0001). CNR did not differ significantly between benign and malignant lymph nodes. The receiver operating curve analysis yielded an area under the curve of 0.96, and the point with optimal accuracy was found at a threshold value of 13.5% SNR decrease. Overlap of SI and SNR changes between benign and malignant lymph nodes were attributed to partial voluming, lipomatosis, histiocytosis or focal lymphoreticular hyperplasia. USPIO-enhanced MRI improves the diagnostic ability of lymph node staging in normal-sized lymph nodes, although some overlap of SI/SNR-changes remained. Quantification of USPIO-dependent SNR decrease will enable the validation of this promising technique with the final goal of improving and individualizing patient care.
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http://dx.doi.org/10.1002/cmmi.503DOI Listing
December 2012

Plexiform hybrid granular cell tumor/perineurioma: a novel variant of benign peripheral nerve sheath tumor with divergent differentiation.

Pathol Res Pract 2012 May 10;208(5):310-4. Epub 2012 Apr 10.

Department of Clinical Histopathology, Institute of Pathology, University of Bern, Switzerland.

The descriptive term hybrid peripheral nerve sheath tumor refers to any neoplasm of the neurilemmal apparatus composed of more than one pathologically defined tumoral equivalent derived from its constituent cells. Within this uncommon nosological category, participation of granular cell tumor - a neoplasm of modified Schwann cells - has been reported only exceptionally. We describe a hitherto not documented variant composed of an organoid mixture of granular cell tumor and perineurioma with plexiform growth. A solitary subcutaneous nodule of 1.5 cm diameter was excised from the right ring finger of a 19-year-old female with no antecedents of neurofibromatosis or relevant trauma. Histology revealed a monotonous, yet cytologically dimorphic proliferation of classical granular cells intermingled with flattened, inconspicuous perineurial cells. Immunohistochemical double labeling detected expression of S100 protein in the former and of EMA and GLUT-1 in the latter. While the respective staining patterns for S100 protein and EMA or GLUT-1 tended to be mutually exclusive, a minority of cells exhibited transitional granular cell/perineurial immunophenotype. Electron microscopy permitted direct visualization of a plethora of lysosomes in the granular cell moiety, and of pinocytotic vesicles and tight junctions in perineurial cells. Intratumoral axons were not detected. Expanding intraneurally, the lesion showed discrete encapsulation by the local perineurium, and resulted in plexiform growth. The MIB-1 labeling index averaged 1%. We interpret our findings as supporting evidence for the dual cell lineage to have arisen through metaplasia, with the tumor's dynamics probably having been driven by the granular cell component.
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http://dx.doi.org/10.1016/j.prp.2012.02.014DOI Listing
May 2012

High CD10 expression predicts favorable outcome in surgically treated lymph node-positive bladder cancer patients.

Hum Pathol 2012 Feb 10;43(2):269-75. Epub 2011 Aug 10.

Institute of Pathology, University of Bern, CH-3010 Bern, Switzerland.

CD10 predicts survival in different cancers. The prognostic significance in bladder cancer still has to be documented. One hundred fifty lymph node-positive bladder cancer patients were treated by cystectomy and standardized pelvic lymphadenectomy in curative intent. CD10 expression was evaluated in tissue microarrays (TMAs) constructed from histopathological normal urothelium, primary tumor (tumor center and invasion front), and corresponding lymph node metastases and correlated with tumor characteristics (stage, extracapsular extension, number, and total diameter of metastases) and survival. CD10 expression was successively lost from normal urothelium to primary tumor to metastases (P < .05) and decreased from the tumor center to the invasion front (P < .002). High CD10 expression in tumor center or invasion front (P < .05) but not in the metastases predicted favorable outcome; the prognostic information in the tumor center was independent from tumor stage and lymph node parameters. High CD10 expression level was not associated with specific tumor characteristics. A well-defined sampling strategy for TMAs allows detection of specific biomarker expression patterns and may generate prognostic information inherent in particular tumor areas. The favorable outcome in bladder cancer patients with high CD10 expression might suggest a tumor suppressive function of CD10.
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http://dx.doi.org/10.1016/j.humpath.2011.04.030DOI Listing
February 2012

MMP-2 and MMP-9 in lymph-node-positive bladder cancer.

