Laurent Doucet

TARGETED SCREENING FOR PROSTATE CANCER IN HIGH RISK FAMILIES: EARLY ONSET IS A SIGNIFICANT RISK FACTOR FOR DISEASE IN FIRST DEGREE RELATIVES

PURPOSE Targeted screening for prostate cancer in high risk families is generally suggested by ages 40 to 45 years in first degree relatives. We support this concept by reporting higher risk and earlier onset of the disease in these families. MATERIALS AND METHODS We proposed serum prostate specific antigen (PSA) testing in 40 to 70-year-old first degree relatives of 435 patients with prostate cancer treated between July 1994 and June 1997. A previous systematic genealogical analysis allowed us to define the familial prostate cancer status of each patient as sporadic or familial. RESULTS Of the 747 potential candidates 442 (59%) accepted into the study have been screened, including 240 who were 40 to 49 years old (mean age 44.8) and 202 who were 50 to 70 years old (mean age 57.4). Two of the 240 subjects (0.8%) had PSA greater than 4 ng./ml. in the 40 to 49-year-old group. Prostate biopsies were negative in 1 relative but diagnostic for prostate cancer in the other. In the 50 to 70-year-old group 25 of 202 subjects (12.4%) had a PSA of greater than 4 ng./ml. Prostate cancer was diagnosed in 9 individuals (4.5%), 9 had negative biopsy results, 1 died before biopsy and 6 refused biopsy. The proportion of relatives with PSA greater than 4 ng./ml. and prostate cancer detection was not different according to familial status (sporadic or familial) but it was significantly higher in first degree relatives with early onset prostate cancer in the family at ages younger than 65 years (p = 0.037 and 0.012, respectively). CONCLUSIONS Our results emphasize the usefulness of PSA screening in high risk families, including those without obvious hereditary features. Furthermore, early onset prostate cancer is a significant risk factor for prostate cancer in first degree relatives.

BCAR1 expression improves prediction of biochemical reccurence after radical prostatectomy

Because prostate cancer exhibits a great variability in clinical outcome, biomarkers that can be used in daily practice are needed to better stratify patients into prognostic groups. Since steroid hormones play a central role in the development and progression of prostate cancer, we aimed to analyze in a matched nested case–control study the value of molecules involved in steroid signaling, to predict recurrence after radical prostatectomy, independently from standard prognostic tools.

Three Rounds of External Quality Assessment in France to Evaluate the Performance of 28 Platforms for Multiparametric Molecular Testing in Metastatic Colorectal and Non-Small Cell Lung Cancer

Personalized medicine has gained increasing importance in clinical oncology, and several clinically important biomarkers are implemented in routine practice. In an effort to guarantee high quality of molecular testing in France, three subsequent external quality assessment rounds were organized at the initiative of the National Cancer Institute between 2012 and 2014. The schemes included clinically relevant biomarkers for metastatic colorectal (KRAS, NRAS, BRAF, PIK3CA, microsatellite instability) and non-small cell lung cancer (EGFR, KRAS, BRAF, PIK3CA, ERBB2), and they represent the first multigene/multicancer studies throughout Europe. In total, 56 laboratories coordinated by 28 regional molecular centers participated in the schemes. Laboratories received formalin-fixed, paraffin-embedded samples and were asked to use routine methods for molecular testing to predict patient response to targeted therapies. They were encouraged to return results within 14 calendar days after sample receipt. Both genotyping and reporting were evaluated separately. During the three external quality assessment rounds, mean genotype scores were all above the preset standard of 90% for all biomarkers. Participants were mainly challenged in case of rare insertions or deletions. Assessment of the written reports showed substantial progress between the external quality assessment schemes on multiple criteria. Several essential elements such as the clinical interpretation of test results and the reason for testing still require improvement by continued external quality assessment education.

Prevalence and topography of intestinal metaplasia in columnar lined esophagus.

