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, SAZU, SBCE, SBMB, UL, UM, UPUK
BACKGROUND
Obesity is associated with risk of aggressive prostate cancer (PCa), but not with over‐all PCa risk. However, obese men have larger prostates which may lower biopsy accuracy and cause a ...systematic bias toward the null in epidemiologic studies of over‐all risk.
METHODS
Within a cohort of 6692 men followed‐up after a biopsy or transurethral resection of the prostate (TURP) with benign findings, a nested case‐control study was conducted of 495 prostate cancer cases and controls matched on age, race, follow‐up duration, biopsy versus TURP, and procedure date. Data on body mass index and prostate volume at the time of the initial procedure were ed from medical records.
RESULTS
Prior to consideration of differences in prostate volume, overweight (OR = 1.41; 95%CI 1.01, 1.97), and obese status (OR = 1.59; 95%CI 1.09, 2.33) at the time of the original benign biopsy or TURP were associated with PCa incidence during follow‐up. Prostate volume did not significantly moderate the association between body‐size and PCa, however it did act as an inverse confounder; adjustment for prostate volume increased the effect size for overweight by 22% (adjusted OR = 1.52; 95%CI 1.08, 2.14) and for obese status by 23% (adjusted OR = 1.77; 95%CI 1.20, 2.62). Larger prostate volume at the time of the original benign biopsy or TURP was inversely associated with PCa incidence during follow‐up (OR = 0.92 per 10 cc difference in volume; 95%CI 0.88, 0.97). In analyses that stratified case‐control pairs by tumor aggressiveness of the case, prostate volume acted as an inverse confounder in analyses of non‐aggressive PCa but not in analyses of aggressive PCa.
CONCLUSIONS
In studies of obesity and PCa, differences in prostate volume cause a bias toward the null, particularly in analyses of non‐aggressive PCa. A pervasive underestimation of the association between obesity and overall PCa risk may exist in the literature.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Primary bladder paraganglioma is rare. A 57-year old man presented with a mass in the inferior wall of the bladder identified on computerized tomography imaging. We investigated the mass with office ...cystoscopy followed by transurethral resection, which was found to be a nonfunctioning paraganglioma. 68Ga-DOTA-conjugated somatostatin receptor-targeting peptide positron emission tomography revealed no other locations of the disease. The mass was then completely removed through robotic assisted partial cystectomy. Succinate dehydrogenase B immunohistochemistry was normal, arguing against a succinate dehydrogenase-deficient paraganglioma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Prostate cancer is frequently multifocal. Although there may be morphological variation, the genetic underpinnings of each tumor are not clearly understood. To assess the inter and intra tumor ...molecular heterogeneity in prostate biopsy samples, we developed a combined immunohistochemistry and RNA in situ hybridization method for the simultaneous evaluation of ERG, SPINK1, ETV1, and ETV4. Screening of 601 biopsy cores from 120 consecutive patients revealed multiple alterations in a mutually exclusive manner in 37% of patients, suggesting multifocal tumors with considerable genetic differences. Furthermore, the incidence of molecular heterogeneity was higher in African Americans patients compared with Caucasian American patients. About 47% of the biopsy cores with discontinuous tumor foci showed clonal differences with distinct molecular aberrations. ERG positivity occurred in low-grade cancer, whereas ETV4 expression was observed mostly in high-grade cancer. Further studies revealed correlation between the incidence of molecular markers and clinical and pathologic findings, suggesting potential implications for diagnostic pathology practice, such as defining dominant tumor nodules and discriminating juxtaposed but molecularly different tumors of different grade patterns.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Expression profiles of erythroblast transformation‐specific (ETS)‐related gene fusions and serine protease inhibitor Kazal‐type 1 (SPINK1) in early onset prostate cancer have not been ...thoroughly explored.
Methods
We retrieved 151 radical prostatectomy specimens from young men with prostate cancer (<55 years) and characterized the expression of ETS‐related gene (ERG), SPINK1, ETS Variant 1 (ETV1), and ETV4 by dual immunohistochemistry and dual RNA in situ hybridization. Age, race, family history, preoperative prostate‐specific antigen, biochemical recurrence, and pathological variables using whole‐mount radical prostatectomy tissue were collected.
