Histopathological Diagnosis Of Prostate Cancer Research Articles

Artificial Intelligence and Histopathological Diagnosis of Prostate Cancer

As of today, the diagnosis and management of prostate cancer involve the interpretation of data from multiple modalities and tools such as serum prostate-specific antigen levels, magnetic resonance imaging-guided biopsies, genomic biomarkers, and Gleason grading which are used to diagnose, risk stratify, and then monitor patients during respective follow-ups. Artificial intelligence (AI) can allow clinicians to recognize difficult relationships and manage enormous data sets, which is a task that is both extraordinarily difficult and time-consuming for humans. By using AI algorithms and reducing the level of subjectivity, it is possible to use fewer resources while improving the overall efficiency and accuracy in prostate cancer diagnosis and management. In this short review, we have made a case for the use of AI in the histopathological diagnosis of prostate cancer.

AtlasGrabber: a software facilitating the high throughput analysis of the human protein atlas online database

BackgroundThe human protein atlas (HPA) is an online database containing large sets of protein expression data in normal and cancerous tissues in image form from immunohistochemically (IHC) stained tissue microarrays. In these, the tissue architecture is preserved and thus provides information on the spatial distribution and localization of protein expression at the cellular and extracellular levels. The database is freely available online through the HPA website but currently without support for large-scale screening and analysis of the images in the database. Features like spatial information are typically lacking in gene expression datasets from homogenized tissues or single-cell analysis. To enable high throughput analysis of the HPA database, we developed the AtlasGrabber software. It is available freely under an open-source license. Based on a predefined gene list, the software fetches the images from the database and displays them for the user. Several filters for specific antibodies or images enable the user to customize her/his image analysis. Up to four images can be displayed simultaneously, which allows for the comparison of protein expression between different tissues and between normal and cancerous tissues. An additional feature is the XML parser that allows the extraction of a list of available antibodies, images, and genes for specific tissues or cancer types from the HPA’s database file.ResultsCompared to existing software designed for a similar purpose, ours provide more functionality and is easier to use. To demonstrate the software’s usability, we identified six new markers of basal cells of the prostate. A comparison to prostate cancer showed that five of them are absent in prostate cancer.ConclusionsThe HPA is a uniquely valuable database. By facilitating its usefulness with the AtlasGrabber, we enable researchers to exploit its full capacity. The loss of basal cell markers is diagnostic for prostate cancer and can help refine the histopathological diagnosis of prostate cancer. As proof of concept, with the AtlasGrabber we identified five new potential biomarkers specific for prostate basal cells which are lost in prostate cancer and thus can be used for prostate cancer diagnostics.

Validation of the Brazilian Version of Functional Assessment of Cancer Therapy-Prostate-FACT-P (Version 4) in Prostate Cancer Patients.

The purpose of this study is to validate the Brazilian version of Functional Assessment of Cancer Therapy-Prostate FACT-P (version 4) in nonmetastatic prostate cancer (PC) patients. Patients with histopathological diagnosis of PC were submitted to health-related quality of life (HRQOL) questionnaires - SF-36 (Medical Outcomes Study 36 - Item Short-Form Health Survey) and FACT-P (version 4). After 7 to 15days, FACT-P (version 4) was reapplied in the sample's percentage that participated the first evaluation. Cronbach alpha coefficient was used to determine internal consistency and intraclass correlation coefficient (ICC) certified stability. Correlations between FACT-P (version 4) and SF-36 tested convergent validity. Regarding known groups validity, the hypothesis tested was that FACT-P (version 4) is capable of discriminating HRQOL in patients with different PC risk classifications. A total of 112 patients with nonmetastatic PC were evaluated. Cronbach alpha coefficients (0.64-0.88) and ICC (0.75-0.93) obtained satisfactory results of reliability. Verified correlations (r 0.3-0.72) between FACT-P (version 4) and SF-36 suggest convergent validity. In the studied sample, FACT-P (version 4) was unable to discriminate HRQOL in nonmetastatic patients. The Brazilian version of FACT-P questionnaire (version 4) showed evidences of reliability and validity on evaluating HRQOL in Brazilian men with nonmetastatic PC.