J Clin Pathol 2011 Dec 21;64(12):1078-82. Epub 2011 Jun 21.

Institute of Pathology, University of Bern, Bern, Switzerland.

Background: Matrix metalloproteinases (MMP), particularly MMP-2 and MMP-9, participate in tumour progression and metastasis in various cancers. Their significance in urothelial cancer of the bladder (UCB) is unclear. Expression analysis of MMP-2 and MMP-9 in tissue microarrays (TMA) constructed of corresponding samples from histopathological normal urothelium, tumour centre and invasion front of primary tumours and lymph-node (LN) metastases might help to elucidate their relevance in UCB.

Method: MMP-2 and MMP-9 expression was evaluated in TMA of 150 surgically treated LN-positive UCB patients. Biomarker expression was correlated with tumour characteristics (primary tumour and LN stage, number, total diameter and extracapsular extension of LN metastases) and overall survival.

Results: While there was a significant increase in MMP-9 expression from normal urothelium over primary tumours to metastases (median scores: 20, 50, 65; p<0.005), no such trend was observed in MMP-2 (median scores: 5, 22, 10; p<0.005). A comparison of expression in the tumour centre and the invasion front showed no difference in both MMP. No association between expression and histopathological tumour characteristics was identified. There was a non-significant trend for a more favourable outcome for patients with high MMP-2 expression in primary tumours.

Conclusion: In LN-positive UCB, MMP-2 and MMP-9 expression was not increased at the invasion front, suggesting an infiltration strategy independent of MMP-2 and MMP-9 activity. Larger series are needed to detect a potential significant trend for favourable outcome in cancers with high MMP-2 expression.
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http://dx.doi.org/10.1136/jclinpath-2011-200153DOI Listing
December 2011

Her2 amplification is significantly more frequent in lymph node metastases from urothelial bladder cancer than in the primary tumours.

Eur Urol 2011 Aug 25;60(2):350-7. Epub 2011 May 25.

Institute of Pathology, University of Bern, Bern, Switzerland.

Background: Her2, an alias for the protein of v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian), might be an attractive therapeutic target in metastasising bladder cancer. Genotype and phenotype of primary tumours and their metastases may differ.

Objectives: Determine Her2 status in both tumour components to better assess the potential of anti-Her2 therapies.

Design, Setting, And Participants: Histologic examination revealed lymph node metastases in 150 patients with urothelial bladder cancer clinically staged as N0M0. A tissue microarray was constructed with four tumour samples per patient: two from the primary tumour and two from nodal metastases. Her2 status was determined at the gene level by fluorescence in situ hybridisation (FISH) and at the protein level by immunohistochemistry (IHC).

Interventions: All patients underwent cystectomy and standardised extended lymphadenectomy.

Measurements: Overall survival was assessed according to HER2 gene status and protein expression in primary bladder cancers and lymph node metastases.

Results And Limitations: Her2 amplification was significantly more frequent in lymph node metastases (15.3%) than in matched primary bladder cancers (8.7%; p = 0.003). Her2 amplification in primary tumours was highly preserved in the corresponding metastases as indicated by only one amplified primary tumour without amplification of the metastasis. There was a high concordance in HER2 FISH results between both samples from the primary tumour (κ = 0.853) and from the metastases (κ = 0.930). IHC results were less concordant (κ=0.539 and 0.830). FISH and IHC results were poorly correlated in primary tumours (κ = 0.566) and metastases (κ = 0.673). While Her2 amplification in the primary tumour significantly predicted poor outcome (p = 0.044), IHC-based survival prediction was unsuccessful.

