Pathology without microscope: From a projection screen to a virtual slide.

We have witnessed successive stages since the Seventies in the advancements towards digital pathology. We agree with Dr Pallua et al on the tremendous changes that are taking place in pathology, all leading toward greater role of digitalization in the field of pathology, both in terms of consultation and teaching. In particular, distance teaching using digital pathology will grow into a mainstream mode of pathology teaching, something that has been reinforced by COVID-19.

Epigenetic modulations and lineage plasticity in advanced prostate cancer.

Prostate cancer is the most common cancer and second leading cause of cancer-related death in American men. Antiandrogen therapies are part of the standard of therapeutic regimen for advanced or metastatic prostate cancers; however, patients who receive these treatments are more likely to develop castration-resistant prostate cancer (CRPC) or neuroendocrine prostate cancer (NEPC). In the development of CRPC or NEPC, numerous genetic signaling pathways have been under preclinical investigations and in clinical trials. Accumulated evidence shows that DNA methylation, chromatin integrity, and accessibility for transcriptional regulation still play key roles in prostate cancer initiation and progression. Better understanding of how epigenetic change regulates the progression of prostate cancer and the interaction between epigenetic and genetic modulators driving NEPC may help develop a better risk stratification and more effective treatment regimens for prostate cancer patients.

Dataset for the reporting of carcinoma of the bladder-cystectomy, cystoprostatectomy and diverticulectomy specimens: recommendations from the International Collaboration on Cancer Reporting (ICCR).

The International Collaboration on Cancer Reporting (ICCR) is a not for profit organisation whose goal is to produce standardised internationally agreed and evidence-based datasets for pathology reporting. With input from pathologists worldwide, the datasets are intended to be uniform and structured. They include all items necessary for an objective and accurate pathology report which enables clinicians to apply the best treatment for the patient. This dataset has had input from a multidisciplinary ICCR expert panel. The rationale for some items being required and others recommended is explained, based on the latest literature. The dataset incorporates data from the World Health Organization (WHO) 2016, and also from the latest (8th edition) TNM staging system of the American Joint Committee on Cancer (AJCC). Fifteen required elements and eight recommended items are described. This dataset provides all the details for a precise and valuable pathology report required for patient management and prognostication. This dataset is intended for worldwide use, and should facilitate the collection of standardised comparable data on bladder carcinoma at an international level.

Dataset for the reporting of urinary tract carcinoma-biopsy and transurethral resection specimen: recommendations from the International Collaboration on Cancer Reporting (ICCR).

The International Collaboration on Cancer Reporting (ICCR) is an alliance of major pathology organisations in Australasia, Canada, Europe, United Kingdom, and United States of America that develops internationally standardised, evidence-based datasets for the pathology reporting of cancer specimens. This dataset was developed by a multidisciplinary panel of international experts based on previously published ICCR guidelines for the production of cancer datasets. It is composed of Required (core) and Recommended (noncore) elements identified on the basis of literature review and expert consensus. The document also includes an explanatory commentary explaining the rationale behind the categorization of individual data items and provides guidance on how these should be collected and reported. The dataset includes nine required and six recommended elements for the reporting of cancers of the urinary tract in biopsy and transurethral resection (TUR) specimens. The required elements include specimen site, operative procedure, histological tumor type, subtype/variant of urothelial carcinoma, tumor grade, extent of invasion, status of muscularis propria, noninvasive carcinoma, and lymphovascular invasion (LVI). The recommended elements include clinical information, block identification key, extent of T1 disease, associated epithelial lesions, coexistent pathology, and ancillary studies. The dataset provides a structured template for globally harmonized collection of pathology data required for management of patients diagnosed with cancer of the urinary tract in biopsy and TUR specimens. It is expected that this will facilitate international collaboration, reduce duplication of effort in updating current national/institutional datasets, and be particularly useful for countries that have not developed their own datasets.

