Evaluating Biochemically Recurrent Prostate Cancer: Histologic Validation of 18F-DCFPyL PET/CT with Comparison to Multiparametric MRI.

Background Prostate cancer recurrence is found in up to 40% of men with prior definitive (total prostatectomy or whole-prostate radiation) treatment. Prostate-specific membrane antigen PET agents such as 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) may improve detection of recurrence compared with multiparametric MRI; however, histopathologic validation is lacking. Purpose To determine the sensitivity, specificity, and positive predictive value (PPV) of 18F-DCFPyL PET/CT based on histologic analysis and to compare with pelvic multiparametric MRI in men with biochemically recurrent prostate cancer. Materials and Methods Men were prospectively recruited after prostatectomy and/or radiation therapy with rising prostate-specific antigen level (median, 2.27 ng/mL; range, 0.2-27.45 ng/mL) and a negative result at conventional imaging (bone scan and/or CT). Participants underwent 18F-DCFPyL PET/CT imaging and 3.0-T pelvic multiparametric MRI. Statistical analysis included Wald and modified χ2 tests. Results A total of 323 lesions were visualized in 77 men by using 18F-DCFPyL or multiparametric MRI, with imaging detection concordance of 25% (82 of 323) when including all lesions in the MRI field of view and 53% (52 of 99) when only assessing prostate bed lesions. 18F-DCFPyL depicted more pelvic lymph nodes than did MRI (128 vs 23 nodes). Histologic validation was obtained in 80 locations with sensitivity, specificity, and PPV of 69% (25 of 36; 95% confidence interval [CI]: 51%, 88%), 91% (40 of 44; 95% CI: 74%, 98%), and 86% (25 of 29; 95% CI: 73%, 97%) for 18F-DCFPyL and 69% (24 of 35; 95% CI: 50%, 86%), 74% (31 of 42; 95% CI: 42%, 89%), and 69% (24 of 35; 95% CI: 50%, 88%) for multiparametric MRI (P = .95, P = .14, and P = .07, respectively). In the prostate bed, sensitivity, specificity, and PPV were 57% (13 of 23; 95% CI: 32%, 81%), 86% (18 of 21; 95% CI: 73%, 100%), and 81% (13 of 16; 95% CI: 59%, 100%) for 18F-DCFPyL and 83% (19 of 23; 95% CI: 59%, 100%), 52% (11 of 21; 95% CI: 29%, 74%), and 66% (19 of 29; 95% CI: 44%, 86%) for multiparametric MRI (P = .19, P = .02, and P = .17, respectively). The addition of 18F-DCFPyL to multiparametric MRI improved PPV by 38% overall (P = .02) and by 30% (P = .09) in the prostate bed. Conclusion Findings with 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine 3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid (18F-DCFPyL) were histologically validated and demonstrated high specificity and positive predictive value. In the pelvis, 18F-DCFPyL depicted more lymph nodes and improved positive predictive value and specificity when added to multiparametric MRI. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Zukotynski and Rowe in this issue.

Fatty-Acid Uptake in Prostate Cancer Cells Using Dynamic Microfluidic Raman Technology.

It is known that intake of dietary fatty acid (FA) is strongly correlated with prostate cancer progression but is highly dependent on the type of FAs. High levels of palmitic acid (PA) or arachidonic acid (AA) can stimulate the progression of cancer. In this study, a unique experimental set-up consisting of a Raman microscope, coupled with a commercial shear-flow microfluidic system is used to monitor fatty acid uptake by prostate cancer (PC-3) cells in real-time at the single cell level. Uptake of deuterated PA, deuterated AA, and the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were monitored using this new system, while complementary flow cytometry experiments using Nile red staining, were also conducted for the validation of the cellular lipid uptake. Using this novel experimental system, we show that DHA and EPA have inhibitory effects on the uptake of PA and AA by PC-3 cells.

A novel fluorescent probe for the early detection of prostate cancer based on endogenous zinc sensing.