Conclusions: Her2 amplification in metastasising bladder cancer is relatively frequent, is homogeneous in each tumour component, and predicts early death. This suggests a high potential for anti-Her2 therapies. For patient selection, FISH might be more accurate than IHC.
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http://dx.doi.org/10.1016/j.eururo.2011.05.035DOI Listing
August 2011

Concomitant vascular GRP-receptor and VEGF-receptor expression in human tumors: molecular basis for dual targeting of tumoral vasculature.

Peptides 2011 Jul 13;32(7):1457-62. Epub 2011 May 13.

Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Bern, PO Box 62, Murtenstrasse 31, CH-3010 Bern, Switzerland.

Gastrin-releasing peptide (GRP) and GRP receptors (GRPR) play a role in tumor angiogenesis. Recently, GRPR were found to be frequently expressed in the vasculature of a large variety of human cancers. Here, we characterize these GRPR by comparing the vascular GRPR expression and localization in a selection of human cancers with that of an established biological marker of neoangiogenesis, the vascular endothelial growth factor (VEGF) receptor. In vitro quantitative receptor autoradiography was performed in parallel for GRPR and VEGF receptors (VEGFR) in 32 human tumors of various origins, using ¹²⁵I-Tyr-bombesin and ¹²⁵I-VEGF₁₆₅ as radioligands, respectively. Moreover, VEGFR-2 was evaluated immunohistochemically. All tumors expressed GRPR and VEGFR in their vascular system. VEGFR were expressed in the endothelium in the majority of the vessels. GRPR were expressed in a subpopulation of vessels, preferably in their muscular coat. The vessels expressing GRPR were all VEGFR-positive whereas the VEGFR-expressing vessels were not all GRPR-positive. GRPR expressing vessels were found immunohistochemically to co-express VEGFR-2. Remarkably, the density of vascular GRPR was much higher than that of VEGFR. The concomitant expression of GRPR with VEGFR appears to be a frequent phenomenon in many human cancers. The GRPR, localized and expressed in extremely high density in a subgroup of vessels, may function as target for antiangiogenic tumor therapy or angiodestructive targeted radiotherapy with radiolabeled bombesin analogs alone, or preferably together with VEGFR targeted therapy.
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http://dx.doi.org/10.1016/j.peptides.2011.05.007DOI Listing
July 2011

High CD10 expression in lymph node metastases from surgically treated prostate cancer independently predicts early death.

Virchows Arch 2011 Jun 3;458(6):741-8. Epub 2011 May 3.

Institute of Pathology, University of Bern, Bern, Switzerland.

Patients with nodal positive prostate cancers are an important cohort with poorly defined risk factors. CD10 is a cell surface metallopeptidase that has been suggested to play a role in prostate cancer progression. CD10 expression was evaluated in 119 nodal positive prostate cancer patients using tissue microarrays constructed from primary tumors and lymph node metastases. All patients underwent radical prostatectomy and standardized extended lymphadenectomy. They had no neoadjuvant therapy and received deferred androgen deprivation. In the primary tumor, high CD10 expression was significantly associated with earlier death from disease when compared with low CD10 expression (5-year survival 73.7% vs. 91.8%; p = 0.043). In the metastases, a high CD10 expression was significantly associated with larger total size of metastases (median 11.4 vs. 6.5 mm; p = 0.015), earlier death of disease (5-year survival 71.5% vs. 87.3%; p = 0.017), and death of any cause (5-year survival 70.0% vs. 87.2%; p = 0.001) when compared with low CD10 expression. CD10 expression in the metastases added independent prognostic information for overall survival (p = 0.029) after adjustment for Gleason score of the primary tumor, nodal tumor burden, and resection margins. In conclusion, a high CD10 expression in prostate cancer predicts early death. This information is inherent in the primary tumors and in the lymph node metastases and might help to personalize patient management.
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http://dx.doi.org/10.1007/s00428-011-1084-zDOI Listing
June 2011

High-level cytoplasmic cyclin D1 expression in lymph node metastases from prostate cancer independently predicts early biochemical failure and death in surgically treated patients.