Expresión de las proteínas FGFR3, PI3K, AKT, p21Waf1/Cip1 y ciclinas D1 y D3 en pacientes con tumores de vejiga T1: implicaciones clínicas y significado pronóstico / Expression of proteins FGFR3, PI3K, AKT, p21Waf1/Cip1 and cyclins D1 and D3 in patients with T1 bladder tumours: clinical implications and prognostic significance

Objetivo: Determinar la expresión proteica diferencial de los biomarcadores FGFR3, PI3K (subunidades PI3Kp110α, PI3KClassIII, PI3Kp85), AKT, p21Waf1/Cip1 y las ciclinas D1 y D3 en el cáncer de vejiga T1 versus tejido sano, así como estudiar su posible papel como marcadores de recidiva precoz. Material y método: Se trata de un estudio prospectivo en el que se utilizaron un total de 67 muestras de tejido (55 casos de tumores de vejiga T1 sometidos a resección transuretral y 12 casos de mucosa sana adyacente). Los niveles de expresión de las proteínas se evaluaron mediante Western blot, y las medias y los porcentajes fueron comparados utilizando el test «t» de Student y la prueba Chi cuadrado. El análisis de supervivencia se realizó mediante el método Kaplan-Meier y el test Log-rank. Resultados: Se detectó una mayor expresión proteica de FGFR3, PI3Kp110α, PI3KClassIII, ciclinas D1 y D3 y p21Waf1/Cip1 en tejido tumoral versus mucosa sana. Sin embargo, estas diferencias no fueron significativas para PI3Kp85 y AKT. Se observaron correlaciones estadísticamente significativas de PI3Kp110α, PI3KClassIII, PI3Kp85 y AKT con la recidiva temprana (p = 0,003, p = 0,045, p = 0,050 y p = 0,028 respectivamente), de ciclina D3 (p=0,001) con el tipo tumoral (primario versus recidivante), de FGFR3 (p = 0,035) con el tamaño tumoral y de ciclina D1 (p = 0,039) con la multifocalidad. El análisis de supervivencia seleccionó a FGFR3 (p = 0,024), PI3Kp110alfa (p = 0,014), PI3KClassIII (p = 0,042) y AKT (p= 0,008) como marcadores de supervivencia libre de recidiva precoz. Conclusiones: Existe un incremento de los niveles de expresión proteica en el tejido tumoral vesical, asimismo, la sobreexpresión de FGFR3, PI3Kp110α, PI3KClassIII y AKT se asocia con una mayor supervivencia libre de recidiva precoz en pacientes con tumores de vejiga T1

Objective: To determine the differential protein expression of biomarkers FGFR3, PI3K (subunits PI3Kp110α, PI3KClassIII, PI3Kp85), AKT, p21Waf1/Cip1 and cyclins D1 and D3 in T1 bladder cancer versus healthy tissue and to study their potential role as early recurrence markers. Material and method: This is a prospective study that employed a total of 67 tissue samples (55 cases of T1 bladder tumours that underwent transurethral resection and 12 cases of adjacent healthy mucosa). The protein expression levels were assessed using Western blot, and the means and percentages were compared using Student's t-test and the chi-squared test. The survival analysis was conducted using the Kaplan-Meier method and the log-rank test. Results: Greater protein expression was detected for FGFR3, PI3Kp110α, PI3KClassIII, cyclins D1 and D3 and p21Waf1/Cip1 in the tumour tissue than in the healthy mucosa. However, these differences were not significant for PI3Kp85 and AKT. We observed statistically significant correlations between early recurrence and PI3Kp110α, PI3KClassIII, PI3Kp85 and AKT (P = .003, P = .045, P = .050 and P = .028, respectively), between the tumour type (primary vs. recurrence) and cyclin D3 (P=.001), between the tumour size and FGFR3 (P = .035) and between multifocality and cyclin D1 (P = .039). The survival analysis selected FGFR3 (P = .024), PI3Kp110α (P = .014), PI3KClassIII (P = .042) and AKT (P = .008) as markers of early-recurrence-free survival. Conclusions:. There is an increase in protein expression levels in bladder tumour tissue. The overexpression of FGFR3, PI3Kp110α, PI3KClassIII and AKT is associated with increased early-recurrence-free survival for patients with T1 bladder tumours