Transmembrane and Tetratricopeptide Repeat Containing 4 Is a Novel Diagnostic Marker for Prostate Cancer with High Specificity and Sensitivity.

The histopathologic diagnosis of prostate cancer (PCa) from biopsies is a current challenge if double or triple staining is needed. Therefore, there is an urgent need for development of a new reliable biomarker to diagnose PCa patients. We aimed to explore and compare the expression of TMTC4 in PCa cells and tissue specimens and evaluate its sensitivity and specificity. The expression of TMTC4 in PCa and normal prostate epithelial cells was determined by real-time PCR and Western blot analyses. Immunohistochemical (IHC) staining of TMTC4 was performed on tissues collected from PCa and benign prostatic hyperplasia (BPH). Our results show a high expression of TMTC4 on mRNA and protein levels in PCa versus BPH1 and normal cells (p < 0.05). IHC results show strong cytoplasmic expressions in PCa cases (p < 0.001) as compared to BPH cases. The overall accuracy as measured by the AUC was 1.0 (p < 0.001). The sensitivity and specificity of the protein were 100% and 96.6%, respectively. Taken together, we report a high TMTC4 expression in PCa cells and tissues and its ability to differentiate between PCa and BPH with high sensitivity and specificity. This finding can be carried over to clinical practice after its confirmation by further studies.

Impact of Pretreatment Total Cholesterol Level Is Associated With Metastasis of Prostate Cancer

Metabolic syndrome is reported to play a role in the genesis and development not only of angina, arteriosclerosis, diabetes, and osteoporosis but also of prostate cancer. Hypercholesterolemia is a strong risk factor in prostate cancer development. The current study was conducted to analyze whether pretreatment serum levels of cholesterol correlate with prostate cancer metastasis. Three hundred fifty-one subjects who received a histopathological diagnosis of prostate cancer were evaluated by clinical factors such as age, body mass index (BMI), disease stage, Gleason score, prostate-specific antigen (PSA), total cholesterol, Luteinizing hormone (LH), testosterone, and free testosterone. A multivariate analysis was performed on these factors, and a statistically significant difference was identified in total cholesterol level (p =.01) and PSA (p < .001). The total cholesterol level was higher in cases of metastatic prostate cancer compared to nonmetastatic prostate cancer in this study and therefore may be a predictive factor for poor prognosis.

Smoking reduces PSA accuracy for detection of prostate cancer: results from an Italian cross-sectional study.

The aim of our study is to evaluate the diagnostic accuracy of prostate-specific antigen (PSA) according to the smoking status in a cohort of European men undergoing prostate biopsy. From 2008 onwards, we consecutively enrolled, at a single institution in Italy, men undergoing 12 core transrectal ultrasound-guided prostate needle biopsy. Demographic, clinical and histopathological data were collected. We excluded men who had PSA >30 ng/mL. Patients were classified in three groups: non-smokers, smokers and former smokers. Receiver-operator characteristics (ROC) curve analysis were used to compare predictive properties of PSA across smoking categories for the final histopathological diagnosis of prostate cancer. 872 patients were enrolled. with a median age and PSA of 67 years (IQR: 61/74) and 6.2 ng/mL (IQR: 4.4/9.7) respectively.402/872 patients (46%) were non-smokers; 151 of 872 were smokers (17%) and 319 of 872 were former smokers (36%); 374 of 872 (43%) had cancer on biopsy. PSA accuracy for smokers (AUC= 0.47, P=0.490) was lower when compared to non-smokers (AUC=0.59, P=0.003) and former smokers (AUC=0.59, P=0.005). In a cohort of Italian men undergoing prostate biopsy, the performance accuracy of PSA, as a predictor of prostate cancer, is lower in smokers. Although the molecular link behind our findings is still unknown, our study firstly showed that the PSA accuracy for PCa diagnosis is significantly influential by smoking.

