Critical evaluation of artificial intelligence as a digital twin of pathologists for prostate cancer pathology.

Prostate cancer pathology plays a crucial role in clinical management but is time-consuming. Artificial intelligence (AI) shows promise in detecting prostate cancer and grading patterns. We tested an AI-based digital twin of a pathologist, vPatho, on 2603 histological images of prostate tissue stained with hematoxylin and eosin. We analyzed various factors influencing tumor grade discordance between the vPatho system and six human pathologists. Our results demonstrated that vPatho achieved comparable performance in prostate cancer detection and tumor volume estimation, as reported in the literature. The concordance levels between vPatho and human pathologists were examined. Notably, moderate to substantial agreement was observed in identifying complementary histological features such as ductal, cribriform, nerve, blood vessel, and lymphocyte infiltration. However, concordance in tumor grading decreased when applied to prostatectomy specimens (κ = 0.44) compared to biopsy cores (κ = 0.70). Adjusting the decision threshold for the secondary Gleason pattern from 5 to 10% improved the concordance level between pathologists and vPatho for tumor grading on prostatectomy specimens (κ from 0.44 to 0.64). Potential causes of grade discordance included the vertical extent of tumors toward the prostate boundary and the proportions of slides with prostate cancer. Gleason pattern 4 was particularly associated with this population. Notably, the grade according to vPatho was not specific to any of the six pathologists involved in routine clinical grading. In conclusion, our study highlights the potential utility of AI in developing a digital twin for a pathologist. This approach can help uncover limitations in AI adoption and the practical application of the current grading system for prostate cancer pathology.

Prevalence of High-Risk HPV Subtypes and Efficacy of the HPV Vaccine in Preventing Cervical Epithelial Lesions: Survey and Insights from a German Study.

BACKGROUND: Historically, cervical cytology has been the standard method for detecting dysplastic cervical changes. However, extensive research has established that human papillomavirus (HPV) infection is a primary cause of these changes, necessitating a shift in screening and preventive strategies towards the molecular detection of high-risk HPV subtypes. To combat HPV infection, prophylactic vaccines have been developed, including the nonavalent, quadrivalent, and bivalent vaccines. An essential criterion for an effective HPV vaccine is to provide comprehensive coverage against the most prevalent high-risk HPV types associated with cervical cancer, ensuring optimal efficacy in preventing cervical lesions. Long-term protection against these types is crucial for effective prevention strategies; Material and Methods: A cohort of 210,510 women's samples was included in the analysis conducted within one year of implementing a screening program in Germany. The screening program involved the molecular detection of high-risk HPV subtypes, targeting specific age groups. The cohort comprised 63,710 women below 35 years of age and 146,800 women aged 35 years and above. The selection of high-risk HPV subtypes followed the guidelines provided by Becton-Dickinson. This study focused exclusively on cases with a documented history of vaccination, which were categorized into two main groups: Group I consisted of vaccinated individuals under 35 years old (12,765 cases), while Group II comprised vaccinated individuals aged 35 years and above (296 cases); Results: The HPV types HPV56/59/66 were found to be widely distributed across all age groups, with certain age groups exhibiting a higher incidence compared to HPV16 and HPV18. Similarly, HPV35/39/69, along with HPV31 and HPV45, were also observed to have a broad distribution among women. The incidence of high-grade squamous intraepithelial lesions (HSIL), including both CIN2 and CIN3, varied between 0.076% and 0.5% across all age groups, regardless of the individuals' vaccination status; Aim of the study: Our study provides valuable insights into the distribution, incidence, and prevalence of various high-risk HPV subtypes, including HPV56/59/66, HPV33/58, HPV35/39/68, and HPV45, in relation to precancerous cervical lesions. These subtypes are not adequately covered by the currently available HPV vaccines. Addressing the discrepancies between the prevalent HPV subtypes and existing vaccines is crucial in developing an ideal HPV vaccine that offers comprehensive protection. Tailoring screening programs and vaccination strategies to the local distribution of HPV subtypes is essential for effective prevention. By raising awareness and implementing targeted preventive measures, including vaccination, we can significantly reduce the incidence of precancerous and cancerous cervical lesions.

Distribution and incidence of atypical glandular lesions in cervical cytology focusing on the association with high-risk human papillomavirus subtypes.