Expression of proteins FGFR3, PI3K, AKT, p21Waf1/Cip1 and cyclins D1 and D3 in patients with T1 bladder tumours: clinical implications and prognostic significance. / Expresión de las proteínas FGFR3, PI3K, AKT, p21Waf1/Cip1 y ciclinas D1 y D3 en pacientes con tumores de vejiga T1: implicaciones clínicas y significado pronóstico.

OBJECTIVE: To determine the differential protein expression of biomarkers FGFR3, PI3K (subunits PI3Kp110α, PI3KClassIII, PI3Kp85), AKT, p21Waf1/Cip1 and cyclins D1 and D3 in T1 bladder cancer versus healthy tissue and to study their potential role as early recurrence markers. MATERIAL AND METHOD: This is a prospective study that employed a total of 67 tissue samples (55 cases of T1 bladder tumours that underwent transurethral resection and 12 cases of adjacent healthy mucosa). The protein expression levels were assessed using Western blot, and the means and percentages were compared using Student's t-test and the chi-squared test. The survival analysis was conducted using the Kaplan-Meier method and the log-rank test. RESULTS: Greater protein expression was detected for FGFR3, PI3Kp110α, PI3KClassIII, cyclins D1 and D3 and p21Waf1/Cip1 in the tumour tissue than in the healthy mucosa. However, these differences were not significant for PI3Kp85 and AKT. We observed statistically significant correlations between early recurrence and PI3Kp110α, PI3KClassIII, PI3Kp85 and AKT (P=.003, P=.045, P=.050 and P=.028, respectively), between the tumour type (primary vs. recurrence) and cyclin D3 (P=.001), between the tumour size and FGFR3 (P=.035) and between multifocality and cyclin D1 (P=.039). The survival analysis selected FGFR3 (P=.024), PI3Kp110α (P=.014), PI3KClassIII (P=.042) and AKT (P=.008) as markers of early-recurrence-free survival. CONCLUSIONS: There is an increase in protein expression levels in bladder tumour tissue. The overexpression of FGFR3, PI3Kp110α, PI3KClassIII and AKT is associated with increased early-recurrence-free survival for patients with T1 bladder tumours.

Variation in reporting of cancer extent and benign histology in prostate biopsies among European pathologists.

It is not known how uropathologists currently report histopathological features of prostate biopsies such as core length, tumor extent, perineural invasion, and non-tumor-associated features such as inflammation and hyperplasia in needle biopsies. A web-based survey was distributed among 661 members of the European Network of Uropathology. Complete replies were received from 266 pathologists in 22 European countries. Total core lengths were reported by 64 %. The numbers of cores positive for cancer was given by 79 %. Linear cancer extent was reported by 81 %, most often given in millimeters for each core (53 %) followed by the estimation of percentage of cancer in each core (40 %). A gap of benign tissue between separate cancer foci in a single core would always be subtracted by 48 % and by 63 % if cancer foci were minute and widely separated. Perineural invasion was reported by 97 %. Fat invasion by tumor was interpreted as extraprostatic extension by 81 %. Chronic and active/acute inflammation was always reported by 32 and 56 % but only if pronounced by 54 and 39 %, respectively. While most (79 %) would never diagnose benign prostatic hyperplasia on needle biopsy, 21 % would attempt to make this diagnosis. Reporting practices for prostate biopsies are variable among European pathologists. The great variation in some methodologies used suggests a need for further international consensus, in order for retrospective data to be comparable between different institutions.