Results
A total of 313 tumor nodules from 151 men including 68 (45%) Caucasians and 61 (40%) African Americans were included in the analysis. Positive family history of prostate cancer was seen in 65 (43%) patients. Preoperative prostate‐specific antigen ranged from 0.3 to 52.7 ng/mL (mean = 7.04). The follow‐up period ranged from 1 to 123.7 months (mean = 30.3). Biochemical recurrence was encountered in 8 of 151 (5%). ERG overexpression was observed in 85 of 151 (56%) cases, followed by SPINK1 in 61 of 151 (40%), ETV1 in 9 of 149 (6%), and ETV4 in 4 of 141 (3%). There were 25 of 151 (17%) cases showing both ERG and SPINK1 overexpression within different regions of either the same tumor focus or different foci. Higher frequency of ERG overexpression was seen in younger patients (≤45 years old; 76% vs 49%, P = .002), Caucasian men (71% vs 41% P = .0007), organ‐confined tumors (64% vs 33%, P = .0008), and tumors of Gleason Grade groups 1 and 2 (62% vs 26%, P = .009). SPINK1 overexpression was more in African American men (68% vs 26%, P = .00008), in tumors with high tumor volume (>20%) and with anterior located tumors. ETV1 and ETV4 demonstrated rare overexpression in these tumors, particularly in the higher‐grade tumors.
Conclusion
This study expands the knowledge of the clonal evolution of multifocal cancer in young patients and support differences in relation to racial background and genetics of prostate cancer.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Aims
To evaluate the molecular underpinnings of the rare aggressive prostate cancer variants adenosquamous carcinoma, pleomorphic giant‐cell carcinoma, and sarcomatoid carcinoma.
Methods and results
...We retrieved 19 tumours with one or more variant(s), and performed ERG immunohistochemistry, a next‐generation sequencing assay targeting recurrent gene fusions, and fluorescence in‐situ hybridisation (FISH) for ERG and BRAF. Divergent differentiation included: sarcomatoid carcinoma (n = 10), adenosquamous carcinoma (n = 7), and pleomorphic giant‐cell carcinoma (n = 7). Five patients had more than one variant. Four had variants only in metastases. ERG rearrangement was detected in nine (47%, seven via sequencing, showing TMPRSS2–ERG fusions and one GRHL2–ERG fusion, and two via FISH, showing rearrangement via deletion). ERG was immunohistochemically positive in the adenocarcinoma in eight of nine (89%) patients, but was immunohistochemically positive in the variant in only five of nine patients (56%, typically decreased). One patient had a false‐positive ERG immunohistochemical result in the sarcomatoid component despite a negative FISH result. Two (11%) harboured BRAF fusions (FAM131A–BRAF and SND1–BRAF).
Conclusions
ERG fusions are present in these rare prostate cancer variants with a frequency close to that in conventional prostate cancer (9/19, 47%). ERG immunohistochemistry usually detects rearrangement in the adenocarcinoma, but is less sensitive for the variant histology, with weak to negative staining. Adenosquamous and sarcomatoid variants can, particularly, occur together. Molecular assessment may be an additional tool in selected cases to confirm the prostatic origin of unusual tumours. The presence of two BRAF rearrangements suggests that this gene fusion may be enriched in this setting, as RAF kinase fusions have been previously reported in 1–2% of prostate cancers.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
When prostate biopsy cores are separately identified in multiple containers, current recommendations are to grade each specimen individually. For treatment algorithms, the highest Gleason score (HGS) ...is typically used as the overall score, even if a lower score predominates. This practice has the potential to misrepresent the overall cancer in the entire gland for some patients and place them in a higher-grade group. We compare a novel composite Gleason score (CGS), integrating grade patterns from contiguous positive biopsy sites, with HGS to determine correlation with the radical prostatectomy (RP) Gleason score (GS). One hundred needle biopsy cases from 2008 to 2012 with >2 GSs in a biopsy set (eg, 3+3=6, 3+4=7, and 4+3=7) or more than a 1-step difference in GS (eg, 3+4=7 and 4+4=8 without 4+3=7) were analyzed. Grades were assigned using both methods (HGS and CGS) and compared with RPGS. Grade groups I to V were used to define downgrade and upgrade. Comparing HGS with RPGS, 31% remained the same and 69% had a change in GS (87% downgraded and 13% upgraded). Comparing CGS with RPGS, 59% remained the same and 41% had a change in GS (10% downgraded and 90% upgraded). Of the 2 methods, the CGS showed better overall correlation with RP (P<0.001) and was less likely to be downgraded compared with HGS. CGS correlates better with RPGS than HGS when >2 grades are present in a biopsy set. CGS has a significantly lower rate of downgrade and predicts the RPGS more accurately than HGS.
