Comparison of Pathologist and Artificial Intelligence-based Grading for Prediction of Metastatic Outcomes After Radical Prostatectomy.

Gleason grade group (GG) is the most powerful prognostic variable in localized prostate cancer; however, interobserver variability remains a challenge. Artificial intelligence algorithms applied to histopathologic images standardize grading, but most have been tested only for agreement with pathologist GG, without assessment of performance with respect to oncologic outcomes. We compared deep learning-based and pathologist-based GGs for an association with metastatic outcome in three surgical cohorts comprising 777 unique patients. A digitized whole slide image of the representative hematoxylin and eosin-stained slide of the dominant tumor nodule was assigned a GG by an artificial intelligence-based grading algorithm and was compared with the GG assigned by a contemporary pathologist or the original pathologist-assigned GG for the entire prostatectomy. Harrell's C-indices based on Cox models for time to metastasis were compared. In a combined analysis of all cohorts, the C-index for the artificial intelligence-assigned GG was 0.77 (95% confidence interval [CI]: 0.73-0.81), compared with 0.77 (95% CI: 0.73-0.81) for the pathologist-assigned GG. By comparison, the original pathologist-assigned GG for the entire case had a C-index of 0.78 (95% CI: 0.73-0.82). PATIENT SUMMARY: Artificial intelligence-enabled prostate cancer grading on a single slide was comparable with pathologist grading for predicting metastatic outcome in men treated by radical prostatectomy, enabling equal access to expert grading in lower resource settings.

Potential Hepatoprotective Effects of Irbesartan, an Accessible Angiotensin II Receptor Blocker, Against Cisplatin-Induced Liver Injury in a Rat Model.

Objectives: Drug-induced liver injury is a common adverse reaction that frequently occurs with chemotherapeutic agents, such as cisplatin (CIS). This study seeks to enhance our understanding of drug actions and their associated adverse effects by examining the toxicity of CIS on rat liver tissue. We aimed to investigate the potential hepatoprotective effects of irbesartan (IRB), an easily accessible angiotensin II receptor blocker, in mitigating CIS-induced hepatotoxicity. Materials and Methods: Wistar albino rats were divided into four groups. These groups included a control group [saline, per oral (p.o.)] for seven days, and 1 mL saline intraperitoneal [(i.p.) on the fourth day]; a CIS group (1 mL saline for seven days and 7.5 mg/kg CIS i.p. on the fourth day); a CIS + IRB group (IRB: 50 mg/kg p.o. for seven days and 7.5 mg/kg CIS i.p. on the fourth day), and an IRB group (50 mg/kg IRB p.o. for seven days). The effect of IRB on interleukin-1 beta (IL-1ß) and caspase 3 levels was evaluated by immunohistochemical analysis, and its effects on mRNA expression levels of CCAAT/enhancer-binding protein homologous protein (CHOP) and immunoglobulin-heavy-chain-binding protein (BiP) were tested by quantitative real-time polymerase chain reaction. Results: IRB administration mitigated CIS-induced liver toxicity by inhibiting endoplasmic reticulum (ER) stress. Specifically, this drug reduced the mRNA expression of ER stress markers, including CHOP and BiP. In addition, IRB treatment decreased oxidative stress, inflammatory responses, and apoptotic markers. Conclusion: These findings suggest that IRB is a promising therapeutic option for preventing CIS-induced liver injury, potentially by modulating ER stress-related pathways.

Chromogenic detection of telomere lengths in situ aids the identification of precancerous lesions in the prostate.

BACKGROUND: Telomeres are terminal chromosomal elements that are essential for the maintenance of genomic integrity. The measurement of telomere content provides useful diagnostic and prognostic information, and fluorescent methods have been developed for this purpose. However, fluorescent-based tissue assays are cumbersome for investigators to undertake, both in research and clinical settings. METHODS: A robust chromogenic in situ hybridization (CISH) approach was developed to visualize and quantify telomere content at single cell resolution in human prostate tissues, both frozen and formalin-fixed, paraffin-embedded (FFPE). RESULTS: This new assay (telomere chromogenic in situ hybridization ["Telo-CISH"]) produces permanently stained slides that are viewable with a standard light microscope, thus avoiding the need for specialized equipment and storage. The assay is compatible with standard immunohistochemistry, thereby allowing simultaneous assessment of histomorphology, identification of specific cell types, and assessment of telomere status. In addition, Telo-CISH eliminates the problem of autofluorescent interference that frequently occurs with fluorescent-based methods. Using this new assay, we demonstrate successful application of Telo-CISH to help identify precancerous lesions in the prostate by the presence of markedly short telomeres specifically in the luminal epithelial cells. CONCLUSIONS: In summary, with fewer restrictions on the types of tissues that can be tested, and increased histologic information provided, the advantages presented by this novel chromogenic assay should extend the applicability of tissue-based telomere length assessment in research and clinical settings.