Reproducibility of histopathologic tumor grading in penile cancer--results of a European project.

Since reliable molecular prognostic parameters for inguinal lymph metastases in penile cancer are not available, tumor grading is often used as a surrogate prognostic tool for the indication of inguinal lymphadenctomy and has been integrated into the current TNM classification for penile cancer. The reliability of tumor grading is under discussion. We examined interobserver grading variability in 90 primary penile carcinomas, assessed by 12 different uropathologists from five European countries. Tumor grading, following the CAP scheme, was compared, and interobserver variability was calculated using kappa statistics. The interobserver variability was high as reflected by an overall low kappa coefficient (mean k = 0.34) and reached a moderate level only in 26.4 % of the cases (range 0.02-0.67). The percentage of G1 tumors assigned ranged from 8.6 to 52.5 %, G2 tumors from 27.1 to 72.6 % and G3 tumors from 11.7 to 48.7 %. Only some observers assigned G4 with a range of 0.6-21.9 %. Subdivision into low and high grade according to UICC and EAU classifications differed significantly (P < 0.001). Low reproducibility of grading in penile carcinomas with the favored method does not allow a reliable prognostication of tumor aggressiveness. Inclusion of histological grading into the TNM classification currently seems not to be a benefit.

Pathology of upper tract urothelial carcinoma with emphasis on staging.

Classification of upper tract urothelial preneoplastic and neoplastic lesions mirrors that of the urinary bladder, with all lesions of the bladder urothelium being possible in the upper tract and vice versa. There are three major groups of non-invasive urothelial neoplasms: flat, papillary, and inverted. These three groups share a similar morphological spectrum of intraurothelial changes, ranging from hyperplasia to dysplasia to carcinoma in situ. However, they differ in terms of architectural growth pattern compared to the surrounding non-neoplastic mucosal surface. Infiltrating urothelial carcinoma is defined as a urothelial tumor that invades beyond the basement membrane. Unlike in non-invasive papillary urothelial neoplasms (pTa), the role of histologic grade in pT1 and higher stage tumors has been suggested to be of only relative importance. The vast majority of tumors of the upper urinary tract are urothelial carcinoma. More commonly seen, however, are foci of squamous differentiation and, less frequently, glandular differentiation. Pure urothelial carcinomas also display a wide range of variant morphologies, and recognition of these morphologies is important for diagnosis, classification, and prognosis.

Targeting prostate-specific membrane antigen for personalized therapies in prostate cancer: morphologic and molecular backgrounds and future promises.

Prostate-specific membrane antigen (PSMA) is an integral, non-shed membrane glycoprotein that is highly expressed on prostate epithelial cells and strongly upregulated in prostate cancer (PCa). Prostatic neoplastic transformation results in the transfer of PSMA from the apical membrane to the luminal surface of the ducts. However, the role of PSMA in tumor angiogenesis and carcinogenesis is poorly understood. PSMA is characterized by folate hydrolase and carboxypeptidase activity and internalization function, and its levels are directly correlated to androgen independence, metastasis and PCa progression. As largely substantiated by preclinical and clinical findings, PSMA could represent a promising target for Positron Emission Tomography (PET) radiopharmaceuticals for PCa imaging. Furthermore, PSMA could prove an important target for the development of new therapeutic approaches, including PSMA-based aptamers, peptides, antibody-drug conjugated therapy, as well as radiotherapy and immunotherapy. This review will summarize the role of PSMA in PCa development and progression and its potential role in the diagnosis and treatment of patients with initial and advanced PCa.

Karyometry and quantitative immunohistochemical analysis of the urothelium in tissue sections: a feasibility study based on chromatin remodeler DAXX immunostaining.