BACKGROUND: The early detection of prostate cancer can significantly optimize the prognosis, prolong patient lifespan, and improve quality of life. It has been well documented that prostate cancer tissues have lower zinc content than normal prostate tissues due to an impairment of the zinc accumulation mechanism. METHODS: A novel diketopyrrolopyrrole (DPP)-based fluorescent zinc ion probe named DPP-C2 was prepared. The fluorescent intensity of this novel molecule is in direct proportion to environmental zinc concentration. Malignant (DU145 and PC3 cells) and normal prostate epithelial RWPE-1 cells were tested. Prostate cancer tissues were also cultured and observed as tissue sections. The probe was also intravenously administered to tumor-bearing (DU145 and PC3 cells) nude mice and observed under a whole-body fluorescence live-imaging system. RESULTS: The probe showed minimal cytotoxicity to malignant and normal prostate cells. The RWPE-1 cells showed not only stronger baseline fluorescence but also a significant increase in signal intensity after culturing in a zinc-supplemented medium. In human prostate sections, the pathologically confirmed cancer tissues exhibited weaker fluorescence signals than normal and benign hyperplastic tissues. With proper excitation, prostate tissues revealed more intense fluorescence signals than tumor tissues, whereas other surrounding tissues showed almost no fluorescence. CONCLUSIONS: The novel zinc ion fluorescent probe DPP-C2 is low toxic and showed potential application for the early detection of prostate cancer based on endogenous zinc sensing.

Prostatic Adenocarcinoma With Focal Pleomorphic Giant Cell Features: A Series of 30 Cases.

Prostatic adenocarcinoma with focal pleomorphic giant cell features is rare with the only prior series consisting of 6 cases. From 2005 to 2018, we identified 29 cases from our consult service and 1 case from our own institution. Men ranged in age from 39 to 90 years (median=75.5). Diagnostic specimens consisted of needle biopsies (n=13); transurethral resections (n=7), urethral/bladder biopsies (n=8), radical prostatectomy (n=1), and orchiectomy (n=1). In all cases, there was usual acinar prostatic adenocarcinoma, where the highest grade in all cases was Gleason score 9 to 10 (Grade Group 5). On average, 68% of the involved cores had cancer with a maximum percent of cancer averaging 55%; on average, transurethral resections had 85% of the area involved by cancer. Areas of cancer showing pleomorphic giant cell features were focal (<5%). Two of the needle biopsies showed extraprostatic extension. The radical prostatectomy had seminal vesicle invasion and positive margins with lymphovascular invasion. Prostatic adenocarcinoma with focal pleomorphic giant cell features is always accompanied by extensive usual acinar prostate adenocarcinoma where the highest grade in all cases was Gleason score 9 to 10 (Grade Group 5). Although the pleomorphic component is focal, it can mimic urothelial carcinoma. IHC can be misleading as PSA staining is often negative or focal in both the pleomorphic and usual prostatic adenocarcinoma components. NKX3.1 is the most sensitive prostate marker, but was still focal in 1 usual prostatic adenocarcinoma and negative in 2 pleomorphic components. Prostatic adenocarcinoma with focal pleomorphic giant cell features has a dismal prognosis. In men with no prior diagnosis of prostate adenocarcinoma and >1-year follow-up, 7/19 (37%) were dead at a median of 8 months after diagnosis. Of the 7 men with a prior history of prostate adenocarcinoma, 4/7 (57%) were dead at a median of 7 months after diagnosis of recurrent prostate adenocarcinoma with pleomorphic giant cell features.

Targeted nanomedicine for prostate cancer therapy: docetaxel and curcumin co-encapsulated lipid-polymer hybrid nanoparticles for the enhanced anti-tumor activity in vitro and in vivo.

OBJECTIVE: Docetaxel (DTX) remains the only effective drug for prolonging survival and improving quality of life of metastatic castration-resistant prostate cancer (mCRPC) patients. Combination anticancer therapy encapsulating DTX and another extract of traditional Chinese medicine is one nano-sized drug delivery system promising to generate synergistic anticancer effects, to maximize the treatment effect, and to overcome multi-drug resistance. The purpose of this study is to construct lipid-polymer hybrid nanoparticles (LPNs) as nanomedicine for co-encapsulation of DTX and curcumin (CUR). METHODS: DTX and CUR co-encapsulated LPNs (DTX-CUR-LPNs) were constructed. DTX-CUR-LPNs were evaluated in terms of particles size, zeta potential, drug encapsulation, and drug delivery. The cytotoxicity of the LPNs was evaluated on PC-3 human prostate carcinoma cells (PC3 cells) by MTT assays. In vivo anti-tumor effects were observed on the PC3 tumor xenografts in mice. RESULTS: The particle size of DTX-CUR-LPNs was 169.6 nm with a positive zeta potential of 35.7 mV. DTX-CUR-LPNs showed highest cytotoxicity and synergistic effect of two drugs in tumor cells in vitro. In mice-bearing PC-3 tumor xenografts, the DTX-CUR-LPNs inhibited tumor growth to a greater extent than other contrast groups, without inducing any obvious side effects. CONCLUSION: According to these results, the novel nanomedicine offers great promise for the dual drugs delivery to the prostate cancer cells, showing the potential of synergistic combination therapy for prostate cancer.