Renal cell tumors with mixed morphology resembling multiple renal cell carcinoma (RCC) subtypes are generally regarded as unclassified RCC. However, occasionally, papillary adenoma or RCC appears ...admixed with a larger, different tumor histology. We retrieved 17 renal tumors containing a papillary adenoma or papillary RCC component admixed with another tumor histology and studied them with immunohistochemistry and fluorescence in situ hybridization (FISH). Larger tumors were oncocytomas (
n
= 10), chromophobe RCCs (
n
= 5), borderline oncocytic tumor (
n
= 1), and clear cell RCC (
n
= 1). The size of papillary component ranged from 1 to 34 mm. One tumor was an oncocytoma encircled by a cyst (2.0 cm) with papillary hyperplasia of the lining. The papillary lesions were diffusely cytokeratin 7 positive (17/17), in contrast to “host” tumors. Alpha-methylacyl-coA-racemase labeling was usually stronger in the papillary lesions (13/15). KIT was negative in all papillary lesions and the clear cell RCC and positive in 16/16 oncocytic or chromophobe tumors. Eight of 15 (53%) collision tumors had differing FISH results in the two components. A papillary renal cell proliferation within another tumor is an uncommon phenomenon with predilection for oncocytoma and chromophobe RCC, possibly related to their common entrapment of benign tubules. When supported by distinct morphology and immunohistochemistry in these two components, this phenomenon should be diagnosed as a collision of two processes. A diagnosis of unclassified RCC should be avoided, due to potential misrepresentation as an aggressive renal cancer.
Background
Rising prostate‐specific antigen (PSA) levels are associated with both increased risk of prostate cancer and prostatic inflammation. The confounding effects of inflammation on the utility ...of PSA kinetics to predict prostate cancer may be partially mitigated by anti‐inflammatory drug use. We investigated the influence of anti‐inflammatory drug use on the association of PSA kinetics with prostate cancer risk.
Methods
We studied 488 prostate cancer case‐control pairs (290 white, 198 African American (AA)) nested in a retrospective cohort of men with a benign prostate biopsy. A series of multivariable models estimated prostate cancer risk associated with PSA velocity (PSAV) at different levels of anti‐inflammatory drug use while adjusting for the presence of both clinical and histologic prostatitis.
Results
In men with one, two, or three or more courses of anti‐inflammatory drug use, for each ng/mL/year increase in PSAV, prostate cancer risk increased 1.21‐fold, 1.83‐fold, and 1.97‐fold, respectively (
P < 0.0001). In controls with histologic prostatitis, anti‐inflammatory drug use was associated with a significantly lower PSAV (
P < 0.0001). This association was not observed in men with histologic prostatitis who were subsequently diagnosed with prostate cancer. A positive interaction between anti‐inflammatory drug use and PSAV‐associated prostate cancer risk was only observed in AA men, as well as a strong positive association between any anti‐inflammatory drug use and clinical prostatitis (
P = 0.004).
Conclusions
In men with benign prostate biopsy, accounting for the presence of histologic prostatitis and anti‐inflammatory drug use, particularly in AA men, may help distinguish between men with rising PSA because of prostatitis vs undiagnosed cancer.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
We describe 3 ovarian and 5 renal anastomosing hemangiomas. One manifested with polycythemia, others were incidental; none recurred. The mean patient age was 58 years. Three hemangiomas developed in ...end-stage renal disease. Tumors were well-demarcated, mahogany brown, spongy lesions measuring 0.1 to 5 cm. Tortuous large vessels fed and drained tightly packed anastomosing sinusoidal capillary channels. Four hemangiomas exhibited lobular architecture, central edema/hyalinization, and intravascular growth. Five cases had thrombosis, hemorrhage, and hemosiderin. One ovarian tumor induced stromal luteinization. Three tumors had foci of extramedullary hematopoiesis (one associated with polycythemia). Six cases demonstrated eosinophilic intracytoplasmic globules. Three cases included hobnail endothelial cells. Atypia was minimal and mitoses were absent in all cases. We find this vascular neoplasm unique for the genitourinary system. Despite selected features mimicking angiosarcoma, our data support its benign nature. The current study expands the gross and radiographic appearance, clinical aspects, and ultrastructure, with the first report of the lesion occurring in the ovary.
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