The aim of this study was to investigate the feasibility of applying a software traditionally used in the field of engineering to pathology, in particular to tissue sections from normal urothelium (NU) immuno-stained for the chromatin remodeler DAXX (death domain-associated protein). The study included 5 cases of NU. Images were recorded with a Nikon digital camera. The nuclear area and the intensity of nuclear staining were analyzed with a software package developed in LabVIEW environment. The nuclear size is 14.8 plus or minus 6.5 square microns. The nuclei in the cells adjacent to the stroma are slightly smaller than in the intermediate cells by a factor of 0.86. The mean nuclear area of the nuclei in the superficial cell layer in NU is identical to the nuclei in the intermediate cell layers. For each nucleus intensity of nuclear staining is calculated based on the gray value of the individual picture elements in the green color plane. The mean and standard deviation of nuclear gray value are 106 plus or minus 15. The mean value in the nuclei adjacent to the stroma is slightly greater by a factor 1.02 and 1.04 compared to the intermediate and superficial cell layers. In conclusion, this exploratory study shows that karyometry and quantitative immunohistochemical analysis can be done accurately by using a digital camera commonly available to pathologists and an image analysis software routinely used in the field of engineering.

Valor pronóstico de la invasión microvascular en la predicción de la supervivencia en el carcinoma de células renales / Prognostic value of microvascular invasion in predicting survival in renal cell carcinoma

Objetivos: Evaluar el significado de la invasión microvascular y de otras variables clínicas e histológicas como factores predictivos de supervivencia libre de progresión y supervivencia cáncer-específica de pacientes con carcinoma renal tras cirugía. Material y métodos: Se realizó un estudio analítico retrospectivo sobre 238 pacientes consecutivos con carcinoma renal sometidos a cirugía radical o parcial entre 1990 y 2006, incluyendo tanto casos de enfermedad localizada como aquellos con afectación locorregional o con enfermedad metastásica a distancia en el momento del diagnóstico (pT1-4; N0-1; M0-1). Se evaluó la supervivencia libre de progresión y la supervivencia cáncer-específica tras un seguimiento medio de 75 meses (rango: 1-189). Las variables analizadas incluyeron: edad, sexo, tamaño tumoral, clasificación TNM 2010, gradación nuclear, subtipo histológico e invasión microvascular. Resultados: Se evidenció existencia de invasión microvascular en 79 casos (33,2%). La presencia de invasión microvascular tumoral en el estudio histológico se asoció estadísticamente con la edad (p = 0,010), el tamaño tumoral (p = 0,000), el grado de Fuhrman (p = 0,000), el estadio pT 2010 (p = 0,000), el estadio N 2010 (p = 0,000) y el estadio M 2010 (p = 0,000). En el análisis múltiple las variables que finalmente se mostraron como factores predictores de supervivencia libre de progresión fueron el sexo, el grado de Fuhrman, el estadio pT y el tipo histológico, mientras que lo fueron para supervivencia cáncer específica el sexo, el grado de Fuhrman, el estadio pT 2010, el estadio M 2010, el tipo histológico y la invasión microvascular. Conclusiones: Los resultados de nuestro estudio muestran que la invasión microvascular es un factor predictor de supervivencia cáncer-específica en pacientes con carcinoma renal (AU)

Objective: To assess microvascular tumor invasion and other clinical and histological parameters as potential prognostic factors in surgically treated renal cell carcinoma. Materials and methods: Surgical specimens from 238 consecutive patients who underwent radical or partial surgery between 1990 and 2006 were retrospectively evaluated. The series included clinically localized or metastatic renal cell carcinoma (pT1-4; N0-1; M0-1). Disease-free and cancer-specific survival assessments were the end points with median follow-up of 75 months (range 1-189 months). Variables studied included: age, sex, tumor size, TNM 2010 classification, Fuhrman grade, histological subtype and microvascular tumor invasion. Results: Microvascular tumor invasion was observed in 79 patients (33,2%) and was significantly associated with age (P =0 .010), tumor size (P =0 .000), Fuhrman grade (P = 0.000), pT stage 2010 (P = 0.000), N stage 2010 (P =0 .000) and M stage 2010 (P = 0.000). Multivariate analyses determined that sex, Fuhrman grade, pT stage 2010 and histological subtipe were independent prognostic factors of disease-free survival, while sex, Fuhrman grade, pT stage 2010, M stage 2010, histological subtype and microvascular invasion were prognostic factors for cancer-specific survival. Conclusions: Our study shows that microvascular tumor invasion is an independent prognostic factor for cancer-specific survival in surgically treated patients with renal cell carcinoma (AU)