PSA-PSMA profiles and their impact on sera PSA levels and angiogenic activity in hyperplasia and human prostate cancer.

AIM: The relevance of prostate specific antigen (PSA)-prostate specific membrane antigen (PSMA) profiles in pathologic prostate (hyperplasia and cancer) has not been fully understood. The aim of this study is to investigate the impact of PSA-PSMA profiles on sera PSA levels and angiogenic activity in benign prostate hyperplasia (BPH) and prostate carcinoma (PC). PATIENTS AND METHODS: The study has been carried out in 6 normal prostate (NP), 29 BPH and 33 PC with dominant Gleason grade>8. Immunohistochemical analysis has been performed. Monoclonal antibodies 3E6 and ER-PR8 have been used to assess PSMA and PSA expression respectively. The evaluation of angiogenesis has been made by CD34 immune marker. Serum levels of PSA have been assayed by Immulite autoanalyser. RESULTS: The study of each protein separately among sera PSA levels showed that PSMA expression and angiogenic activity have the highest intensity in PC patients with serum PSA levels>20 ng/mL. Nevertheless, the lowest tissue PSA expression was found in PC patients with this latter sera PSA group. The most relevant results showed that in PC patients (PSA+, PSMA+) and (PSA-, PSMA+) profile were found to be inversely related to sera PSA levels. In PC patients, a high immunoexpression of (PSA+, PSMA+) profile has detected in the sera PSA group>20 ng/mL; whereas a high immunoexpression of (PSA-, PSMA+) profile was detected in the sera PSA group between 0 and 4 ng/mL. The highest angiogenic activity was found in PC patients with (PSA+, PSMA+) profile. CONCLUSIONS: Our findings clearly have supported the feasibility of PSA-PSMA profiles to improve in vivo diagnostic and therapeutic approaches in prostate cancer patients.

High density of S100A9 positive inflammatory cells in prostate cancer stroma is associated with poor outcome.

PURPOSE: To elucidate if the density of inflammatory cells expressing S100A9 in malignant and surrounding non-malignant prostate tissues is a prognostic marker for outcome in prostate cancer patients. EXPERIMENTAL DESIGN: Tissue was obtained from 358 men diagnosed with prostate cancer at transurethral resection of the prostate due to obstructive voiding problems, of which 260 were then followed with watchful waiting. Tissue microarrays of both malignant and non-malignant tissues were stained with an antibody against S100A9. The number of stained inflammatory cells was scored and related to clinical outcome and histopathological parameters of known prognostic value. RESULTS: A high number of inflammatory cells expressing S100A9 in both malignant and surrounding non-malignant tissues were associated with significantly shorter cancer-specific survival. This association remained significant when Gleason score and local tumour stage were analysed together with S100A9 in a Cox regression model. Low number of S100A9 positive cells in non-malignant stroma was correlated to significantly longer cancer-specific survival also in patients with Gleason score 8-10 tumours. S100A9 positive cells in tumour stroma were correlated with Gleason score, hyaluronan, platelet-derived growth factor receptor beta (PDGFR-ß), and androgen receptor (inverse correlation) in tumour stroma. S100A9 positive cells in non-malignant stroma correlated with androgen receptor in this tissue compartment (inverse correlation). CONCLUSIONS: A high number of S100A9 positive inflammatory cells in tumour stroma and in non-malignant stroma were associated with shorter cancer-specific survival in prostate cancer patients.

De novo large cell neuroendocrine carcinoma of the prostate gland with pelvic lymph node metastasis: a case report with review of literature.