Report of the third Asian Prostate Cancer study meeting

The Asian Prostate Cancer (A-CaP) study is an Asia-wide initiative that was launched in December 2015 in Tokyo, Japan, with the objective of surveying information about patients who have received a histopathological diagnosis of prostate cancer (PCa) and are undergoing treatment and clarifying distribution of staging, the actual status of treatment choices, and treatment outcomes. The study aims to clarify the clinical situation for PCa in Asia and use the outcomes for the purposes of international comparison. Following the first meeting in Tokyo in December 2015, the second A-CaP meeting was held in Seoul, Korea, in September 2016. This, the third A-CaP meeting, was held on October 14, 2017, in Chiang Mai, Thailand, with the participation of members and collaborators from 12 countries and regions. In the meeting, participating countries and regions presented the current status of data collection, and the A-CaP office presented a preliminary analysis of the registered cases received from each country and region. Participants discussed ongoing challenges relating to data input and collection, institutional, and legislative issues that may present barriers to data sharing, and the outlook for further patient registrations through to the end of the registration period in December 2018. In addition to A-CaP–specific discussions, a series of special lectures were also delivered on the situation for health insurance in the United States, the correlation between insurance coverage and PCa outcomes, and the outlook for robotic surgery in the Asia-Pacific region. Members also confirmed the principles of authorship in collaborative studies, with a view to publishing original articles based on A-CaP data in the future.

Comparison of likert and PI-RADS v2 scoring in the diagnosis of prostate cancer

Aim: We aimed to compare the inter- and intra-observer variability and diagnostic performance of PI-RADS v2 and Likert scoring in the evaluation of prostate cancer on multiparametric prostate MR imaging. Material and Methods: MRI findings of 53 patients who had histopathologic diagnosis of prostate cancer and 51 patients who had one or more negative transrectal ultrasound guided prostate biopsy were evaluated retrospectively. The images were assessed by three independent observers blinded to histopathologic results of the patients. Intra-observer and inter-observer variability were evaluated by CohenÂ’s Kappa coefficient for all possible pairs of observers. ROC curve analysis was used to determine AUC to evaluate diagnostic performance of Likert and PI-RADS v2 scoring with a 1.5T MR in the diagnosis of prostate cancer. Results: Kappa values for 4 or higher PI-RADS v2 scores were calculated and κ=0.59-0.71 for intra-observer and κ=0.48-0.67 for inter-observer variability were obtained. κ=0.54-0.69 for intra-observer and κ=0.42-0.75 for inter-observer reliability were obtained for 4 or higher Likert scoring. AUC was 72% for PI-RADS v2 scores and was 75.9% for Likert scores for determining Gleason 6 or higher prostate cancers. There was not a statistically significant difference in the comparison of Likert and PI-RADS v2 ROC curves. Conclusion: PI-RADS v2 has no significant superiority compared to Likert scoring in intra-observer and inter-observer reliability. Likert and PI-RADS v2 scoring has no difference in the terms of diagnostic capability of prostate cancers.

Evaluation of Prostate CancerDetection Rates in PatientsUndergoing TransrectalUltrasound (TRUS) GuidedProstate Biopsy

Background: Prostate cancer is one of the most common types of organ cancer among males in Turkey as well as all over the world. The gold standard method for histopathological diagnosis of prostate cancer is Trans rectal Ultrasound (TRUS)-guided prostate biopsy. Today, the most common indications for prostate biopsy are suspicious findings on digital rectal examination and increased serum Prostate Specific Antigen (PSA) level. Although there is no generally accepted guideline regarding the preparation and performing prostate biopsies, it has been reported that prostate cancer is detected at different frequencies with different techniques. In this study, we aimed to investigate the frequency of prostate cancer detected in patients undergoing TRUS-guided prostate biopsy and its relationship with patient characteristics and technique.

The Current State of MR Imaging-targeted Biopsy Techniques for Detection of Prostate Cancer.