Update on selected renal cell tumors with clear cell features. With emphasis on multilocular cystic clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (CCRCC) is the most common malignant tumor of renal epithelial origin and, with the exception of some rare tumors, the most deadly. The exception is represented by the multilocular cystic CCRCC, whose prognosis is excellent with survival rates of 100% when diagnosis is made according to the WHO definition. For this reason a proposal has been made to rename this tumor as multilocular cystic renal cell neoplasms of low malignant potential. Another exemption could be the clear cell (tubulo) papillary renal cell carcinoma/clear cell papillary renal cell carcinoma (CCPRCC), a tumor with tubulopapillary architecture and clear cytoplasm. Published data indicates that these are neoplasms with indolent clinical behavior. No cases with metastasis have been reported. Neoplasms meeting criteria for CCPRCC will subsequently be reclassified as of "low malignant potential" rather than carcinoma. The stroma of CCPRCC not infrequently demonstrates smooth muscle metaplasia. It should be remembered, however, that smooth muscle stromal metaplasia and proliferation are not entirely specific to this entity. Hence, it is suggested that smooth muscle metaplasia in the kidney may be a nonspecific common reaction to a variety of stimuli. Xp11 translocation renal cell carcinomas are a group of neoplasms distinguished by chromosomal translocations with breakpoints involving the TFE3 transcription factor gene, which maps to the Xp11.2 locus. The most distinctive histologic pattern of the Xp11 translocation renal cell carcinoma is that of a neoplasm with both clear cells and papillary architecture, and abundant psammoma bodies. TFE3 immunohistochemical staining is reported to be sensitive and specific for a diagnosis of translocation-associated carcinoma as long as the labeling is strong, diffuse, and nuclear. This immunostaining is particularly useful if the differential diagnosis includes CCRCC and CCPRCC. In conclusion, recognition of CCRCC and differentiation from other renal cell neoplasms with clear cytoplasm is important not only for prognostication but also for treatment-related reasons.

Treatment effects in prostate cancer following traditional and emerging therapies.

Treatment options for prostate cancer consist of radical prostatectomy, hormonal therapy and radiation therapy. Hormonal and radiation therapy have well-known, often profound, effects on the histological appearance of benign and malignant prostate tissue. Novel therapies including focal ablative treatments, chemotherapies and targeted molecular therapies are beginning to emerge and pathologists will play a central role in documenting the effects of these treatments at the tissue level. As such, knowledge of treatment-related changes and access to clinical information are essential to ensure accurate interpretation and reporting of post-treatment prostate specimens by pathologists.

Prognostic value of microvascular invasion in predicting survival in renal cell carcinoma.

OBJECTIVE: To assess microvascular tumor invasion and other clinical and histological parameters as potential prognostic factors in surgically treated renal cell carcinoma. MATERIALS AND METHODS: Surgical specimens from 238 consecutive patients who underwent radical or partial surgery between 1990 and 2006 were retrospectively evaluated. The series included clinically localized or metastatic renal cell carcinoma (pT1-4; N0-1; M0-1). Disease-free and cancer-specific survival assessments were the end points with median follow-up of 75 months (range 1-189 months). Variables studied included: age, sex, tumor size, TNM 2010 classification, Fuhrman grade, histological subtype and microvascular tumor invasion. RESULTS: Microvascular tumor invasion was observed in 79 patients (33,2%) and was significantly associated with age (P=.010), tumor size (P=.000), Fuhrman grade (P=.000), pT stage 2010 (P=.000),N stage 2010 (P=.000) and M stage 2010 (P=.000). Multivariate analyses determined that sex, Fuhrman grade, pT stage 2010 and histological subtipe were independent prognostic factors of disease-free survival, while sex, Fuhrman grade, pT stage 2010, M stage 2010, histological subtype and microvascular invasion were prognostic factors for cancer-specific survival. CONCLUSIONS: Our study shows that microvascular tumor invasion is an independent prognostic factor for cancer-specific survival in surgically treated patients with renal cell carcinoma.