Histopathology 2011 Apr 25;58(5):781-9. Epub 2011 Mar 25.

Institute of Pathology, University of Bern, Bern, Switzerland.

Aims: To test the prognostic significance of cyclin D1 in nodal-positive prostate cancer.

Methods And Results: Nuclear and cytoplasmic cyclin D1 expression was evaluated in 119 nodal-positive prostate cancer patients undergoing radical prostatectomy and extended lymphadenectomy. Cyclin D1 was correlated with various tumour features and biochemical recurrence-free survival (bRFS), disease-specific survival (DSS) and overall survival (OS). In the metastases, high-level cytoplasmic cyclin D1 expression independently predicted poor outcome (5-year bRFS, 12.5% versus 26.4%, P = 0.006; 5-year DSS, 56.3% versus 80.7%, P = 0.007; 5-year OS, 56.3% versus 78.7%, P = 0.011). These patients had a 2.62-fold elevated risk of dying from prostate cancer as compared with patients with low-level cytoplasmic cyclin D1 expression (P = 0.024). All other subcellular compartments of cyclin D1 expression in primary tumours and metastases were prognostically non-significant.

Conclusions: The subcellular location of cyclin D1 expression in prostate cancer is linked to specific clinical courses. Survival stratification according to biomarker expression in metastases indicates an important role for tumour sampling from these tissues.
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http://dx.doi.org/10.1111/j.1365-2559.2011.03800.xDOI Listing
April 2011

Extracapsular extension but not the tumour burden of lymph node metastases is an independent adverse risk factor in lymph node-positive bladder cancer.

Histopathology 2011 Mar 14;58(4):571-8. Epub 2011 Mar 14.

Department of Pathology, University of Bern, Bern, Switzerland.

Aims: To evaluate risk factors in lymph node-positive bladder cancer.

Methods And Results: Lymph node-positive bladder cancer patients (n=162), preoperatively staged N0M0, underwent cystectomy and standardized extended lymphadenectomy. Five-year overall survival of the cohort was 33%. In univariate analysis, tumour stage (P<0.006), extracapsular extension of lymph node metastases (P<0.001), total diameter of metastases (P<0.04) and lymph node stage (P<0.03) were significantly correlated with overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS). On multivariate analysis, only extracapsular extension (OS, P<0.002; DSS, P<0.02; RFS, P=0.058) and primary tumour stage (OS, P=0.058; DSS, P<0.02; RFS, P<0.02) added independent prognostic information. Extracapsular extension of lymph node metastases did not correlate with a specific recurrence pattern; patients with organ-confined tumours (pT1/2) never had pelvic relapse.

Conclusions: Extracapsular extension of lymph node metastases but not lymph node tumour burden adds independent prognostic information in lymph node-positive bladder cancer. These biological differences in lymph node-positive bladder cancer are not reflected in the sixth, and challenge future, TNM classification.
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http://dx.doi.org/10.1111/j.1365-2559.2011.03778.xDOI Listing
March 2011

Androgen receptors are differentially expressed in Gleason patterns of prostate cancer and down-regulated in matched lymph node metastases.

Prostate 2011 Apr 28;71(5):453-60. Epub 2010 Sep 28.

Institute of Pathology, University of Bern, Bern, Switzerland.

Background: Androgen receptor (AR) expression profile in the different Gleason patterns (GP) of primary prostate cancers and nodal metastases is unknown. More information about AR distribution is needed to optimize evaluation methods and to better understand the role of AR in development and progression of prostate cancer.

Methods: A tissue microarray was constructed from 119 hormone-naïve nodal positive, surgically treated prostate cancers containing tissues from all GP present in every primary tumor and the matched metastases. ARs were evaluated immunohistochemically and an expression score (intensity × percentage of positive cells) was assigned for each tissue spot.