Adenocarcinoma in situ (AIS) is considered a precursor of adenocarcinoma. Cervical adenocarcinoma has been associated with human papillomavirus (HPV), while other subtypes of AIS and endocervical adenocarcinoma have no precursor lesions and are not associated with HPV. Cervical cytology and HPV genotyping are important in the detection of these different subtypes. Notably, endometrial lesions and infiltration with secondary adenocarcinoma may lead to misdiagnosis of endocervical lesions. The aim of the present study was to avoid misdiagnosis of squamous cell changes and endometrial lesions as endocervical lesions in cervical screening. A total of 210,510 female cytological samples were analyzed between the beginning of January 2020 and the beginning of January 2021. The samples were processed for conventional cytological techniques, and for molecular detection and subtyping of high-risk HPV (HPV-HR) according to the advice and measurements of BD Biosciences (117,765 samples) and the PapilloCheck® HPV test (5,579 samples). The present study was carried out in Germany using the Munich classification III. II-g (Bethesda classification: atypical glandular cells not otherwise specified) was detected in 0.12% of cases under the age of 35 years. Another peak was noticed within the 41-60-years age group (0.11%). In the 41-50-years age group, a peak for II-e (Bethesda classification: Endometrial cells) (1.5%) was identified. An association was revealed between HPV16, HPV18 and HPV45 with cervical intraepithelial neoplasia III, AIS, endocervical adenocarcinoma and squamous cell carcinoma, in addition to other HPV-HR subtypes, such as HPV33/58, as well as 52, 56/59/66 in the different age groups. In patients aged <35 years, 0.03% of cases were vaccinated cases against HPV. In the 35-40-years age group, there was only one vaccinated case (0.0045%); in the 41-50-years age group, there were 11 vaccinated cases (0.031%); and in the 51-60-years age group, there was one vaccinated case (0.002%). No patients aged >60 years were vaccinated against HPV in the analyzed cohort. In conclusion, most cases of HPV-associated glandular dysplastic changes and neoplasia occurred in sexually active women aged between 35 and 60 years. In addition, endocervical adenocarcinoma may occur at any age with or without an HPV infection.

HPV-genotyping versus conventional cervical cytology as a screening method to detect dysplastic cervical epithelial changes.

The world health organization (WHO) called for coordinated global action in 2018 to eliminate cervical cancer, ensuring that every woman is screened and treated for precancerous lesions (World Health Organization. Cervical cancer: an NCD we can overcome. Geneva, 2018. http://www.who.int/director-general/speeches/detail/cervical-cancer-an-ncd-we-can-overcome.tegy ). Cytology-based screening has been for decades the conventional method of screening. Ancillary techniques have been added like immunocytochemistry with P16/Ki67 and L1-Capsid, but these methods require maintenance of complex infrastructure and highly trained personnel as well as relatively short screening intervals. HPV-based screening method to detect high-risk groups is a faster and automated method, which does not need morphologically highly qualified personal with high social costs. In the study, we have focused on the distribution of cervical lesions in the age groups with concordance of detection HPV high-risk subtypes (HPV-HR) and on the safety of the screening method. In the Institute for Pathology and Cytology-Schuettorf-Leer-Germany 146.800 samples of women from the age of and above 35 years were analyzed between the beginnings of 2020 until the beginning of 2021. 63.710 cases under 35 years old were analyzed. The samples were processed for both conventional cytological techniques and for molecular detection and subtyping of HPV-HR according to the advice and measurements of BD-manufacture. In this study, we have studied the histopathological results (Table 2) after colposcopy according to the age subgroups. The histopathological results were subdivided into no dysplasia, cervical intraepithelial neoplasia I (CIN I), cervical intraepithelial neoplasia II (CIN II), cervical intraepithelial neoplasia III (CIN III), squamous cell carcinoma (Sq.c.c), adenocarcinoma in situ (AIS), endometrial carcinoma, endocervical adenocarcinoma and cases without biopsy during the colposcopy (COB). We have used the muenchener classification III (Table 3) as a subgrading system for the cytological specimens. The frequency of detecting HPV56/59/66 is higher as detecting HPV-16 and HPV18 in age groups under 35 years old, 41-50 years old and 51-60 years old. HPV16 is detected higher in age groups 35-40 years old and above 60 years. The incidence of high squamous intraepithelial lesions (CIN II and III) is 0.92% in age group 35-40 years, 0.54% in age under 35 years, 0.59% in age group 41-50 years old, 0.35% in age group 51-60 years old and 0.15% in age group above 60 years old. There is no significance (p value = 0.4060). Low grade cervical lesions (CIN I) were 0.13% (< 35 Ys), 0.35% (35-40 Ys), 0.36% (41-50 Ys), 0.25% (51-60 Ys) and 0.098% (> 60Y s), which was statistically significant (p value = 0.04,0.60). Without dysplasia 0.19% (< 35 Ys), 0.5% (35-40 Ys), 0.56% (41-50 Ys), 0.51 (51-60 Ys) and 0.26% (> 60 Ys). There is no significance between occurrence of cervical dysplasia and without dysplasia despite of detection of HPV-HR subtypes (p value = 0.1754). The only use of HPV-subtyping is not a secure method and a protective way for women. There are worldwide many HPV-positive cases, which have been psychologically impaired with higher costs, although they have no cervical epithelial changes during the HPV-infection. There are many HPV-negative cases, in some studies up to 13% of cases, which develop cervical cancer. We have the opinion and are convinced that the screening should be both morphologically via cytological examination and may be with adding immunocytochemistry to detect the really dysplastic cervical lesions. HPV-subtyping may be added every three years to detect the concomitant subtype.