A contemporary update on pathology reporting for urinary bladder cancer.

Providing the best management for patients with bladder cancer relies on close cooperation among uro-oncologists and pathologists. The pathologist is involved in the diagnosis and assessment of prognostic and therapeutic factors in bladder biopsies, transurethral resection (TUR) and cystectomy specimens. The pathologist must report accurately the key features using terms that are well understood by clinicians. Adequate clinical information is important to pathologists in deciding the best approach in handling and processing the surgical specimens.

Immunohistochemical expression and localization of somatostatin receptors in normal prostate, high grade prostatic intraepithelial neoplasia and prostate cancer and its many faces.

Data on the immunohistochemical expression and localization of the five somatostatin receptors (SSTRs) have been obtained by our group in separate studies concerning the many faces of prostate cancer (PCa), its precursor high grade prostatic intraepithelial neoplasia (HGPIN) and normal epithelium (Nep). This publication highlights the key findings, with special reference to: normal prostate epithelium; untreated HGPIN and PCa, both clinically and incidentally detected; PCa with NE differentiation; HGPIN and PCa following complete androgen ablation (CAA); and hormone refractory (HR) PCa. Taken together, the data obtained in these investigations demonstrate that SSTR profiling in individual patients with HGPIN and the multifaceted PCa is feasible and is of relevance to better tailor the somatostatin analogue-based treatment.

Is there a role for prostate tumour overexpressed-1 in the diagnosis of HGPIN and of prostatic adenocarcinoma? A comparison with alpha-methylacyl CoA racemase.

Prostate Tumour Overexpressed-1 (PTOV1) was recently identified as a novel gene and protein during a differential display screening for genes overexpressed in prostate cancer (PCa). Alpha-Methyl-CoA racemase (AMACR) mRNA was identified as being overexpressed in PCa. PTOV1 and racemase were immunohistochemically evaluated in PCa, high-grade prostatic intraepithelial neoplasia (HGPIN), atrophy and normal-looking epithelium (NEp) in 20 radical prostatectomies (RPs) with pT2a Gleason score 6 prostate cancer with the aim of analyzing the differences in marker expression between PTOV1 and AMACR. The level of expression of PTOV1 and AMACR increased from NEp and atrophy through HGPIN, away from and adjacent to prostate cancer, to PCa. With the ROC curve analysis the overall accuracy in distinguishing PCa vs HGPIN away from and adjacent to cancer was higher for AMACR than for PTOV1. In conclusion, AMACR can be considered a more accurate marker than PTOV1 in the identification of HGPIN and of PCa. However, PTOV1 may aid in the diagnosis of PCa, at least to supplement AMACR as another positive marker of carcinoma and to potentially increase diagnostic accuracy.

Global acetylation and methylation changes predict papillary urothelial neoplasia of low malignant potential recurrence: a quantitative analysis.