Neuroendocrine (NE) differentiation in prostate carcinomas can be seen in two settings: as a focal finding in conventional acinar adenocarcinoma, identifiable by immunohistochemical staining, or as a primary NE tumor of the prostate gland, such as carcinoid, small cell carcinoma, or large cell NE carcinoma. Of particular interest is the large cell NE carcinoma, which had been previously reported in isolated cases or in limited case series. In this report, we describe a case of a large cell NE carcinoma diagnosed in a 48-year-old man who presented with difficulty in voiding and urine retention. A cystoscopy revealed an enlarged, elongated prostate with an intra-urethral obstructing mass in the prostatic urethra. Subsequently, a transurethral resection of prostate (TURP) was performed at an outside hospital under the clinical diagnosis of benign prostatic hyperplasia (BPH). Microscopic examination of the TURP specimen revealed several foci of low-grade transitional-zone-type adenocarcinoma corresponding to Gleason score 5 (3 + 2), and a focus of high-grade large cell NE carcinoma. Concurrent x-ray computed tomography scans of the chest, abdomen, and pelvis demonstrated an enlarged left pelvic lymph node, which was biopsied and the patient was diagnosed with metastatic large cell NE carcinoma. He subsequently underwent 8 cycles of neoadjuvant chemotherapy with Lupron, a laparoscopic robotic-assisted radical retropubic prostatectomy, and pelvic lymphadenectomy. He died of widely metastatic prostatic carcinoma with leptomeningeal metastases 13 months after radical prostatectomy. Here, we present a rare case of large cell NE carcinoma with a review of the published literature.

Association between trace element and heavy metal levels in hair and nail with prostate cancer.

While associations between trace elements and heavy metals with prostate cancer are still debatable, they have been considered as risk factors for prostate cancer. Thus, this study aimed to detect any links between selected minerals and heavy metals including Se, Zn, Cu, Mn and Fe with prostate cancer. A case control study was carried out among 100 subjects (case n=50, control n=50), matched for age and ethnicity. Trace elements and heavy metals level in hair and nail samples were determined by ICP-MS. Mean selenium levels in hair and nail of the cases were significantly lower as compared to controls. A similar trend was noted for zinc in both hair and nail samples, whereas the mean level of copper was significantly higher in cases than controls. Similar elevation was noted for iron and manganese (p<0.05 for all parameters). Low levels of selenium and zinc and high levels of copper, iron and manganese appear to be associated with the risk of prostate cancer. Further studies to elucidate the causal mechanisms and appropriate chemopreventive measures are needed.

Incidental prostatic stromal tumor of uncertain malignant potential (STUMP): histopathological and immunohistochemical findings.

Stromal prostate tumors are rare neoplastic proliferative lesions that have been classified into prostatic stromal tumor of uncertain malignant potential (STUMP) and prostatic stromal sarcoma (SS) based on these criteria: stromal cellularity, presence of mitotic figures, necrosis, and stromal overgrowth. A prostatic stromal tumor of uncertain malignant potential (STUMP) is a non-epithelial, mesenchymal spindle-cell tumor that can be classified as a specialized stromal tumor of the prostate. STUMPs have the capability to diffusely infiltrate the prostate gland and extend into adjacent tissues. Furthermore, they often recur and this is why they are considered as neoplastic entities. STUMPs usually tend to be not aggressive, but occasional cases have been reported with an extension into adjacent tissues. A few cases develop a sarcomatous dedifferentiation. A 67-year-old male referred to the Department of Urology, Sapienza Rome University, with acute urinary retention (AUR) and bladder overdistention. Digital rectal examination (DRE) showed the presence of a severe prostatic hyperplasia and a transvesical prostatic adenomectomy (TVPA) was performed. The pathological evaluation performed at the Department of Pathology, Sapienza Rome University, revealed an incidental diagnosis of prostatic STUMP. The patient's follow-up is made every year with transrectal ultrasonography and nuclear magnetic resonance with spectroscopy, and every two years with a transperineal prostate biopsy to exclude a progression to a stromal sarcoma. After 5 years of follow-up the STUMP is still detectable but there is no sign of sarcoma. As a result of its relative rarity and lack of long-term follow-up, the prognosis of STUMP is unclear. Therapy varies from a wait-and-see approach to a radical retropubic prostatectomy.

Identification of estrogen receptor dimer selective ligands reveals growth-inhibitory effects on cells that co-express ERα and ERß.