OBJECTIVES Barretts mucosa is considered as a mosaic of three epithelial types but little is known about the topography of intestinal metaplasia in columnar lined esophagus. The aims of the study were to determine the prevalence of intestinal metaplasia within long and short segments of columnar lined esophagus and to analyze the distribution of the intestinal metaplasia within long segments of Barretts esophagus. PATIENTS AND METHODS The study was performed on the initial endoscopy carried out among 112 patients enrolled in an endoscopic surveillance program. Seventy-two patients with columnar mucosa extending more than 3 cm into the esophagus (group I) and 40 patients with a short segment of columnar mucosa (group II) had multiple biopsies according to a standardized protocol. 1163 biopsies were analyzed on the whole: 949 biopsies in group I and 214 biopsies in group II. RESULTS Intestinal metaplasia was identified among 650 (68.5%) and 50 (23.4%) biopsies in groups I and II respectively (P<10-7). The proportion of biopsies with foci of intestinal metaplasia increased significantly with the length of the columnar mucosa. The diagnosis of Barretts esophagus was confirmed in 100% of the patients in group I and in 45% of the patients in group II. In long segments of Barretts esophagus, intestinal metaplasia was more frequently observed in the 2 upper thirds of the columnar mucosa that in the lower third (P<10-7). Detailed mapping of the distribution of epithelial types within the columnar lined esophagus identified three patterns of distribution of intestinal metaplasia within long segments of Barretts esophagus: unifocal, multifocal and diffuse, in 5%, 56% and 39% of the patients respectively. Dysplasia was present in 15% of patients with long segments of Barretts esophagus and 11% of patients with short segments (NS). CONCLUSION The distribution of intestinal metaplasia within columnar lined esophagus is heterogeneous and three distinct patterns can be identified: unifocal, multifocal and diffuse. Considering the risk of sampling error, the current recommendations concerning the biopsy protocols are mandatory until the validation of new techniques such as chromoendoscopy or magnifying endoscopy.

Mismatch repair–deficient colorectal cancer: a model of immunogenic and immune cell–rich tumor despite nonsignificant programmed cell death ligand-1 expression in tumor cells

Mismatch repair-deficient (dMMR) colorectal cancers (CRCs) are good responders to anti-programmed cell death ligand-1 (PD-L1) immunotherapy, but the value of PD-L1 testing remains unclear. We studied PD-L1 expression and the tumor immune microenvironment in dMMR CRC as a model of good responders to immunotherapy. We examined 35 dMMR and 34 mismatch repair-proficient (pMMR) CRCs using immune cell markers (CD3, CD4, CD8, CD20, CD68, and FOXP3) as well as programmed cell death receptor-1 (PD-1) and PD-L1 immunohistochemistry staining in whole tumor specimens and tissue microarray slides to compare 4 PD-L1 immunohistochemistry clones (SP142, E1L3N, 22C3, and 28.8). We observed no significant difference in PD-L1 expression between dMMR and pMMR CRCs. Only 2 dMMR tumors had membranous PD-L1 staining. Expression of PD-L1 was greater in stromal immune cells of dMMR CRC, which also contained more numerous intraepithelial (CD3+, CD8+, FOXP3+, and PD-1+) and stromal (CD8+, PD-1+) lymphocytes than did pMMR tumors. Immune cell quantification discriminated better between dMMR and pMMR tumors than did PD-L1 expression. Tumor heterogeneity and variations in PD-L1 expression were noted with different antibodies, especially for PD-L1+ immune cells, which were more numerous at the invasion margin. Given the poor correlation with mismatch repair status and technical limitations, the value of PD-L1 testing to accompany the development of anti-PD-1/PD-L1 immunotherapy remains unclear. Further clinical trials are required to determine which parameters are valuable predictive biomarkers of the response to immunotherapy among mismatch repair status, PD-L1 expression, and immune cell quantification in CRC.