Evaluation of P16/Ki67 (CINtecPlus) and L1-capsid compared with HPV-genotyping in cervical cytology in women ≥35 years old focusing on patients with atypical squamous cells of undetermined significance.

Cervical cancer is the third most common cancer in women worldwide. Conventional cytological examination as a screening method with Papanicolaou has been established to reduce the incidence of dysplasia and cervical cancer for years. In addition to the conventional screening, the introduction of immunocytochemical examinations, including CINtecPlus and L1-capsid, has been demonstrated to have a positive impact on screening results. In addition to morphological screening methods, human papillomavirus (HPV)-testing has also been demonstrated to possess an enormous potential in the cervical screening process. Additionally, different screening models ranging from conventional cytological screening to primary HPV-testing do exist in different countries. At the beginning of the year 2020, a combination of cytological screening and HPV-testing was introduced in Germany for women ≥35 years. The aim of the present study was to evaluate the role of morphological screening, including immunocytochemistry, and to compare it with HPV-genotyping. Immunocytochemistry was added to confirm the diagnosis but needs established infrastructure and well-trained personnel. Furthermore, there was a need to establish the HPV-screening method. In the Institute for Pathology and Cytology (Schuettorf, Leer, Germany), 146,800 samples of women (>35 years old) were examined between January 2020 and January 2021. The present study retrospectively analyzed 146,800 samples. Each sample was examined using a conventional cytological technique and HPV-high risk-Test (HPV-HR-Test) with Viper-BD. Immunocytochemistry with CINtecPlus and L1-capsid was added in some cases. A total of 555 cases were cytological diagnosed as atypical squamous cells of undetermined significance (ASC-US; IIp). After performing immunocytochemistry, 79% of cases were suspected to be positive and 1.48% of cases were definitely positive. The HPV-HR-Test was positive in 26.4% of cases. Among cases of ASC-US and HPV-HR-negativity, 33.7% were suspicious of immunocytochemical positivity and 0.5% were definitely positive. Among patients with HPV-16-negativity, 13.6% were patients with highly squamous intraepithelial lesion (HSIL) and 22.7% were patients with low-grade squamous intraepithelial lesion (LSIL) and HSIL. Among patients with HPV-18-negativity, 14.3% were patients with HSIL and 19.5% were patients with LSIL and HSIL. There were 107 cases in this group of cases with negativity of both HPV-16 and HPV-18. After performing the colposcopy and biopsy, there were 6.5% with cervical intra-epithelial neoplasia (CIN) I, 8.4% with CIN II and 5.6% with CIN III. In conclusion, there is still a need for conventional cytological examination and maybe the addition of immunocytochemistry to confirm the diagnosis and to exclude dysplasia of cervical epithelium. The HPV-HR-Test is not enough as a screening method and may be misleading.

Incidental occurrence of papillary renal cell carcinoma in the native kidney with autosomal dominant polycystic kidney disease after renal transplantation: A case report.

Autosomal dominant polycystic kidney disease (ADPKD) is one of the best-known genetic diseases. Almost half of the patients with ADPKD will develop end-stage renal disease, and the majority of patients are treated with renal transplantation. The current study presents a case that developed papillary renal cell carcinoma (PRCC) in the native right kidney 10 years after renal transplantation. PRCC is a not common malignant tumour entity (18.5% of all cases of renal cell carcinoma) compared with common clear cell renal carcinoma (65-70% of all cases of RCC).

Specific spatial distribution patterns of tumor foci are associated with a low risk of biochemical recurrence in pT2pN0R0 prostate cancer.