Estrogens play essential roles in the progression of mammary and prostatic diseases. The transcriptional effects of estrogens are transduced by two estrogen receptors, ERα and ERß, which elicit opposing roles in regulating proliferation: ERα is proliferative while ERß is anti-proliferative. Exogenous expression of ERß in ERα-positive cancer cell lines inhibits cell proliferation in response to estrogen and reduces xenografted tumor growth in vivo, suggesting that ERß might oppose ERα's proliferative effects via formation of ERα/ß heterodimers. Despite biochemical and cellular evidence of ERα/ß heterodimer formation in cells co-expressing both receptors, the biological roles of the ERα/ß heterodimer remain to be elucidated. Here we report the identification of two phytoestrogens that selectively activate ERα/ß heterodimers at specific concentrations using a cell-based, two-step high throughput small molecule screen for ER transcriptional activity and ER dimer selectivity. Using ERα/ß heterodimer-selective ligands at defined concentrations, we demonstrate that ERα/ß heterodimers are growth inhibitory in breast and prostate cells which co-express the two ER isoforms. Furthermore, using Automated Quantitative Analysis (AQUA) to examine nuclear expression of ERα and ERß in human breast tissue microarrays, we demonstrate that ERα and ERß are co-expressed in the same cells in breast tumors. The co-expression of ERα and ERß in the same cells supports the possibility of ERα/ß heterodimer formation at physio- and pathological conditions, further suggesting that targeting ERα/ß heterodimers might be a novel therapeutic approach to the treatment of cancers which co-express ERα and ERß.

Disturbed homeostasis of zinc and other essential elements in the prostate gland dependent on the character of pathological lesions.

Pathophysiological changes in the prostate take the form of benign prostate hyperplasia (BPH) and prostate adenocarcinoma (PCa). In prostate, zinc is particularly important to its normal functioning, especially in terms of the consequences of hormone disturbance. The aim of this study was to assess the levels of Zn, Cu, Ca, Mg, and Se in the prostate dependent on the character of patological changes. Zinc, copper, magnesium and calcium were determined by AAS and selenium with spectrofluorometric method. Zn levels in BPH patients were over twofold higher than in controls. On the other hand, in the patients with PCa, the levels of Zn were found almost three times lower than in BPH patients and by almost 50% lower than in controls. In this study, significant changes in the levels of other essential elements were observed. The results apparently confirm the disturbed homeostasis of zinc and other essential elements in the etiology of BPH and PCa.

Zyflamend in men with high-grade prostatic intraepithelial neoplasia: results of a phase I clinical trial.

Subjects diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN) at biopsy are at increased risk for developing prostate cancer (CaP). A prospective clinical trial was done to determine the safety and tolerability of a novel herbal amalgam, Zyflamend (New Chapter, Inc., Brattleboro, VT), with various dietary supplements in subjects with HGPIN. Men ages 40 to 75 years with HGPIN were eligible. Subjects were evaluated for 18 months. Every 3 months, standard blood chemistries and prostate-specific antigen (PSA) were monitored. Rebiopsy was done every 6 months. Tissue was evaluated for HGPIN or CaP and stained for cyclooxygenase-2, nuclear factor kappaB (NF-kappaB), interleukin-6, and thromboxane. Twenty-three subjects were evaluable. The median age was 64.1 years (range 46-75 years), and the mean (+/- SD) PSA level was 6.13 +/- 3.56 ng/mL. Side effects, when present, were mild and gastrointestinal in nature. There were no reported serious adverse events or toxicities. No significant changes in blood chemistries, testosterone, or cardiac function were noted. Forty-eight percent of subjects demonstrated a 25 to 50% decrease in PSA after 18 months. Of subjects who had the 18-month biopsy, 60% (9 of 15) had benign tissue, 26.7% (4 of 15) had HGPIN in one core, and 13.3% (2 of 15) had CaP at 18 months. A reduction in serum C-reactive protein was observed (95% confidence interval [CI] 0.7-1.7, p = .045). Immunoreactive staining demonstrated a reduction in NF-kappaB in the 18-month samples (95% CI 0.8-3.0, p = .017). Zyflamend alone and in combination with various dietary supplements is associated with minimal toxicity and no serious adverse events when administered orally for 18 months. Further studies are warranted to evaluate these agents in patients who are at risk for CaP.

Effective prostate cancer chemopreventive intervention with green tea polyphenols in the TRAMP model depends on the stage of the disease.