The combination of targeted and systematic prostate biopsies is the best protocol for the detection of clinically significant prostate cancer

Abstract Objective: Compared with standard systematic transrectal ultrasound (TRUS)-guided biopsies (SBx), targeted biopsies (TBx) using magnetic resonance imaging (MRI)/TRUS fusion could increase the detection of clinically significant prostate cancer (PCa-s) and reduce non-significant PCa (PCa-ns). This study aimed to compare the performance of the two approaches. Materials and methods: A prospective, single-center study was conducted on all consecutive patients with PCa suspicion who underwent prebiopsy multiparametric MRI (mpMRI) using the Prostate Imaging Reporting and Data System (PI-RADS). All patients underwent mpMRI/TRUS fusion TBx (two to four cores/target) using UroStation™ (Koelis, Grenoble, France) and SBx (10–12 cores) during the same session. PCa-s was defined as a maximal positive core length ≥4 mm or Gleason score ≥7. Results: The study included 191 patients (at least one suspicious lesion: PI-RADS ≥3). PCa was detected in 55.5% (106/191) of the cases. The overall PCa detection rate and the PCa-s detection rate were not significantly higher in TBx alone versus SBx (44.5% vs 46.1%, p = .7, and 38.2% vs 33.5%, p = .2, respectively). Combined TBx and SBx diagnosed significantly more PCa-s than SBx alone (45% vs 33.5%, p = .02). PCa-s was detected only by TBx in 12% of cases (23/191) and only by SBx in 7.3% (14/191). Gleason score was upgraded by TBx in 16.8% (32/191) and by SBx in 13.6% (26/191) of patients (p = .4). Conclusions: The combination of TBx and SBx achieved the best results for the detection and prognosis of PCa-s. The use of SBx alone would have missed the detection of PCa-s in 12% of patients.

Metabolic syndrome and low high-density lipoprotein cholesterol are associated with adverse pathological features in patients with prostate cancer treated by radical prostatectomy

BACKGROUND Previous studies have suggested a link between metabolic syndrome (MetS) and prostate cancer (PCa). In the present study, we aimed to assess the association between MetS and markers of PCa aggressiveness on radical prostatectomy (RP). METHODS All patients consecutively treated for PCa by RP in 6 academic institutions between August 2013 and July 2016 were included. MetS was defined as at least 3 of 5 components (obesity, elevated blood pressure, diabetes, low high-density lipoprotein (HDL)-cholesterol, and hypertriglyceridemia). Demographic, biological, and clinical parameters were prospectively collected, including: age, biopsy results, preoperative serum prostate-specific antigen, surgical procedure, and pathological data of RP specimen. Locally advanced disease was defined as a pT-stage ≥3. International Society of Urological Pathology (ISUP) groups were used for pathological grading. Qualitative and quantitative variables were compared using chi-square and Wilcoxon tests; logistic regression analyses assessed the association of MetS and its components with pathological data. Statistical significance was defined as a P<0.05. RESULTS Among 567 men, 249 (44%) had MetS. In a multivariate model including preoperative prostate-specific antigen, biopsy ISUP-score, clinical T-stage, age, and ethnicity: we found that MetS was an independent risk factor for positive margins, and ISUP group ≥4 on the RP specimen (odds ratio [OR] = 1.5; 95% CI: 1.1-2.3; P = 0.035; OR = 2.0; 95% CI: 1.1-4.0; P = 0.044, respectively). In addition, low HDL-cholesterol level was associated with locally advanced PCa (OR = 1.6; 95% CI: 1.1-2.4; P = 0.024). Risks of adverse pathological features increased with the number of MetS components: having ≥ 4 MetS components was significantly associated with higher risk of ISUP group ≥ 4 and higher risk of positive margins (OR = 1.9; 95% CI: 1.1-3.3; P = 0.017; OR = 1.8; 95% CI: 1.1-2.8; P = 0.007, respectively). CONCLUSION MetS was an independent predictive factor for higher ISUP group and positive margins at RP. Low HDL-cholesterol alone, and having 4 and more MetS components were also associated with higher risk of adverse pathological features.

PD07-11 PROSTATE CANCER SCREENING IN HIGH RISK FAMILIES. A EIGHT-YEAR PROSPECTIVE PROGRAM IN YOUNG FIRST DEGREE RELATIVES AGED 40-49.

mutation (8%), and 3/62 patients with BRCA2 (5%). Overall,16/24 patients (67%) were surgically treated for their cancer. CONCLUSIONS: Malignancy rates in male BRCA mutation carriers are substantially higher than those reported for the general population in corresponding age groups. Prostate cancer is the most prevalent cancer apparent in up to 8% of patients at a median age of 50 years. Unlike other reports, prostate cancer was prevalent among BRCA1 carriers and not restricted to BRCA2.

