Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The DACH1 gene encodes a winged helix/Forkhead ...DNA-binding protein that competes for binding to FOXM1 sites. Herein, DACH1 gene deletion within the 13q21.31-q21.33 region occurs in up to 18% of human PCa and was associated with increased AR activity and poor prognosis. In prostate OncoMice, prostate-specific deletion of the Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN), and was associated with increased TGFβ activity and DNA damage. Reduced Dach1 increased DNA damage in response to genotoxic stresses. DACH1 was recruited to sites of DNA damage, augmenting recruitment of Ku70/Ku80. Reduced Dach1 expression was associated with increased homology directed repair and resistance to PARP inhibitors and TGFβ kinase inhibitors. Reduced Dach1 expression may define a subclass of PCa that warrants specific therapies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The past decade has brought major changes in prostate biopsy sampling, interpretation, and reporting.
To summarize current information on diagnostic decision making, Gleason grading, "atypical" ...diagnoses, and use of immunostaining.
Pertinent literature from 1985 to 2005 is reviewed, emphasizing recent findings.
Diagnosis begins by evaluating a focus of atypical single-cell layer lined acini according to the 3 minimal diagnostic criteria for cancer: an infiltrative pattern, nuclear enlargement and hyperchromasia, and prominent nucleoli. The Gleason score and linear extent or percent of each core containing cancer should be reported. Atypical small acinar proliferation suspicious for malignancy designates foci that have either qualitative or quantitative limitations in atypia precluding a definite cancer diagnosis. It has about a 3% incidence as an isolated finding. Contemporary studies indicate a 39% predictive value for cancer on repeat biopsy. Isolated high-grade prostatic intraepithelial neoplasia has a 3% to 14% incidence and predicts cancer on repeat biopsy in 23% of cases. Immunostaining for a marker of benign prostate (cytoplasmic keratin 34betaE12 or nuclear p63) and a marker of cancer (alpha-methylacyl coA racemase, clone P504S) may or may not resolve atypical small acinar proliferation diagnoses. Performance of 34betaE12 and P504S immunostains resolved 76% of atypical small acinar proliferation diagnoses per consensus of 3 urologic pathologists studied; a technical limitation is preservation of the focus in question on the levels used for immunostaining.
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DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
To evaluate the clinical features, pathologic features, and prevalence of human papilloma virus (HPV) in squamous cell carcinoma (SCC) of the bladder. SCC of the bladder is known to be associated ...with conditions that cause chronic inflammation/irritation. The literature is inconsistent regarding the association of HPV with pure SCC of the bladder.
A multi-institutional study identified cases of SCC of the bladder. Pure squamous histology and the absence of urothelial carcinoma in situ were required for inclusion. Clinical and pathologic features were collected, and tissues were evaluated for high-risk HPV using p16 immunohistochemistry and in situ hybridization.
We identified 207 cases of SCC of the bladder. Risk factors for bladder cancer included smoking (133/207, 64%) and chronic bladder irritation (83/207, 40%). The majority (155/207, 75%) of patients had > pT2 disease. Mean tumor size was 5.6 ± 3.0 cm and 36/207 (17%) patients had lymph node positive disease. p16 immunohistochemistry was positive in 52/204 (25%) cases but high-risk HPV was identified with in situ hybridization in only 1 (0.5%) case. Tumor size, stage, number of lymph nodes removed, number of positive lymph nodes, lymphovascular invasion, perineural invasion, and positive margins each were associated with cancer-specific mortality when adjusted for demographic factors. A multivariate analysis of variable importance further revealed sex and race as important factors in predicting cancer-specific mortality.
SCC of the bladder is an aggressive histologic subtype. Although bladder SCC can express p16, it is not typically associated with high-risk HPV, although rare cases can occur.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Corpora amylacea (CAM), in benign prostatic acini, contain acute‐phase proteins. Do CAM coincide with carcinoma?
Methods
Within 270 biopsies, 83 prostatectomies, and 33 transurethral ...resections (TURs), CAM absence was designated CAM 0; corpora in less than 5% of benign acini: CAM 1; in 5% to 25%: CAM 2; in more than 25%: CAM 3. CAM were compared against carcinoma presence, clinicopathologic findings, and grade groups (GG) 1 to 2 vs 3 to 5. The frequency of CAM according to anatomic zone was counted. A pilot study was conducted using paired initial benign and repeat biopsies (33 benign, 24 carcinoma).