Predicting Prostate Cancer Molecular Subtype With Deep Learning on Histopathologic Images.

Microscopic examination of prostate cancer has failed to reveal a reproducible association between molecular and morphologic features. However, deep-learning algorithms trained on hematoxylin and eosin (H&E)-stained whole slide images (WSI) may outperform the human eye and help to screen for clinically-relevant genomic alterations. We created deep-learning algorithms to identify prostate tumors with underlying ETS-related gene (ERG) fusions or PTEN deletions using the following 4 stages: (1) automated tumor identification, (2) feature representation learning, (3) classification, and (4) explainability map generation. A novel transformer-based hierarchical architecture was trained on a single representative WSI of the dominant tumor nodule from a radical prostatectomy (RP) cohort with known ERG/PTEN status (n = 224 and n = 205, respectively). Two distinct vision transformer-based networks were used for feature extraction, and a distinct transformer-based model was used for classification. The ERG algorithm performance was validated across 3 RP cohorts, including 64 WSI from the pretraining cohort (AUC, 0.91) and 248 and 375 WSI from 2 independent RP cohorts (AUC, 0.86 and 0.89, respectively). In addition, we tested the ERG algorithm performance in 2 needle biopsy cohorts comprised of 179 and 148 WSI (AUC, 0.78 and 0.80, respectively). Focusing on cases with homogeneous (clonal) PTEN status, PTEN algorithm performance was assessed using 50 WSI reserved from the pretraining cohort (AUC, 0.81), 201 and 337 WSI from 2 independent RP cohorts (AUC, 0.72 and 0.80, respectively), and 151 WSI from a needle biopsy cohort (AUC, 0.75). For explainability, the PTEN algorithm was also applied to 19 WSI with heterogeneous (subclonal) PTEN loss, where the percentage tumor area with predicted PTEN loss correlated with that based on immunohistochemistry (r = 0.58, P = .0097). These deep-learning algorithms to predict ERG/PTEN status prove that H&E images can be used to screen for underlying genomic alterations in prostate cancer.

Chromogenic detection of telomere lengths in situ aids the identification of precancerous lesions in the prostate.

Telomeres are terminal chromosomal elements that are essential for the maintenance of genomic integrity. The measurement of telomere content provides useful diagnostic and prognostic information, and fluorescent methods have been developed for this purpose. However, fluorescent-based tissue assays are cumbersome for investigators to undertake, both in research and clinical settings. Here, a robust chromogenic in situ hybridization (CISH) approach was developed to visualize and quantify telomere content at single cell resolution in human prostate tissues, both frozen and formalin-fixed, paraffin-embedded (FFPE). This new assay ("Telo-CISH") produces permanently stained slides that are viewable with a standard light microscope, thus avoiding the need for specialized equipment and storage. The assay is compatible with standard immunohistochemistry, thereby allowing simultaneous assessment of histomorphology, identification of specific cell types, and assessment of telomere status. In addition, Telo-CISH eliminates the problem of autofluorescent interference that frequently occurs with fluorescent-based methods. Using this new assay, we demonstrate successful application of Telo-CISH to help identify precancerous lesions in the prostate by the presence of markedly short telomeres specifically in the luminal epithelial cells. In summary, with fewer restrictions on the types of tissues that can be tested, and increased histologic information provided, the advantages presented by this novel chromogenic assay should extend the applicability of tissue-based telomere length assessment in research and clinical settings.

The Prognostic Effect of HER2 Gene Amplification in High-Grade Endometrial Carcinomas and its Correlation with Protein Overexpression.