BACKGROUND: The previous attempts for pT2 substaging of prostate cancer (PCa) were insufficient in providing prognostic subgroups and the search for new prognostic parameters to subcategorize pT2 PCa is, therefore, needed. Therefore, the current study investigated the association between tumor distribution patterns and the biochemical recurrence (BCR)-free survival rate in pT2pN0R0 PCa. METHODS: Following radical prostatectomy, the anatomical distribution of PCa in 743 men with pT1-pT3pN0 disease was analyzed to determine 20 types of PCa distribution patterns. Then, 245 men with pT2pN0R0 PCa was considered for prognostic evaluation with a mean follow-up period of 60 months. The spatial distribution patterns of PCa were evaluated using a cMDX©-based map model of the prostate. An analysis including 552,049 comparison operations was performed to assist in the evaluation of the similarity levels of the distribution patterns. A k-mean cluster analysis was applied to determine groups with similar distribution patterns. A decision-tree analysis was performed to divide these groups according to frequency of BCR. The BCR-free survival rate was analyzed using Kaplan-Meier curves. Predictors of progression were investigated using a Cox proportional hazards model. RESULTS: BCR occurred in 8.2% of the 245 men with pT2pN0R0 PCa. The median time of recurrence was 60 months (interquartile range [IQR]: 42-77). In univariate and multivariate analyses, the prostate volume and the distribution patterns were independent predictors for BCR, whereas the sub-staging of pT2 tumors, Gleason grading, prostate-specific antigen (PSA) level, and relative tumor volume were not. In the patients with pT2pN0R0 disease, PCa distribution patterns with the apical involvement were significantly associated with the risk of BCR (P = 0.001). CONCLUSION: The spread tumor patterns with the apical involvement are associated with a high-risk of BCR in the pT2 tumor stage. The vertical tumor spread could be considered in developing improved prognostic pT2 sub-categories.

Blind Biobanking of the Prostatectomy Specimen: Critical Evaluation of the Existing Techniques and Development of the New 4-Level Tissue Extraction Model With High Sampling Efficacy.

BACKGROUND: Fresh tissue is mandatory to perform high-quality translation studies. Several models for tissue extraction from prostatectomy specimens without guidance by frozen sections are already introduced. However, little is known about the sampling efficacy of these models, which should provide representative tissue in adequate volumes, account for multifocality and heterogeneity of tumor, not violate the routine final pathological examination, and perform quickly without frozen section-based histological control. The aim of the study was to evaluate the sampling efficacy of the existing tissue extraction models without guidance by frozen sections ("blind") and to develop an optimized model for tissue extraction. METHODS: Five hundred thirty-three electronic maps of the tumor distribution in prostates from a single-center cohort of the patients subjected to radical prostatectomy were used for analysis. Six available models were evaluated in silico for their sampling efficacy. Additionally, a novel model achieving the best sampling efficacy was developed. RESULTS: The available models showed high efficacies for sampling "any part" from the tumor (up to 100%), but were uniformly low in efficacy to sample all tumor foci from the specimens (with the best technique sampling only 51.6% of the all tumor foci). The novel 4-level extraction model achieved a sampling efficacy of 93.1% for all tumor foci. CONCLUSIONS: The existing "blind" tissue extraction models from prostatectomy specimens without frozen sections control are suitable to target tumor tissues but these tissues do not represent the whole tumor. The novel 4-level model provides the highest sampling efficacy and a promising potential for integration into routine. Prostate 77: 396-405, 2017. © 2016 Wiley Periodicals, Inc.

Analysis of topographical distribution of prostate cancer and related pathological findings in prostatectomy specimens using cMDX document architecture.

INTRODUCTION: Understanding the topographical distribution of prostate cancer (PCa) foci is necessary to optimize the biopsy strategy. This study was done to develop a technical approach that facilitates the analysis of the topographical distribution of PCa foci and related pathological findings (i.e., Gleason score and foci dimensions) in prostatectomy specimens. MATERIAL & METHODS: The topographical distribution of PCa foci and related pathologic evaluations were documented using the cMDX documentation system. The project was performed in three steps. First, we analyzed the document architecture of cMDX, including textual and graphical information. Second, we developed a data model supporting the topographic analysis of PCa foci and related pathologic parameters. Finally, we retrospectively evaluated the analysis model in 168 consecutive prostatectomy specimens of men diagnosed with PCa who underwent total prostate removal. The distribution of PCa foci were analyzed and visualized in a heat map. The color depth of the heat map was reduced to 6 colors representing the PCa foci frequencies, using an image posterization effect. We randomly defined 9 regions in which the frequency of PCa foci and related pathologic findings were estimated. RESULTS: Evaluation of the spatial distribution of tumor foci according to Gleason score was enabled by using a filter function for the score, as defined by the user. PCa foci with Gleason score (Gls) 6 were identified in 67.3% of the patients, of which 55 (48.2%) also had PCa foci with Gls between 7 and 10. Of 1173 PCa foci, 557 had Gls 6, whereas 616 PCa foci had Gls>6. PCa foci with Gls 6 were mostly concentrated in the posterior part of the peripheral zone of the prostate, whereas PCa foci with Gls>6 extended toward the basal and anterior parts of the prostate. The mean size of PCa foci with Gls 6 was significantly lower than that of PCa with Gls>6 (P<0.0001). CONCLUSION: The cMDX-based technical approach facilitates analysis of the topographical distribution of PCa foci and related pathologic findings in prostatectomy specimens.