Upfront immunohistochemistry improves specificity of Helicobacter pylori diagnosis. A French pathology laboratory point of view

There is no consensus about the histopathologic methods to detect Helicobacter pylori in gastric biopsies to date. We aimed to question about the value of upfront anti‐H. pylori immunohistochemistry in this field.

Cystic Epithelial Tumors of the Prostate: One Case Supporting a Continuous Spectrum From Cystadenoma to Cystadenocarcinoma With Ductal Features.

To the Editor: Paner et al reported a very interesting series of prostatic giant cystic tumors including 3 giant cystadenocarcinomas and 1 giant multilocular cystadenoma. These tumors are very rare, and, as mentioned by Paner and colleagues, the clinicopathologic spectrum of cystic epithelial tumors of the prostate remains to be defined. We intend to report an exceptional and, to our knowledge, first case of a prostatic giant cystic tumor consisting of a cystadenocarcinoma associated with a cystadenoma. A 50-year-old man presented with acute abdominal pain leading to the discovery of a large multicystic mass in the pelvis. Multiple surgical biopsies were performed. Pathologic examination of the biopsies showed round to ovoid dilated glandular structures with a flattened cell layer or with a papillary pseudohyperplastic to a tall columnar and stratified epithelial cell layer with some mitosis figures and prominent nucleoli. A prostatic primary tumor was diagnosed because of a positive prostatic-specific antigen (PSA) immunohistochemistry, and a mesothelial multicystic proliferation was ruled out. The glands were p63 negative and p504s positive. Those features were of a small ductal prostatic adenocarcinoma component in a prostatic and extraprostatic cystic tumor. The PSA serum level was 4 ng/ mL at the time of this first sampling. Because of the recurrence of pain and dysuria 16 months after the first surgical biopsies, a new pelvic computed tomography was performed and revealed a voluminous mass measuring 13 9 14 cm involving the perirectal and presacral area, reaching the sacral nerve roots, surrounding the rectum and the sigmoid and pushing the bladder-prostate complex to the anterior and the right. The PSA level was elevated at 14.72 ng/mL. New samples of the tumor and of the surrounding prostate were obtained by transurethral bladder resection and by transrectal biopsies. The histologic examination of the biopsies did not reveal any intraprostatic tumor but argued for a tumor developed in the periprostatic tissue. The pattern of this tumor was multicystic, and the cysts were lined by a flattened monostratified epithelium without mitosis or prominent nucleoli. These glands were p63 positive and p504s negative. These data were in favor of a benign cystic prostatic tumor consisting in a cystadenoma. However, the transurethral bladder resection samples presented some foci of prostatic ductal adenocarcinoma as described previously. Finally, the patient underwent a total pelvic exenteration 17 months after initial surgical biopsies (ie, anterior and posterior pelvectomy with colo-anal anastomosis and Bricker urinary diversion). The piece measured 16 10.5 24cm and included the urinary bladder, the prostate, the seminal vesicles, and a 24-cm-long colorectal segment (Fig. 1). An anterior-posterior section revealed a 9.5 9cm honeycomb tumor with cysts ranging from 0.2 to 1.7 cm developed from the posterior wall of the urinary bladder and posterior part of the prostatic base. This tumor extended through the perirectal adipose tissue with important hemorrhagic and necrotic changes. Seminal vesicles appeared well preserved but elongated. Several enlarged lymph nodes were identified adjacent to the urinary bladder and the rectum. Histologically, the samples from the junction between the urinary bladder and the prostate and from the posterior wall of the bladder presented the previously described features of a prostatic cystadenoma with a p63-positive and p504s-negative immunohistochemistry (Figs. 2A, C, E, G). In the retrovesical part of the tumor, the epithelium lining the glands showed various levels of atypia from a single layer of cuboid nonatypical prostatic cells with neither mitotic activity nor evident nucleoli, with columnar cells drawing papillae and glandular tubules that were p63 negative and p504s positive. These features were consistent with a cystadenocarcinoma with focal ductal features (Figs. 2A, B, D, F). No perinervous infiltration or lymphovascular invasion was noted. The tumor infiltrated the perirectal adipose tissue reaching the muscularis propria without destructing it. Seminal vesicles were