Systematic transrectal ultrasonography (US)-guided biopsy is the standard approach for histopathologic diagnosis of prostate cancer. However, this technique has multiple limitations because of its inability to accurately visualize and target prostate lesions. Multiparametric magnetic resonance (MR) imaging of the prostate is more reliably able to localize significant prostate cancer. Targeted prostate biopsy by using MR imaging may thus help to reduce false-negative results and improve risk assessment. Several commercial devices are now available for targeted prostate biopsy, including in-gantry MR imaging-targeted biopsy and real-time transrectal US-MR imaging fusion biopsy systems. This article reviews the current status of MR imaging-targeted biopsy platforms, including technical considerations, as well as advantages and challenges of each technique. © RSNA, 2017.

Assessment of Whether Patients' Knowledge, Satisfaction, and Experience Regarding Their 18F-Fluoride PET/CT Examination Affects Image Quality.

The aim of this study was to investigate patients' previous knowledge, satisfaction, and experience regarding an (18)F-fluoride PET/CT examination and to explore whether any discomfort or pain during the examination was associated with reduced image quality. A further aim was to explore whether patients' health-related quality of life (HRQoL) was associated with their satisfaction and experience regarding the examination. Between November 2011 and April 2013, 50 consecutive patients with a histopathologic diagnosis of prostate cancer who were scheduled for (18)F-fluoride PET/CT were asked to participate in the study. A questionnaire was used to collect information on the patients' previous knowledge and experience regarding the examination. Image quality was assessed according to an arbitrary scale. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and the prostate cancer-specific module (QLQ-PR25) were used to assess HRQoL. Forty-six patients (96%) completed the questionnaire. Twenty-six percent did not at all know what a (18)F-fluoride PET/CT examination was. Most (52%-70%) were satisfied to a very high degree with the care provided by the nursing staff but were less satisfied with the information given before the examination. Image quality was similar between patients who were exhausted or claustrophobic during the examination and those who were not. No correlations between HRQoL and the patients' experience regarding (18)F-fluoride PET/CT were found. Most patients were satisfied with the care provided by the nursing staff, but there is still room for improvement, especially regarding the information provided before the examination. A long examination time may be strenuous for the patient, but there was no difference in image quality between patients who felt discomfort or pain during the examination and those who did not.

Abstract 1475: Plasma circulating miRNAs: a new potential biomarker for prostate cancer diagnosis

Abstract MicroRNAs (miRNAs) are a class of small, non-coding, single-stranded RNAs that negatively regulate gene expression mainly binding to 3′-untranslated region (UTR) of target mRNAs at the post-transcriptional level. Recent studies have demonstrated that aberrant expressions of miRNAs are closely associated with the development, invasion, metastasis and prognosis of various cancers including prostate cancer (PCa). However, while the majority of miRNAs are found at the intracellular level, a significant number of miRNAs have been observed outside the cells, including various body fluids. Circulating miRNAs act as ‘extracellular communication RNAs’ that could be particularly relevant in the context of neoplastic diseases and may be useful for early diagnosis as well as to predict the clinical outcome and the treatment response. The aim of this study was to investigate the hypothesis that changes in circulating miRNAs represent potentially useful minimally invasive biomarkers for the diagnosis, staging and prediction of outcome in prostate cancer. From 2012 onwards, consecutive men undergoing 12-core prostate biopsy at Sant’Andrea Hospital of Rome were enrolled into a prospective database. Indications for a prostatic biopsy were a PSA value ≥ 4 ng/ml and/or a positive digital rectal examination (DRE). We selected, as a training set, 32 patients with a mean age and PSA of 66.6 years (SD ±7.9) and 14.3 (range to 0,53-185) ng/ml, respectively. Among them 16 patients (50%) have cancer on biopsy; 8 with Gleason score 6; 3 with a Gleason score 7 and 5 with a Gleason score ≥8 and 16 patients (50%) are control individuals with non-neoplastic prostate disease (i.e. prostatitis). Profiling of microRNAs by deep sequencing allowed us to identify a “signature” of 27 microRNAs aberrant expressed in prostate cancer samples. Receiver-operator characteristics (ROC) curve analysis was used to evaluate the diagnostic accuracy of miRNAs for the final histopathological diagnosis of prostate cancer. An AUC of 0.77; 95%CI was observed for the diagnosis of prostate cancer using all 27 microRNAs, which is correlated with the Gleason score of the analyzed samples, while results to be independent from the respective values of serum PSA. Moreover, ROC curve analysis also highlighted a small subgroup consisting of 6 miRNAs with a high predictive power able to discriminate patients with prostate cancer (AUC = 0.805; 95%CI). This signature is under validation in an indipendent cohort of patients. These preliminary observations suggest that circulating miRNAs could represent promising biomarkers for non-invasive diagnosis in prostate cancer unrelated to PSA. Citation Format: Simona Giglio, Cosimo De Nunzio, Roberto Cirombella, Stefano Volinia, Emidio Luciani, Andrea Tubaro, Andrea Vecchione. Plasma circulating miRNAs: a new potential biomarker for prostate cancer diagnosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1475. doi:10.1158/1538-7445.AM2014-1475