Preoperative Serum Prostate-Specific Antigen Levels Vary According to the Topographical Distribution of Prostate Cancer in Prostatectomy Specimens.

OBJECTIVE: To evaluate whether the spatial distribution of prostate cancer (PCa) influences the concentration of prostate-specific antigen (PSA). METHODS: An observational prospective study was performed in 775 consecutive men with preoperative PSA levels ≤20 ng/mL who underwent radical prostatectomy for organ-confined PCa. We evaluated prostate specimens using a cMDX-based map model of the prostate and determined the prostate volume, number of cancer foci, relative tumor volume, Gleason score, zone of origin, localization, and pathologic stage after stratification according to PSA levels categorized into 3 groups: <4 ng/mL, 4-10 ng/mL, and 10.1-20 ng/mL. The distribution of 5254 PCa foci was analyzed after stratification according to PSA levels and visualized on heat maps. A logistic regression analysis was performed to assess the odds ratios of PSA levels for the presence of PCa in 16 regions. RESULTS: PCa with PSA <4 ng/mL was predominantly localized to the apical part and the peripheral zone of the prostate. PCa with a PSA level 10.1-20 ng/mL (16.4% of cases) was observed more frequently in the anterior part and the base of the prostate than PCa with a PSA level <4 or 4-10 ng/mL (6% and 10%, respectively). CONCLUSION: Preoperative PSA levels vary according to the spatial distribution of PCa in radical prostatectomy specimens. The probability of anterior PCa is increased with higher PSA serum levels. Regions of interest harboring the PCa can be defined according to preoperative PSA and prostate volume. These findings are useful to optimize the focal therapy or to adjust the radiation fields.

Prostate cancers detected on repeat prostate biopsies show spatial distributions that differ from those detected on the initial biopsies.

OBJECTIVE: To evaluate the spatial distribution of prostate cancer detected at a single positive biopsy (PBx) and a repeat PBx (rPBx). PATIENTS AND METHODS: We evaluated 533 consecutive men diagnosed with prostate cancer who underwent radical prostatectomy using a clinical map document based on XML (cMDX©)-based map model of the prostate. We determined the number of cancer foci, relative tumour volume, Gleason score, zone of origin, localisation, and pathological stage after stratification according to the number of PBx sessions (PBx vs rPBx). The distribution of 3966 prostate cancer foci was analysed and visualised on heat maps. The colour gradient of the heat map was reduced to six colours representing the frequency classification of prostate cancer using an image posterisation effect. Additionally, the spatial distribution of organ-confined prostate cancer between PBx and rPBx was evaluated. RESULTS: Prostate cancer diagnosed on PBx was mostly localised to the apical portion and the peripheral zone of the prostate. Prostate cancer diagnosed on rPBx was more frequently found in the anterior portion and the base of the prostate. Organ-confined prostate cancer foci were mostly localised in the dorsolateral zone of the prostate in men at PBx, whereas men at rPBx had more prostate cancer foci in the anterior portion. CONCLUSIONS: The spatial distribution of prostate cancer with rPBx differs significantly from the spatial distribution of prostate cancer with PBx. The whole anterior portion of the prostate should be considered by rPBx.

Preoperative prostate-specific antigen isoform p2PSA ≤ 22.5 pg/ml predicts advanced prostate cancer in patients undergoing radical prostatectomy.