Introduction. New therapeutic agents and biomarkers are needed for the treatment of aggressive endometrial cancer subtypes. Recently, HER2 has been recommended to be tested routinely in serous endometrial cancers. The aim of this study is to investigate the correlation between HER2 (ERBB2) protein overexpression and HER2 gene amplification and the relationship of HER2 gene amplification with prognosis in cancers with serous morphology. In addition, the concordance of HER2 testing in paired curettage and hysterectomy specimens is also investigated. Methods. Twenty five serous carcinomas and 8 carcinosarcomas with a serous morphology were included in the study. HER2 staining was performed on whole tissue sections by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). The system, which was proposed by Fader et al was used to evaluate the stainings. Results. Protein overexpression was detected in 27.3% (n = 9) of the cases, and gene amplification in 30.3% (n = 10). A significant positive correlation was found between the two methods (P < .0001). HER2 IHC revealed a heterogeneous staining pattern, such as intense complete membranous in solid areas, and basolateral in papillary and glandular areas. HER2 gene amplification was significantly associated with shorter overall (P = .005) and disease-free (P = .014) survival. The concordence of the results in curettage and hysterectomy specimens was also significantly high. Conclusion. HER2 is an important prognostic and predictive marker for endometrial cancers with serous morphology. HER2 IHC/ISH testing can be performed by using diagnostic curettage specimens which contain enough viable tumor cells. However, pathologists should be aware of the intratumoral heterogeneity for HER2 staining.

Cell Cycle Progression Score, but Not Phosphatase and Tensin Homolog Loss, Is an Independent Prognostic Factor for Metastasis in Intermediate- and High-risk Prostate Cancer in Men Treated With and Without Salvage Radiotherapy.

PURPOSE: The prognostic value for metastasis of the cell-cycle progression score and phosphatase and tensin homolog haven't been evaluated jointly in contemporary men with exclusively intermediate- or high-risk prostate cancer. We evaluated associations of cell-cycle progression and phosphatase and tensin homolog with metastasis-free survival in contemporary intermediate/high-risk prostate cancer patients overall, and intermediate/high-risk men receiving salvage radiotherapy. MATERIALS AND METHODS: In a case-cohort of 209 prostatectomy patients with intermediate/high-risk prostate cancer, and a cohort of 172 such men who received salvage radiotherapy, cell-cycle progression score was calculated from RNA expression, and phosphatase and tensin homolog was analyzed by immunohistochemistry. Proportional hazards regression, weighted for case-cohort design or unweighted for the salvage radiotherapy cohort, was used to evaluate associations of cell-cycle progression, phosphatase and tensin homolog with metastasis-free survival. Improvement in model discrimination was evaluated with the concordance index. RESULTS: In the case-cohort 41 men had metastasis, and 17 developed metastasis in the salvage radiotherapy cohort, at median follow-up of 3 and 4 years, respectively. For both case-cohort and salvage radiotherapy cohort, cell-cycle progression was independently associated with metastasis-free survival after adjustment for Cancer of the Prostate Risk Assessment Post-Surgical: hazard ratio (95% confidence interval) = 3.11 (1.70-5.69) and 1.85 (1.19-2.85), respectively. Adding cell-cycle progression to Cancer of the Prostate Risk Assessment Post-Surgical increased the concordance index from 0.861 to 0.899 (case-cohort), and 0.745 to 0.819 (salvage radiotherapy cohort). Although statistically significant in univariate analyses, phosphatase and tensin homolog was no longer significant after adjustment for Cancer of the Prostate Risk Assessment Post-Surgical. Analysis of interaction with National Comprehensive Cancer Network risk group showed that cell-cycle progression had the strongest effect among unfavorable intermediate-risk men. CONCLUSIONS: In the first study to evaluate metastasis risk associated with cell-cycle progression and phosphatase and tensin homolog in exclusively intermediate/high-risk prostate cancer, and in such men with salvage radiotherapy, cell-cycle progression but not phosphatase and tensin homolog was associated with significantly increased 2- to 3-fold risk of metastasis after Cancer of the Prostate Risk Assessment Post-Surgical adjustment.

Bladder Urothelial Carcinoma: Machine Learning-based Computed Tomography Radiomics for Prediction of Histological Variant.