Imaging-guided Prostate Biopsy: Conventional and Emerging Techniques

Transrectal ultrasonography (US)-guided biopsy is the standard approach for histopathologic diagnosis of prostate cancer. However, this technique has multiple limitations owing to the operator's inability in most cases to directly visualize and target prostate lesions. Magnetic resonance (MR) imaging of the prostate overcomes many of these limitations by directly depicting areas of abnormality and allowing targeted biopsies. Accuracy in the detection of prostate cancer is improved by the combined use of standard T2-weighted MR imaging and advanced MR imaging techniques such as diffusion-weighted imaging, dynamic contrast-enhanced imaging, and MR spectroscopy. Suspicious-appearing regions of the prostate seen on MR images can be targeted at real-time transrectal US-guided biopsy to improve the diagnostic yield. MR imaging also can be performed for real-time guidance of transrectal prostate biopsy. Studies among patients who underwent at least one transrectal US-guided biopsy with a negative result before undergoing an MR imaging-guided biopsy showed improved detection rates with MR imaging-guided biopsy in comparison with the detection rates achieved with a repeat transrectal US-guided biopsy; however, MR imaging-guided biopsy is a more time-consuming procedure. A technique known as fused MR imaging- and transrectal US-guided biopsy, which relies on the coregistration of previously acquired MR images with real-time transrectal US images acquired during the procedure, shows promise but is limited by deformation of the prostate; this limitation is the subject of ongoing investigation. Another technique that is currently under investigation, MR imaging-guided prostate biopsy with robotic assistance, may one day help improve the accuracy of biopsy needle placement.

LH-receptor polymorphisms and response to androgen deprivation therapy in prostate cancer.

4597 Background: Androgen deprivation therapy (ADT) is the cornerstone of treatment for advanced prostate cancer. Our recent data demonstrates an integral role of luteinizing hormone (LH) signaling in androgen synthesis in prostate cancer cells. We therefore hypothesized that genetic variation in the LH receptor may impact the efficiency of signal transduction and influence the degree of castration, the duration of response to ADT and overall course. We now report the association between LH receptor genotype and response to ADT. Methods: Fifty eligible patients had a histopathological diagnosis of prostate cancer and had received ADT for advanced prostate cancer. The blood was collected from each patient after obtaining informed consent. DNA was extracted from blood and genotypes for LHR were assayed using the TaqMan method. The time to castration resistance and level of testosterone suppression were obtained by linking to clinical records. Genotype groups were compared using ANOVA or Kruskal-Wallis tests. Results: The median age at diagnosis was 59 (range 48-69). Of the 50 patients enrolled, 29 were treated for primary metastatic disease, 18 at biochemical recurrence (BCR) and 12 with BCR accompanied by radiographic metastases. The median PSA at initiation of ADT was 109.4 ng/ml for primary metastatic disease and 9.8 ng/ml for recurrent disease. The median time to castration resistance was 12 months in the primary metastatic group and 32.4 months in the recurrent group. In the recurrent group, the presence of minor alleles in the LH receptor genotype was associated with a shorter time to castration resistance with a median of 39 months in men with no minor alleles, 23 months in men with 1 minor allele and 16 months in men with 2 minor alleles (p<.05). Median testosterone levels (T) during ADT were higher for men carrying any minor alleles. Median nadir T was 7 ng/dL for men with no minor alleles compared to 22.5 ng/dL for those with 1-2 minor alleles (p=0.07) with median peak T of 19 ng/dL vs. 43 ng/dL, respectively (p=0.01). Conclusions: Genetic variation in the LH receptor was clearly linked with time to castration resistance and depth of castration and warrants further analysis to define its role as a prognostic and predictive marker.