BACKGROUND: The prediction value of prostate-specific antigen (PSA) isoform [-2]proPSA (p2PSA) for detecting advanced prostate cancer (PCa) remains unclear. Our objective was to evaluate the additional clinical utility of p2PSA compared with total PSA (tPSA), free PSA (fPSA), and preoperative Gleason score (Gls) in predicting locally advanced PCa (pT3/T4) with high-accuracy discrimination. The aim was to develop a novel classification based on p2PSA and preoperative Gls for predicting advanced PCa. MATERIALS AND METHODS: In 208 consecutive men diagnosed with clinically localized PCa who underwent radical prostatectomy, we determined the predictive and discriminatory accuracy of serum tPSA, fPSA, percentage of fPSA to tPSA, p2PSA, p2PSA density, percentage of p2PSA to fPSA, and the Prostate Health Index. The cutoff level of p2PSA with best accuracy was estimated. The novel classification was developed by analyzing the interaction between p2PSA and Gls in predicting pathologic outcomes using a chi-square automatic interaction detection analysis. Decision curve analysis was applied to test the clinical consequences of using the novel classification. RESULTS: On univariate analyses, p2PSA, p2PSA density, percentage of p2PSA to fPSA, and Prostate Health Index were accurate but were not independent predictors by multivariate analysis. The p2PSA cutoff level of 22.5 pg/ml showed the best accuracy level for predicting and discriminating advanced diseases (area under the curve [AUC] = 0.725, sensitivity = 51.4%, specificity = 81.8%). By chi-square automatic interaction detection, univariate and multivariate analysis, a p2PSA level > 22.5 pg/ml was significantly associated with an increased frequency and risk of advanced disease. In patients with a p2PSA level ≤ 22.5 pg/ml, 91.8% of Gleason sum 6 PCa was organ confined. The combination of p2PSA and Gls enhanced slightly but significantly the predictive and discriminatory accuracy for advanced disease (0.6%-3.6%). CONCLUSIONS: The p2PSA cutoff level of 22.5 pg/ml can accurately discriminate between organ-confined and advanced PCa. The additional use of p2PSA enhanced slightly the predictive accuracy for advanced PCa (pT3/pT4) and has limited additional predictive value in identifying aggressive PCa (Gls > 7a).

The presence of positive surgical margins in patients with organ-confined prostate cancer results in biochemical recurrence at a similar rate to that in patients with extracapsular extension and PSA ≤ 10 ng/ml.

PURPOSES: We investigated whether patients with organ-confined prostate cancer (PCa) and positive surgical margins (SMs) had a similar biochemical recurrence (BCR) risk compared with patients with pT3a and preoperative prostate-specific antigen (PSA) levels ≤ 10ng/ml. Furthermore, we examined the effects of incorporating SM status, Gleason score (Gls), and preoperative PSA level into the discrimination accuracy of the current tumor node metastasis-staging system. MATERIALS AND METHODS: We analyzed 863 PCa patients treated with radical prostatectomy from 1999 to 2008. Only individuals with pT2N0 or pT3N0, without neoadjuvant or adjuvant therapy, were included. We performed chi-square automatic interaction detection analysis to generate a classification model for predicting BCR by analyzing interactions between age at surgery, SM status, Gls, PSA, and tumor stage, tumor volume and relative tumor volume. Cox regression analyses tested the relationship between SM status and BCR rate after stratification according to T-stage and the novel classification. The predictive and discrimination accuracy of the current T-stage and of the classification model was quantified with time-dependent receiver operating characteristics and integrated discrimination improvement. The topographical association between extracapsular extension of PCa and positive SM was analyzed in patients with pT3aR1 using a computational reconstruction diagram of the prostate. RESULTS: The chi-square automatic interaction detection analysis found interactions among pT Stage, SM status, PSA and Gls and generated a classification model for BCR prediction: pT2R0, pT2R1, pT3a PSA ≤ 10 ng/ml, pT3a PSA>10 ng/ml and pT3b. Men with pT2R1 had a shorter time to BCR compared with men with pT3a-PSA ≤ 10 ng/ml (P<0.0001). Gls≥7a was correlated with a poorer BCR rate than Gls≤7a in men with pT2R1 or pT3a PSA ≤ 10 ng/ml (P = 0.012). The rank order (highest to lowest) for the risk of developing BCR was pT3b>pT2R1/pT3a-PSA>10 ng/ml>pT2R1/pT3a PSA ≤ 10 ng/ml>pT2R0 (P<0.0001). Discrimination accuracy gains were observed when PCa was stratified according to the novel classification (P<0.0001). A topographical association between extracapsular extension and positive SM was found in patients with pT3aR1 (P = 0.01). CONCLUSION: Patients with pT2R1 develop a similar BCR risk to that of patients with pT3a PSA ≤ 10 ng/ml. Gls≥7b is associated with a high BCR risk in these patient groups. Including SM status, PSA, and Gls in pT stage appears to improve prognostic stratification in patients with PCa.

Tumor percentage but not number of tumor foci predicts disease-free survival after radical prostatectomy especially in high-risk patients.