RATIONALE AND OBJECTIVES: Histological variant (HV) of bladder urothelial carcinoma (UC) is a significant factor for therapy management. We aim to assess the predictive performance of machine learning (ML)-based Computed Tomography radiomics of UC for HV. MATERIALS AND METHODS: Volume of interest of 37 bladder UC tumors, of which 21 were pure and 16 were HV, were manually segmented. The extracted first- and second-order texture features (n = 117) using 3-D Slicer radiomics were compared to the radical cystectomy histopathological results. ML algorithms were performed to determine the significant models using Python 2.3, Pycaret library. The sample size was increased to 74 by synthetic data generation, and three outliers from the training set were removed (training dataset; n = 52, test dataset; n = 19). The predictive performances of 15 ML algorithms were compared. Then, the best two models were evaluated on the test set and ensembled by Voting Classifier. RESULTS: The ML algorithms demonstrated area under curve (AUC) and accuracy ranging 0.79-0.97 and 50%-90%, respectively on the train set. The best models were Gradient Boosting Classifier (AUC: 0.95, accuracy: 90%) and CatBoost Classifier (AUC: 0.97, accuracy: 85%). On the test set; the Voting Classifier of these two models demonstrated AUC, accuracy, recall, precision, and F1 scores as follows; 0.93, 79%, 86%, 67%, and 75%, respectively. CONCLUSION: ML-based Computed Tomography radiomics of UC can predict HV, a prognostic factor that is indeterminable by qualitative radiological evaluation and can be missed in the preoperative histopathological specimens.

The Movember Global Action Plan 1 (GAP1): Unique Prostate Cancer Tissue Microarray Resource.

BACKGROUND: The need to better understand the molecular underpinnings of the heterogeneous outcomes of patients with prostate cancer is a pressing global problem and a key research priority for Movember. To address this, the Movember Global Action Plan 1 Unique tissue microarray (GAP1-UTMA) project constructed a set of unique and richly annotated tissue microarrays (TMA) from prostate cancer samples obtained from multiple institutions across several global locations. METHODS: Three separate TMA sets were built that differ by purpose and disease state. RESULTS: The intended use of TMA1 (Primary Matched LN) is to validate biomarkers that help determine which clinically localized prostate cancers with associated lymph node metastasis have a high risk of progression to lethal castration-resistant metastatic disease, and to compare molecular properties of high-risk index lesions within the prostate to regional lymph node metastases resected at the time of prostatectomy. TMA2 (Pre vs. Post ADT) was designed to address questions regarding risk of castration-resistant prostate cancer (CRPC) and response to suppression of the androgen receptor/androgen axis, and characterization of the castration-resistant phenotype. TMA3 (CRPC Met Heterogeneity)'s intended use is to assess the heterogeneity of molecular markers across different anatomic sites in lethal prostate cancer metastases. CONCLUSIONS: The GAP1-UTMA project has succeeded in combining a large set of tissue specimens from 501 patients with prostate cancer with rich clinical annotation. IMPACT: This resource is now available to the prostate cancer community as a tool for biomarker validation to address important unanswered clinical questions around disease progression and response to treatment.

Multiplex immunohistochemical phenotyping of T cells in primary prostate cancer.

BACKGROUND: Most prostate cancers are "immune cold" and poorly responsive to immune checkpoint inhibitors. However, the mechanisms responsible for the lack of a robust antitumor adaptive immune response in the prostate are poorly understood, which hinders the development of novel immunotherapeutic approaches. AIMS: Most inflammatory infiltrates in the prostate are centered around benign glands and stroma, which can confound the molecular characterization of the antitumor immune response. We sought to analytically validate a chromogenic-based multiplex immunohistochemistry (IHC) approach applicable to whole slide digital image analysis to quantify T cell subsets from the tumor microenvironment of primary prostatic adenocarcinomas. As an initial application, we tested the hypothesis that PTEN loss leads to an altered antitumor immune response by comparing matched regions of tumors within the same individual with and without PTEN loss. MATERIALS & METHODS: Using the HALO Image Analysis Platform (Indica Labs), we trained a classifier to quantify the densities of eight T cell phenotypes separately in the tumor epithelial and stromal subcompartments. RESULTS: The iterative chromogenic approach using 7 different antibodies on the same slide provides highly similar findings to results using individually stained slides with single antibodies. Our main findings in carcinomas (benign removed) include the following: i) CD4+ T cells are present at higher density than CD8+ T cells; ii) all T cell subsets are present at higher densities in the stromal compartment compared to the epithelial tumor compartment; iii) most CD4+ and CD8+ T cells are PD1+; iv) cancer foci with PTEN loss harbored increased numbers of T cells compared to regions without PTEN loss, in both stromal and epithelial compartments; and v) the increases in T cells in PTEN loss regions were associated with ERG gene fusion status. DISCUSSION: This modular approach can apply to any IHC-validated antibody combination and sets the groundwork for more detailed spatial analyses. CONCLUSION: Iterative chromogenic IHC can be used for whole slide analysis of prostate tissue samples and can complement transcriptomic results including those using single cell and spatial genomic approaches.