Results: ARs were up-regulated in primary tumors compared to normal glands and significantly different expressed in the GP (mean AR scores: GP 3=128.7, GP 4=159.1, GP 5=123.5; P=0.016). A similar expression profile was observed in metastases, however, on significantly (P<0.001) lower level (mean AR scores: GP 3=70.5, GP 4=90.4, GP 5=71.7; P=0.114). High AR expression in metastases was associated with larger total size of metastases (P=0.008). All other correlations of AR expression in primary tumors and metastases with quantitative (age, prostate cancer volume, number of metastases) or categorical (tumor stage, Gleason score of the primary tumor and metastases) tumor characteristics or with survival were insignificant.

Conclusion: ARs are differentially expressed in GP what should be considered in prognostic models which include AR. In nodal metastases, ARs are significantly down-regulated suggesting decreased dependence on androgens already under hormone-naïve conditions. AR expression level is not prognostic in nodal positive disease.
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http://dx.doi.org/10.1002/pros.21259DOI Listing
April 2011

Pelvic lymph nodes: distribution and nodal tumour burden of urothelial bladder cancer.

J Clin Pathol 2010 Jun 3;63(6):504-7. Epub 2010 Apr 3.

Department of Pathology, University of Bern, Switzerland.

Aims: To evaluate the number of lymph nodes and the lymph node tumour burden in different anatomical pelvic regions to better asses the impact of variations in the extent of lymphadenectomy on reported LN parameters and pelvic tumour clearance.

Methods: 162 patients with lymph-node-positive urothelial carcinoma of the bladder were treated by cystectomy and extended pelvic lymphadenectomy. Various lymph node parameters were determined separately for the three pelvic regions (external iliac, obturator and internal iliac).

Results: Of 4,080 evaluated lymph nodes (median 25 per patient, range 8-55) 39%, 35% and 26% (p<0.05) were found in the external iliac, obturator and internal iliac region, respectively. The distribution of the 625 lymph node metastases (median two per patient, range 1-35) was not significantly different between the regions (external iliac 33%, obturator 38%, internal iliac 29%). However, the median diameter of largest metastasis and total diameter of all metastases were smallest in the internal iliac region (external iliac 0.85 cm, 1.1 cm; obturator 0.8 cm, 1.0 cm; internal iliac 0.6 cm, 0.8 cm; p<0.03, p<0.05; for median diameter of largest metastasis and total diameter of all metastases, respectively). Metastases in only one region were found in 33% of patients (external iliac 13%, obturator 10%, internal iliac 10%); these three groups showed no significant difference in survival. No difference was detected in lymph node parameters between genders.

Conclusions: Lymph node counts and retrieval of metastases depends on the extent of pelvic lymphadenectomy. Dissection not including the internal iliac region misses 26% of all pelvic lymph nodes, 29% of metastases, and understages a substantial number of patients as pN0 (10%).
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http://dx.doi.org/10.1136/jcp.2009.075077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981017PMC
June 2010

Local resection of metanephric adenoma with kidney preservation.

J Pediatr Surg 2009 Aug;44(8):E21-3

Department for Paediatric Surgery, Inselspital, University of Berne, 3010 Berne, Switzerland.

Metanephric adenoma (MA) is a rare renal neoplasm present at any age. Usually, a total nephrectomy is performed. Some successful partial nephrectomies or selective tumor resections are described in adults but not in children. We present here the case of a 15-month-old boy, the youngest patient yet to be reported with an MA. We performed a local resection of the tumor. Today, 2 1/2 years after surgery, we can document a favorable clinical course and normal ultrasound findings in the follow-up of the operated kidney. This case gives further evidence that organ-sparing resection of MA is feasible in selected cases. A close clinical and ultrasound follow-up is mandatory for this approach.
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http://dx.doi.org/10.1016/j.jpedsurg.2009.05.028DOI Listing
August 2009