OBJECTIVE: To evaluate the predictive value of tumor volume (TV), tumor percentage (TP), and number of tumor foci (NF) in patients with prostate cancer. The prognostic relevance of TV, TP, and NF as predictors of biochemical recurrence (BCR) following radical prostatectomy (RPE) is controversial. PATIENTS AND METHODS: The cohort consisted of 758 referred subjects who underwent RPE between 2000 and 2005 at the University of Muenster. The mean time of follow-up was 62 months. TV, TP, and NF were estimated visually with the assistance of a pathologic mapping grid for embedded whole-mount RPE specimens. In addition, TV and TP were assessed in a categorized fashion by using quartiles as cutoff points. Subgroup analyses for high- and low-risk patients using univariate and multivariate Cox proportional hazard analyses for BCR were performed. RESULTS: TV, TP, and NF were strongly related to tumor stage, Gleason score, surgical margin status, and preoperative prostate-specific antigen (PSA). In univariate analysis, all pathologic parameters including TV, TP, and NF were predictive for BCR. In multivariate analysis, only TP, tumor stage, and PSA level were independent predictors. In subgroup analysis, TP was an independent predictor for BCR in the high-risk group but not in the low-risk group. CONCLUSIONS: TP, but not TV or NF, was found to be an independent predictor for BCR in patients after RPE. TP seems to be more relevant in high-risk patients (i.e., any of the following: > pT2, Gleason score > 6, or PSA > 20 ng/ml).

High-grade prostatic intraepithelial neoplasia (HGPIN) and topographical distribution in 1,374 prostatectomy specimens: existence of HGPIN near prostate cancer.

PURPOSE: High-grade prostatic intraepithelial neoplasia (HGPIN) is believed to be a precursor of prostate cancer (PCa). This study evaluated whether HGPIN was located close to PCa in whole radical prostatectomy specimens (RPSs). MATERIALS AND METHODS: We evaluated 1,374 prostate specimens from 1999 to 2010 using a cMDX-based map model of the prostate. The distribution of 10,439 PCa foci was analyzed and visualized on a heat map. The color gradient of the heat map was reduced to six colors representing the frequency classification of the relative frequency of PCa using an image posterization effect. We defined 22 regions in the prostate according to the frequency of PCa occurrence. Seven hundred ninety RPSs containing 6,374 PCa foci and 4,502 HGPIN foci were evaluated. The topographical association between PCa and HGPIN in the RPSs was analyzed by estimating the frequencies of PCa and HGPIN in 22 regions. A logistic regression analysis was performed to assess the odds ratios of HGPIN for the presence of PCa in 22 regions. RESULTS: Fifty-eight percent of PCa specimens included HGPIN and had significantly more favorable Gleason scores, lower PSA levels and smaller relative tumor volumes than isolated PCa specimens. HGPIN (68%) and PCa (69%) were predominantly localized to the apical half of the prostate. HGPIN was mainly concentrated in the peripheral zone medial to regions with high PCa frequencies. Upon logistic regression analysis, HGPIN was a significant predictor of PCa co-existence in 11 regions. CONCLUSIONS: HGPIN was located adjacent to PCa in whole RPSs. PCa concomitant with HGPIN had more favorable pathologic features than isolated PCa.

CMDX©-based single source information system for simplified quality management and clinical research in prostate cancer.

BACKGROUND: Histopathological evaluation of prostatectomy specimens is crucial to decision-making and prediction of patient outcomes in prostate cancer (PCa). Topographical information regarding PCa extension and positive surgical margins (PSM) is essential for clinical routines, quality assessment, and research. However, local hospital information systems (HIS) often do not support the documentation of such information. Therefore, we investigated the feasibility of integrating a cMDX-based pathology report including topographical information into the clinical routine with the aims of obtaining data, performing analysis and generating heat maps in a timely manner, while avoiding data redundancy. METHODS: We analyzed the workflow of the histopathological evaluation documentation process. We then developed a concept for a pathology report based on a cMDX data model facilitating the topographical documentation of PCa and PSM; the cMDX SSIS is implemented within the HIS of University Hospital Muenster. We then generated a heat map of PCa extension and PSM using the data. Data quality was assessed by measuring the data completeness of reports for all cases, as well as the source-to-database error. We also conducted a prospective study to compare our proposed method with recent retrospective and paper-based studies according to the time required for data analysis. RESULTS: We identified 30 input fields that were applied to the cMDX-based data model and the electronic report was integrated into the clinical workflow. Between 2010 and 2011, a total of 259 reports were generated with 100% data completeness and a source-to-database error of 10.3 per 10,000 fields. These reports were directly reused for data analysis, and a heat map based on the data was generated. PCa was mostly localized in the peripheral zone of the prostate. The mean relative tumor volume was 16.6%. The most PSM were localized in the apical region of the prostate. In the retrospective study, 1623 paper-based reports were transferred to cMDX reports; this process took 15 ± 2 minutes per report. In a paper-based study, the analysis data preparation required 45 ± 5 minutes per report. CONCLUSIONS: cMDX SSIS can be integrated into the local HIS and provides clinical routine data and timely heat maps for quality assessment and research purposes.