The Importance of Prostate-Specific Membrane Antigen Expression in Salivary Gland Tumors.

Objective: Prostate-specific membrane antigen (PSMA) is a cell membrane protein expressed by prostate tissues. It is not prostate specific and is also expressed by some non-prostatic solid neoplasms. Our study aimed to investigate the potential role of PSMA in salivary gland tumors. Methods: The present study was designed to retrospectively analyze our cases that presented with salivary gland tumors. The files of 105 patients were reviewed and their paraffin embedded blocks were retrieved from the pathology department. Immunohistochemical examination and staining were done using PSMA antibody. Tumor tissue PSMA immunohistochemical staining was scored semi-quantitatively with the modified quartile approach. Negative staining was scored 0, >0% and ≤25% tissue expression was considered weak (score 1), >25% and ≤50% tissue expression was considered mild (score 2), >50% and ≤75% tissue expression was considered moderate (score 3), and >75% tissue expression was considered strong (score 4). Results: Eighty-eight patients (55 males, 33 females) were included in the study. Forty-eight patients had pleomorphic adenoma (PA), 35 had Warthin's tumor (WT), two had mucoepidermoid carcinoma, two had adenoid cystic carcinoma, and one had squamous cell carcinoma. There was statistically significant difference in terms of PSMA expression between PA and WT (p=0.003). PSMA expression was high in PA and absent in WT. Conclusion: PSMA is a potential source of inspiration for future studies on the development of novel diagnostic and theranostic investigations of salivary gland tumors. Prospective studies targeting intratumoral PSMA in salivary gland tumors should be planned.

A Nobel-Winning Scientist: Aziz Sancar and the Impact of his Work on the Molecular Pathology of Neoplastic Diseases.

Aziz Sancar, Nobel Prize winning Turkish scientist, made several discoveries which had a major impact on molecular sciences, particularly disciplines that focus on carcinogenesis and cancer treatment, including molecular pathology. Cloning the photolyase gene, which was the initial step of his work on DNA repair mechanisms, discovery of the "Maxicell" method, explanation of the mechanism of nucleotide excision repair and transcription-coupled repair, discovery of "molecular matchmakers", and mapping human excision repair genes at single nucleotide resolution constitute his major research topics. Moreover, Sancar discovered the cryptochromes, the clock genes in humans, in 1998, and this discovery led to substantial progress in the understanding of the circadian clock and the introduction of the concept of "chrono-chemoterapy" for more effective therapy in cancer patients. This review focuses on Aziz Sancar's scientific studies and their reflections on molecular pathology of neoplastic diseases. While providing a new perspective for researchers working in the field of pathology and molecular pathology, this review is also an evidence of how basic sciences and clinical sciences complete each other.

T-Cell Infiltration and Adaptive Treg Resistance in Response to Androgen Deprivation With or Without Vaccination in Localized Prostate Cancer.