Papillary urothelial neoplasia of low malignant potential (PUNLMP) recurs in approximately 35% of patients. Conventional histopathological assessment does not distinguish non-recurrent from recurrent PUNLMP. The aim of this study is to explore the differences in global histone acetylation and global DNA methylation between non-recurrent and recurrent PUNLMP. Acetylated histone H3 lysine 9 (AcH3K9) and 5-methylcytosine (5MeC) were investigated by immunohistochemistry (IHC) in 20 PUNLMP cases (10 non-recurrent and 10 recurrent), in 5 cases of normal urothelium (NU) and in 5 cases of muscle invasive pT2 urothelial carcinoma (UC). The total optical density of the nuclear staining was measured photometrically in at least 40 nuclei separately for the basal, intermediate and luminal positions in each case. Concerning the total optical density values for both acetylation and methylation, a decrease in staining is observed from non-recurrent PUNLMP to recurrent PUNLMP, at all nuclear locations. For acetylation the mean value in non-recurrent PUNLMP, intermediate between NU and UC, is closer to the former than to latter. The mean value in recurrent PUNLMP is closer to UC than to NU. In NU, non-recurrent and recurrent PUNLMP, the acetylation to methylation ratio decreased from the nuclei in basal position to those in the surface, the average for the above groups being 1.491, 1.611 and 1.746, respectively. Setting the observed values for NU at each sampling location to unity, acetylation shows a steady decrease, the percentages of changes in this nuclear location compared to NU being -5% in non-recurrent PUNLMP, -15% in recurrent PUNLMP and -24% in UC. Concerning methylation, there is a slight increase in non-recurrent PUNLMP (+5%), a decrease in recurrent PUNLMP (-19%) followed by a sharp rise for the UC (+61%). In conclusion, there are differences in global histone acetylation and DNA methylation patterns between non-recurrent and recurrent PUNLMP. Further studies are needed to elucidate the complex interplay between chromatin structure, its modifications and recurrence of PUNLMP.

Immunohistochemical expression and localization of somatostatin receptor subtypes in prostate cancer with neuroendocrine differentiation.

The aim of the study is to examine the tissue expression and localization of the somatostatin receptors (SSTRs) in prostate cancer (PCa) with neuroendocrine (NE) differentiation. The five SSTR subtypes (SSTR1 to 5) were evaluated immunohistochemically in the secretory cells of normal-looking epithelium (Nep), high-grade prostatic intraepithelial neoplasia (HGPIN) and PCa in 20 radical prostatectomies (RPs) with Gleason score 3+3=6 acinar PCa; 20 RPs with GS 4+4=8 and 4+5=9 PCa; and 20 RPs with PCa with NE differentiation. The basal cells were evaluated in Nep and HGPIN. In all groups the stromal smooth muscle and endothelial cells were also analyzed. Concerning the secretory cells, (i) the greatest mean proportions of cells with strong cytoplasmic staining in PCa were seen for SSTR2, mainly in the group of RP with NE differentiation, and for SSTR4 in all three groups; the mean values in HGPIN were intermediate between Nep and PCa; (ii) Membrane staining was seen for SSTR3 and SSTR4; the mean percentages of positive cells, higher in SSTR3 than in SSTR4, decreased from Nep to HGPIN and PCa in all three RP groups; in the latter two, the mean percentages were similar; and (iii) Nuclear staining was seen with SSTR4 and SSTR5; for SSTR4, the mean percentages in the PCa of the three groups were higher than in HGPIN and Nep, the highest proportion being with PCa with NE differentiation. Concerning the basal cells, in Nep the mean proportions of cells with strong staining intensity were greater for SSTR1 and SSTR3 than for the other subtypes, the lowest being with SSTR2; in HGPIN the highest mean propositions of positive cells was with SSTR3, the proportions in the three RP groups being similar. Concerning the stromal smooth muscle and endothelial cells, the highest mean values being in SSTR1 and the lowest in SSTR5; for the former subtype the highest proportion of endothelial cells with strong intensity was seen in the RP NE group. In conclusion, this immunohistochemical study expands our knowledge on the expression and localization of five SSTRs in the various tissue components in the prostate with PCa with NE differentiation, compared with conventional PCa. Typing somatostatin receptor expression in NE tumours could be of relevance to target somatostatin analogue-based diagnostic approach and treatment.