Results
A total of 68.9% of biopsies, 96.4% of prostatectomies, and 66.7% of TURs disclosed CAM. CAM ≥1 was common at an older age (P = .019). In biopsies, 204 cases (75%) had carcinoma; and CAM of 2 to 3 (compared to 0‐1) were recorded in 25.0% of carcinomas but only 7.4% of benign biopsies (P = .005; odds ratio OR = 5.1). CAM correlated with high percent Gleason pattern 3, low GG (P = .035), and chronic inflammation (CI). CI correlated inversely with carcinoma (P = .003). CAM disclosed no association with race, body mass index, serum prostate specific antigen (PSA), acute inflammation (in biopsies), atrophy, or carcinoma volume.
With CAM 1, the odds of GG 3 to 5 carcinoma, by comparison to CAM 0, decreased more than 2× (OR = 0.48; P = .032), with CAM 2, more than 3× (OR = 0.33; P = .005), and with CAM 3, almost 3× (OR = 0.39, P = .086). For men aged less than 65, carcinoma predictive model was: Score = (2 × age) + (5 × PSA) − (20 × degree of CAM); using our data, area under the ROC curve was 78.17%. When the transition zone was involved by cancer, it showed more CAM than in cases where it was uninvolved (P = .012); otherwise zonal distributions were similar.
In the pilot study, CAM ≥1 predicted carcinoma on repeat biopsy (P < .05; OR = 8), as did CAM 2 to 3 (P < .0001; OR = 30). CI was not significant, and CAM retained significance after adjusting for CI.
Conclusion
CAM correlate with carcinoma. Whether abundant CAM in benign biopsies adds value amidst high clinical suspicion, warrants further study.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
ABSTRACT
Growth and differentiation factor 15 (GDF‐15), also known as macrophage inhibitory cytokine 1 (MIC‐1), may act as both a tumor suppressor and promotor and, by regulating NF‐κB and macrophage ...signaling, promote early prostate carcinogenesis. To determine whether expression of these two inflammation‐related proteins affect prostate cancer susceptibility, dual immunostaining of benign prostate biopsies for GDF‐15 and NF‐κB was done in a study of 503 case‐control pairs matched on date, age, and race, nested within a historical cohort of 10,478 men. GDF‐15 and NF‐κB expression levels were positively correlated (r = 0.39; p < 0.0001), and both were significantly lower in African American (AA) compared with White men. In adjusted models that included both markers, the odds ratio (OR) for NF‐κB expression was statistically significant, OR =0.87; p = 0.03; 95% confidence interval (CI) =0.77–0.99, while GDF‐15 expression was associated with a nominally increased risk, OR =1.06; p = 0.27; 95% CI =0.96–1.17. When modeling expression levels by quartiles, the highest quartile of NF‐κB expression was associated with almost a fifty percent reduction in prostate cancer risk (OR =0.51; p = 0.03; 95% CI =0.29–0.92). In stratified models, NF‐κB had the strongest negative association with prostate cancer in non‐aggressive cases (p = 0.03), older men (p = 0.03), and in case‐control pairs with longer follow‐up (p = 0.02). Risk associated with GDF‐15 expression was best fit using nonlinear regression modeling where both first (p = 0.02) and second (p = 0.03) order GDF‐15 risk terms were associated with significantly increased risk. This modeling approach also revealed significantly increased risk associated with GDF‐15 expression for subsamples defined by AA race, aggressive disease, younger age, and in case‐control pairs with longer follow‐up. Therefore, although positively correlated in benign prostatic biopsies, NF‐κB and GDF‐15 expression appear to exert opposite effects on risk of prostate tumor development.
In benign prostate biopsies we found expression of GDF‐15 and NF‐κB were positively correlated and lower in African American compared with white men. Prostate cancer risk estimates, however, suggest that NF‐κB and GDF‐15 expression exert opposite effects on prostate tumor development.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The Gleason grading system has been the most reliable tool for the prognosis of prostate cancer since its development. However, its clinical application remains limited by interobserver variability ...in grading and quantification, which has negative consequences for risk assessment and clinical management of prostate cancer.
To examine the impact of an artificial intelligence (AI)-assisted approach to prostate cancer grading and quantification.