Serum proteomic patterns for detection of prostate cancer.

Pathologic states within the prostate may be reflected by changes in serum proteomic patterns. To test this hypothesis, we analyzed serum proteomic mass spectra with a bioinformatics tool to reveal the most fit pattern that discriminated the training set of sera of men with a histopathologic diagnosis of prostate cancer (serum prostate-specific antigen [PSA] > or =4 ng/mL) from those men without prostate cancer (serum PSA level <1 ng/mL). Mass spectra of blinded sera (N = 266) from a test set derived from men with prostate cancer or men without prostate cancer were matched against the discriminating pattern revealed by the training set. A predicted diagnosis of benign disease or cancer was rendered based on similarity to the discriminating pattern discovered from the training set. The proteomic pattern correctly predicted 36 (95%, 95% confidence interval [CI] = 82% to 99%) of 38 patients with prostate cancer, while 177 (78%, 95% CI = 72% to 83%) of 228 patients were correctly classified as having benign conditions. For men with marginally elevated PSA levels (4-10 ng/mL; n = 137), the specificity was 71%. If validated in future series, serum proteomic pattern diagnostics may be of value in deciding whether to perform a biopsy on a man with an elevated PSA level.

Localized prostate cancer and 30 years of follow-up in a population-based setting.

Some patients with a histopathological diagnosis of prostate cancer have a tumour that behaves benignly during long-term follow-up. The proportion of patients with such a tumour is unknown, as is the fraction who die of prostate cancer between 10 and 20 y of follow-up. All men aged 45-84 y obtaining a diagnosis of prostate cancer between 1965 and 1993 and being reported to the Finnish Cancer Registry were observed. Death was recorded as caused by prostate cancer or not. We identified 11,500 men with localized prostate cancer and in this group the disease-specific survival rate reached a plateau at approximately 30% after 23 y of follow-up. In the same cohort, 5% of the patients died of prostate cancer during years 11-20 of follow-up. During the observation period, somewhat less than half of the patients with localized prostate cancer who died, died of the disease. This proportion decreased with duration of follow-up. In conclusion, early aggressive therapy for localized prostate cancer is unnecessary, in terms of survival, for those with a benignly behaving tumour (about 30% in this series) or who die of intercurrent disease (about 50% in this series). Such therapy may, however, prolong life for the patients and may cure the patients that die of prostate cancer after more than 10 y follow-up. Prostate Cancer and Prostatic Diseases (2000) 3, 37-42

Elevated serum vascular endothelial growth factor in patients with hormone-escaped prostate cancer.

To investigate the role of serum vascular endothelial growth factor (VEGF) in the assessment of patients with prostate cancer. Patients, subjects and methods Serum from 78 men was assayed for VEGF using a commercially available enzyme-linked immunosorbent assay kit. Forty-eight patients had a histopathological diagnosis of prostate cancer (16 local disease, 32 metastatic), nine had benign prostatic hyperplasia (BPH) and 21 were healthy controls. The mean serum VEGF level was significantly higher in patients with hormone-escaped prostate cancer than in all other groups (P </= 0. 02). There were no significant differences in serum VEGF levels among the other groups. In 18 patients with serial measurements there was no significant difference in serum VEGF level during either response to or escape from hormonal therapy. The significantly higher serum VEGF level in patients with hormone-escaped prostate cancer suggests a role in the pathogenesis of advanced disease. However, the lack of significant differences among the other groups and the failure to indicate either response to or escape from hormonal therapy suggests that serum VEGF in this setting is of limited use.