PURPOSE: Previous studies suggest that androgen deprivation therapy (ADT) promotes antitumor immunity in prostate cancer. Whether a vaccine-based approach can augment this effect remains unknown. PATIENTS AND METHODS: We conducted a neoadjuvant, randomized study to quantify the immunologic effects of a GM-CSF-secreting allogeneic cellular vaccine in combination with low-dose cyclophosphamide (Cy/GVAX) followed by degarelix versus degarelix alone in patients with high-risk localized prostate adenocarcinoma who were planned for radical prostatectomy. RESULTS: Both Cy/GVAX plus degarelix and degarelix alone led to significant increases in intratumoral CD8+ T-cell infiltration and PD-L1 expression as compared with a cohort of untreated, matched controls. However, the CD8+ T-cell infiltrate was accompanied by a proportional increase in regulatory T cells (Treg), suggesting that adaptive Treg resistance may dampen the immunogenicity of ADT. Although Cy/GVAX followed by degarelix was associated with a modest improvement in time-to-PSA progression and time-to-next treatment, as well as an increase in PD-L1, there was no difference in the CD8+ T-cell infiltrate as compared with degarelix alone. Gene expression profiling demonstrated that CHIT1, a macrophage marker, was differentially upregulated with Cy/GVAX plus degarelix compared with degarelix alone. CONCLUSIONS: Our results highlight that ADT with or without Cy/GVAX induces a complex immune response within the prostate tumor microenvironment. These data have important implications for combining ADT with immunotherapy. In particular, our finding that ADT increases both CD8+ T cells and Tregs supports the development of regimens combining ADT with Treg-depleting agents in the treatment of prostate cancer.

IL8 Expression Is Associated with Prostate Cancer Aggressiveness and Androgen Receptor Loss in Primary and Metastatic Prostate Cancer.

Chronic inflammation and African ancestry are implicated in prostate cancer aggressiveness, and inflammation-related genes are more highly expressed in prostate cancer in African American men. IL8 secretion is also implicated in prostate cancer progression and castration resistance. We used RNA in situ hybridization to localize IL1ß, IL6, IL8, and IL10 mRNA in low- and high-grade prostate cancer from African American and European American men. IL8 was the most abundantly expressed and the only interleukin detected in tumor cells. We further interrogated IL8 expression in primary and metastatic prostate cancer tissue microarrays and both androgen-dependent and castration-resistant patient-derived xenografts (PDX). IL8 was significantly increased in both tumor and benign regions of higher grade cases (ISUP Grade Group 4-5), but there was no difference between races. We determined that IL8 expression in prostate cancer cell lines, distant metastases, and PDX lines was associated with androgen receptor (AR) loss, but not castration resistance. Reciprocal IL8 and AR expression was also observed in high IL8-expressing atrophy lesions with simultaneous AR downregulation. Finally, we show that IL8 is likely repressed by AR binding to the IL8 promoter and is inducible in prostate cancer cells stimulated with lipopolysaccharide only in cells with AR loss. Likewise, AR knockdown in androgen-dependent cells induced IL8 expression, further demonstrating that AR represses IL8 expression. In conclusion, IL8 expression in the tumor microenvironment is associated with aggressive prostate cancer and with AR loss in metastatic disease. IMPLICATIONS: IL8 expression is repressed by AR and is associated with prostate cancer aggressiveness and AR loss in metastatic disease.

A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance.

Understanding the intricacies of lethal prostate cancer poses specific challenges due to difficulties in accurate modeling of metastasis in vivo. Here we show that NPK EYFP mice (for Nkx3.1 CreERT2/+ ; Pten flox/flox ; Kras LSL-G12D/+ ; R26R-CAG-LSL-EYFP/+) develop prostate cancer with a high penetrance of metastasis to bone, thereby enabling detection and tracking of bone metastasis in vivo and ex vivo. Transcriptomic and whole-exome analyses of bone metastasis from these mice revealed distinct molecular profiles conserved between human and mouse and specific patterns of subclonal branching from the primary tumor. Integrating bulk and single-cell transcriptomic data from mouse and human datasets with functional studies in vivo unravels a unique MYC/RAS co-activation signature associated with prostate cancer metastasis. Finally, we identify a gene signature with prognostic value for time to metastasis and predictive of treatment response in human patients undergoing androgen receptor therapy across clinical cohorts, thus uncovering conserved mechanisms of metastasis with potential translational significance.

Secondary Cutaneous Dissemination of Peripheral T-Cell Lymphoma With T-Follicular Helper Phenotype as a Patient's Fourth Primary Malignancy.