This diagnostic study was conducted at the University of Wisconsin-Madison from August 2, 2017, to December 30, 2019. The study chronologically selected 589 men with biopsy-confirmed prostate cancer who received care in the University of Wisconsin Health System between January 1, 2005, and February 28, 2017. A total of 1000 biopsy slides (1 or 2 slides per patient) were selected and scanned to create digital whole-slide images, which were used to develop and validate a deep convolutional neural network-based AI-powered platform. The whole-slide images were divided into a training set (n = 838) and validation set (n = 162). Three experienced academic urological pathologists (W.H., K.A.I., and R.H., hereinafter referred to as pathologists 1, 2, and 3, respectively) were involved in the validation. Data were collected between December 29, 2018, and December 20, 2019, and analyzed from January 4, 2020, to March 1, 2021.
Accuracy of prostate cancer detection by the AI-powered platform and comparison of prostate cancer grading and quantification performed by the 3 pathologists using manual vs AI-assisted methods.
Among 589 men with biopsy slides, the mean (SD) age was 63.8 (8.2) years, the mean (SD) prebiopsy prostate-specific antigen level was 10.2 (16.2) ng/mL, and the mean (SD) total cancer volume was 15.4% (20.1%). The AI system was able to distinguish prostate cancer from benign prostatic epithelium and stroma with high accuracy at the patch-pixel level, with an area under the receiver operating characteristic curve of 0.92 (95% CI, 0.88-0.95). The AI system achieved almost perfect agreement with the training pathologist (pathologist 1) in detecting prostate cancer at the patch-pixel level (weighted κ = 0.97; asymptotic 95% CI, 0.96-0.98) and in grading prostate cancer at the slide level (weighted κ = 0.98; asymptotic 95% CI, 0.96-1.00). Use of the AI-assisted method was associated with significant improvements in the concordance of prostate cancer grading and quantification between the 3 pathologists (eg, pathologists 1 and 2: 90.1% agreement using AI-assisted method vs 84.0% agreement using manual method; P < .001) and significantly higher weighted κ values for all pathologists (eg, pathologists 2 and 3: weighted κ = 0.92 asymptotic 95% CI, 0.90-0.94 for AI-assisted method vs 0.76 asymptotic 95% CI, 0.71-0.80 for manual method; P < .001) compared with the manual method.
In this diagnostic study, an AI-powered platform was able to detect, grade, and quantify prostate cancer with high accuracy and efficiency and was associated with significant reductions in interobserver variability. These results suggest that an AI-powered platform could potentially transform histopathological evaluation and improve risk stratification and clinical management of prostate cancer.
Dysregulated CD44 expression characterizes most human cancers, including prostate cancer (PCa). PCa loses expression of CD44 standard (CD44s) that is present in benign epithelium, and overexpresses ...the novel splice variant isoform, CD44v7-10.
Using retroviral gene delivery to PC-3M PCa cells, we expressed luciferase-only, enforced CD44s re-expression as a fusion protein with luciferase at its C-terminus or as a protein separate from luciferase, or knocked down CD44v7-10 by RNAi. Invasion, migration, proliferation, soft agar colony formation, adhesion, Docetaxel sensitivity, and xenograft growth assays were carried out. Expression responses of merlin, a CD44 binding partner, and growth-permissive phospho-merlin, were assessed by western blot.
Compared to luciferase-only PC-3M cells, all three treatments reduced invasion and migration. Growth and soft agar colony formation were reduced only by re-expression of CD44s as a separate or fusion protein but not CD44v7-10 RNAi. Hyaluronan and osteopontin binding were greatly strengthened by CD44s expression as a separate protein, but not a fusion protein. CD44v7-10 RNAi in PC-3M cells caused marked sensitization to Docetaxel; the two CD44s re-expression approaches caused minimal sensitization. In limited numbers of mouse subcutaneous xenografts, all three alterations produced only nonsignificant trends toward slower growth compared with luciferase-only controls. The expression of CD44s as a separate protein, but not a fusion protein, caused emergence of a strongly-expressed, hypophosphorylated species of phospho-merlin.