Clinical map document based on XML (cMDX): document architecture with mapping feature for reporting and analysing prostate cancer in radical prostatectomy specimens.

BACKGROUND: The pathology report of radical prostatectomy specimens plays an important role in clinical decisions and the prognostic evaluation in Prostate Cancer (PCa). The anatomical schema is a helpful tool to document PCa extension for clinical and research purposes. To achieve electronic documentation and analysis, an appropriate documentation model for anatomical schemas is needed. For this purpose we developed cMDX. METHODS: The document architecture of cMDX was designed according to Open Packaging Conventions by separating the whole data into template data and patient data. Analogue custom XML elements were considered to harmonize the graphical representation (e.g. tumour extension) with the textual data (e.g. histological patterns). The graphical documentation was based on the four-layer visualization model that forms the interaction between different custom XML elements. Sensible personal data were encrypted with a 256-bit cryptographic algorithm to avoid misuse. In order to assess the clinical value, we retrospectively analysed the tumour extension in 255 patients after radical prostatectomy. RESULTS: The pathology report with cMDX can represent pathological findings of the prostate in schematic styles. Such reports can be integrated into the hospital information system. "cMDX" documents can be converted into different data formats like text, graphics and PDF. Supplementary tools like cMDX Editor and an analyser tool were implemented. The graphical analysis of 255 prostatectomy specimens showed that PCa were mostly localized in the peripheral zone (Mean: 73% ± 25). 54% of PCa showed a multifocal growth pattern. CONCLUSIONS: cMDX can be used for routine histopathological reporting of radical prostatectomy specimens and provide data for scientific analysis.

Negative predictive value of systematic ultrasound-guided prostate biopsy: which tumours do we miss?

BACKGROUND: The aim of the study was the determination of the negative predictive value of sextant core prostate biopsy. PATIENTS AND METHODS: Prostate cancer was diagnosed in 126 patients by systematic ultrasound-guided sextant biopsy and was subsequently treated with radical prostatectomy. The prostatectomy specimens were examined histopathologically using the whole-mount section technique. RESULTS: 81 patients were diagnosed with unilateral and 45 with bilateral prostate cancer after biopsy. In 15/81 patients, the diagnosis of unilateral disease was confirmed by the whole-mount sections; 66 patients turned out to have bilateral disease. In 14/66 cases, the missed tumour foci were diminutive. In the remaining 52 patients, an erroneous diagnosis of unilateral prostate cancer had been made after biopsy, although the missed tumour foci were not diminutive. The negative predictive value of sextant core biopsy with respect to unilateral disease was 36%. CONCLUSION: An unexpectedly high number of tumour foci are missed by systematic ultrasound-guided sextant prostate biopsy.

Chromosomal imbalances, loss of heterozygosity, and immunohistochemical expression of TP53, RB1, and PTEN in intraductal cancer, intraepithelial neoplasia, and invasive adenocarcinoma of the prostate.

Recent studies have shown that intraductal prostate carcinoma (IDC-P) should be considered as a separate lesion distinct from prostatic intraepithelial neoplasia (PIN). The purpose of the present study was to analyze the genetic relationship between benign prostatic tissue, PIN, invasive cancer, IDC-P, and extracapsular tumor tissue to get further information about the role of IDC-P in the development of prostate cancer. One hundred five radical prostatectomy specimens were investigated immunohistochemically, 77 cases were analyzed by PCR for LOH of the tumor suppressor genes TP53 and RB1, and 11 cases of IDC-P and 10 cases of PIN were investigated using comparative genomic hybridization (CGH). At CGH analysis, IDC-P showed several chromosomal imbalances in contrast to PIN, where no changes were found. We could demonstrate a significant increase of LOH for TP53 or RB1 from benign tissue to PIN. LOH of both TP53 and RB1 were frequently found in IDC-P (52%), followed by extracapsular tumor tissue (44%), invasive cancer (24%), PIN (19%), and benign prostatic tissue (17%). Increased immunohistochemical expression was found in invasive cancer for TP53, RB1, and for PTEN. Decreased expression could be demonstrated in extracapsular tumor tissue and in IDC-P. Our results indicate that IDC-P in general follows the genetic pathway from normal epithelium over PIN lesion. IDC-P represents a separate prostatic lesion and should be graded as a poorly differentiated carcinoma.