Peripheral T-cell lymphomas expressing follicular helper T-cell (TFH) markers have recently been identified. Although this type of lymphomas consist of malignant proliferation of T-cells, they may also exhibit B-cell clonality. We report a case of a 72-year-old woman with multiple erythematous to violaceous nonscaling plaques and tumors on her trunk. Histopathological analysis revealed a dense infiltration of medium-to-large-sized atypical cells throughout the entire dermis. The result of immunohistochemical analysis showed that the infiltrating T-cells expressed programmed death-1 (PD-1), CD10, Bcl-6, CD3, CD4, CD2, and CD5. The infiltrate also contained scattered atypical large B-cells. Based on the clinical appearance and the histopathological findings, we diagnosed the patient with secondary cutaneous dissemination of peripheral T-cell lymphoma with expression of a T-follicular helper phenotype.

Molecular Pathology of High-Grade Prostatic Intraepithelial Neoplasia: Challenges and Opportunities.

A better understanding of the early stages of prostate cancer initiation, potentially arising from precursor lesions, may fuel development of powerful approaches for prostate cancer prevention or interception. The best-known candidate for such a precursor lesion has been referred to as high-grade prostatic intraepithelial neoplasia (HGPIN). Although there is significant evidence supporting the notion that such HGPIN lesions can give rise to invasive adenocarcinomas of the prostate, there are also numerous complicating considerations and evidence that cloud the picture in many instances. Notably, recent evidence has suggested that some fraction of such lesions that are morphologically consistent with HGPIN may actually be invasive carcinomas masquerading as HGPIN-a state that we term "postinvasive intraepithelial carcinoma" (PIC). Although the prevalence of such PIC lesions is not fully understood, this and other factors can confound the potential of identifying prostate precursors that can be targeted for disease prevention, interception, or treatment. Here, we review our current understanding of the morphological and molecular pathological features of prostate cancer precursor lesions.

Profiling the Urinary Microbiome in Men with Positive versus Negative Biopsies for Prostate Cancer.

PURPOSE: Studies demonstrating bacterial DNA and cultivable bacteria in urine samples have challenged the clinical dogma that urine is sterile. Furthermore, studies now indicate that dysbiosis of the urinary microbiome is associated with pathological conditions. We propose that the urinary microbiome may influence chronic inflammation observed in the prostate, leading to prostate cancer development and progression. Therefore, we profiled the urinary microbiome in men with positive vs negative biopsies for prostate cancer. MATERIALS AND METHODS: Urine was collected from men prior to biopsy for prostate cancer. DNA was extracted from urine pellet samples and subjected to bacterial 16S rDNA Illumina® sequencing and 16S rDNA quantitative polymerase chain reaction. We determined the association between bacterial species and the presence or absence of cancer, cancer grade, and type and degree of prostate inflammation. RESULTS: Urine samples revealed diverse bacterial populations. There were no significant differences in α or ß diversity and no clear hierarchical clustering of benign or cancer samples. We identified a cluster of pro-inflammatory bacteria previously implicated in urogenital infections in a subset of samples. Many species, including known uropathogens, were significantly and differentially abundant among cancer and benign samples, in low vs higher grade cancers and in relation to prostate inflammation type and degree. CONCLUSIONS: To our knowledge we report the most comprehensive study to date of the male urinary microbiome and its relationship to prostate cancer. Our results suggest a prevalence of pro-inflammatory bacteria and uropathogens in the urinary tract of men with prostate cancer.

Nonfunctional double parathyroid carcinoma with incidental thyroid micropapillary carcinoma: a rare case.

Parathyroid carcinomas are rare endocrine tumors which comprise 0.3-5.6% of all causes of hyperparathyroidism. 90% of them are hormonally active, while 10% of them may be non-functional. They mostly occur in a single parathyroid gland. Concurrent involvement of both parathyroid glands is quite rare. A 57-year-old male patient was admitted to emergency department with the complaint of dyspnea. Thorax tomography revealed a retrosternal mass. The mass was thoracoscopically excised by thoracic surgeons. Histopathological examination result of the mass was reported as parathyroid carcinoma. Parathyroid scintigraphy performed and focal activity increase in the lower pole of the left lobe. Parathyroid hormone level was 118 pg/ml and calcium level was measured as 11.4 mg/dl. The patient with these findings was operated and pathological examination of excised left lower parathyroid tissue was reported as carcinoma. In addition, micropapillary carcinoma was detected in left thyroid lobectomy specimen.Our case was also unusual in that double parathyroid carcinoma, which is a rare condition, was hormonally inactive. We aimed to present our case in the light of the literature due to its rare occurrence.