Stable re-expression of CD44s reduces PCa growth and invasion in vitro, and possibly in vivo, suggesting CD44 alterations have potential as gene therapy. When the C-terminus of CD44s is fused to another protein, most phenotypic effects are lessened, particularly hyaluronan adhesion. Finally, CD44v7-10, although it was not functionally significant for growth, may be a target for chemosensitization.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Melanoma is one of the most aggressive, potentially fatal forms of skin cancer and has been shown to be associated with solar ultraviolet radiation‐dependent initiation and progression. Despite ...remarkable recent advances with targeted and immune therapeutics, lasting and recurrence‐free survival remain significant concerns. Therefore, additional novel mechanism‐based approaches are needed for effective melanoma management. The sirtuin SIRT6 appears to have a pro‐proliferative function in melanocytic cells. In this study, we determined the effects of genetic manipulation of SIRT6 in human melanoma cells, in vitro and in vivo. Our data demonstrated that CRISPR/Cas9‐mediated knockout (KO) of SIRT6 in A375 melanoma cells resulted in a significant (1) decrease in growth, viability and clonogenic survival and (2) induction of G1‐phase cell cycle arrest. Further, employing a RT2 Profiler PCR array containing 84 key transformation and tumorigenesis genes, we found that SIRT6 KO resulted in modulation of genes involved in angiogenesis, apoptosis, cellular senescence, epithelial‐to‐mesenchymal transition, hypoxia signaling and telomere maintenance. Finally, we found significantly decreased tumorigenicity of SIRT6 KO A375 cells in athymic nude mice. Our data provide strong evidence that SIRT6 promotes melanoma cell survival, both in vitro and in vivo, and could be exploited as a target for melanoma management.
SIRT6 has been shown to act as a tumor promoter or suppressor depending on the cancer type. This study supports the tumor promoter role of SIRT6 in melanoma, one of the deadliest forms of UV‐related skin cancers. We found CRISPR/Cas9‐mediated SIRT6 knockout (KO) imparted marked antiproliferative effects in human melanoma cells in vitro and antitumorigenic response in vivo. Additionally, we found SIRT6 KO significantly affected several cancer‐associated pathways, including apoptosis, cellular senescence and epithelial‐to‐mesenchymal transition, suggesting SIRT6 has an important role in melanoma progression. Thus, SIRT6 inhibitory approaches could potentially be used in melanoma management and should be explored further.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Invasive micropapillary carcinoma (IMPC) of the urinary tract is a well-described variant of the urothelial carcinoma with aggressive clinical behavior. Recent studies have proposed that patients ...with IMPC on transurethral resection should be treated with radical cystectomy regardless of the pathologic stage. Despite the potentially important therapeutic implications of this diagnosis, interobserver variation in the diagnosis of IMPC has not been studied. Sixty digital images, each from hematoxylin and eosin-stained slides, representing 30 invasive urothelial carcinomas (2 images per case), were distributed to 14 genitourinary subspecialists and each pathologist was requested to classify cases as IMPC or not. These cases included "classic" IMPC (n=10) and urothelial carcinoma with retraction and variably sized nests that might potentially be regarded as IMPC (n=20). The following 13 morphologic features were recorded as positive/negative for all cases independent of the reviewers' diagnoses: columnar cells, elongate nests or processes, extensive stromal retraction, lumen formation with internal epithelial tufting, epithelial ring forms, intracytoplasmic vacuolization, multiple nests within the same lacunar space, back-to-back lacunar spaces, epithelial nest anastomosis/confluence, marked nuclear pleomorphism, peripherally oriented nuclei, randomly distributed nuclei, and tumor nest size. In addition, a mean tumor nest size was calculated for each image based on the number of nuclei spanning the width of the nests. Interobserver reproducibility was assessed and the morphologic features were correlated with the classic IMPC and nonclassic/potential IMPC groups. In addition, the relationships between morphologic features, pathologists' interpretations, and case type (classic IMPC vs. nonclassic/potential IMPC) were evaluated using unsupervised hierarchical clustering analysis. Interobserver reproducibility for a diagnosis of IMPC in the 30 study cases was moderate (kappa: 0.54). Although classification as IMPC among the 10 "classic" IMPC cases was relatively uniform (93% agreement), the classification in the subset of 20 invasive urothelial carcinomas with extensive retraction and varying sized tumor nests was more variable. Multiple nests within the same lacunar space had the highest association with a diagnosis of classic IMPC. These findings suggest that more study of IMPC is needed to identify the individual pathologic features that might potentially correlate with an aggressive outcome and response to intravesical therapy.
Large-gland proliferations of the prostate have gained considerable attention in the past decade. The differential diagnosis is quite broad but can be refined using histologic criteria and, ...sometimes, immunostains. Pathologists have come to realize that cribriform and intraductal as well as ductal carcinomas are particularly aggressive patterns, and should name them in diagnostic reporting when present.
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