PURPOSE: We have shown previously that oral feeding of green tea polyphenols (GTP) to transgenic adenocarcinoma of the mouse prostate mice in a purely chemopreventive setting significantly inhibits prostate cancer development. To translate this to a human situation, the present study was designed to identify the stage of prostate cancer that is most vulnerable to chemopreventive intervention by GTP. EXPERIMENTAL DESIGN: GTP infusion (0.1% in drinking water) to transgenic adenocarcinoma of the mouse prostate was initiated at ages representing different stage of the disease: (a) 6 weeks (group 1, normal prostate), (b) 12 weeks (group 2, prostatic intraepithelial neoplasia), (c) 18 weeks (group 3, well-differentiated adenocarcinoma), and (b) 28 weeks (group 4, moderately differentiated adenocarcinoma). At age 32 weeks, subsets of animals were evaluated by magnetic resonance imaging, ultrasound, and prostate weight and for serum insulin-like growth factor (IGF)-I/IGF binding protein-3 and IGF signaling. RESULTS: Tumor-free survival was extended to 38 weeks (P < 0.001) in group 1, 31 weeks (P < 0.01) in group 2, and 24 weeks (P < 0.05) in group 3 compared with 19 weeks in water-fed controls. Median life expectancy was 68 weeks in group 1, 63 weeks in group 2, 56 weeks in group 3, and 51 weeks in group 4 compared with 42 weeks in the control mice. IGF-I and its downstream targets including phosphatidylinositol 3-kinase, pAkt, and phosphorylated extracellular signal-regulated kinase were significantly inhibited only when intervention was initiated early when prostatic intraepithelial neoplasia lesions were common. CONCLUSIONS: Our studies indicate that chemopreventive potential of GTP decreases with advancing stage of the disease and underscore the need to design appropriate chemoprevention clinical trails.

Derivatives of prostate-specific antigen as predictors of incidental prostate cancer.

OBJECTIVE To search for an optimal derivative of prostate-specific antigen (PSA) identifying patients at risk of incidental prostate cancer. PATIENTS AND METHODS In all, 693 patients who underwent transurethral resection of the prostate (TURP) with a normal digital rectal examination, no history of prostate cancer and a PSA level of 2.5-10 ng/mL were studied. The total PSA (tPSA), percentage of free/total PSA (%fPSA), complexed PSA (cPSA), PSA density, cPSA density and the ratio of fPSA to cPSA were measured. Specificity, sensitivity, positive and negative predictive values were determined for all possible threshold values indicating the risk of incidental prostate cancer (T1a or T1b). Furthermore, the patients were subdivided according to age and the presence of an indwelling transurethral catheter. The areas under the receiver operating characteristic curves (AUC) were compared. RESULTS In the whole sample, the %fPSA was the best test predicting all incidental prostate cancers (AUC 0.618, reference: tPSA 0.494), whereas cPSA density was the best predictor of T1b disease (AUC 0.720, reference: tPSA 0.548). Stratification by age did not meaningfully alter the results, the presence of a transurethral catheter, however, was associated with a superiority of tests based on fPSA (AUC 0.620-0.670) compared with tests based on tPSA or cPSA (AUC 0.421-0.581). CONCLUSION Replacing tPSA by PSA derivatives (%fPSA or cPSA density) and stratifying by the presence of an indwelling transurethral catheter may improve the prediction of the risk of incidental prostate cancer and spare unnecessary biopsies before TURP in the tPSA range 2.5-10 ng/mL.

High-grade foamy gland prostatic adenocarcinoma on biopsy or transurethral resection: a morphologic study of 55 cases.

Foamy gland carcinoma is a variant of adenocarcinoma of the prostate that typically is assigned a Gleason score 3+3=6. The morphologic features of high foamy gland carcinoma have not been previously studied. We analyzed 55 cases of high-grade (Gleason score 7 or greater) foamy gland carcinoma of the prostate in needle biopsy (n=49) or transurethral resection (n=6) specimens. The number of cores involved by high-grade foamy gland carcinoma ranged from 1 to 12, with more than 1 core involved in 61% of cases (mean 3.4 cores). On average, 84% of the total tumor volume was foamy gland carcinoma, with high-grade foamy gland cancer averaging 73% of the total foamy gland carcinoma. The following results pertain only to the high-grade foamy gland cancer component. The most common architectural pattern was cribriform (73%), followed by fused/poorly defined glands (55%), cords/single cells (11%), and solid sheets (5%). Nuclear enlargement was observed in 45 of the 55 studied cases (82%). Prominent nucleoli were either absent or infrequent in 38 cases (69%). Frequent to numerous prominent nucleoli were seen more frequently in foamy gland carcinoma with Gleason score 8 or above (52%) than those with Gleason score 7 (16%) (P<0.004). Mitotic figures were observed in 22 cases (40%), and present in 65% of the cases with Gleason score 8 or above, but only in 22% of the cases with Gleason score 7 (P<0.002). In 31 cases (56%), intraluminal dense pink secretions were identified. Perineural invasion and extraprostatic extension identified on the biopsy specimens were noted in 18 cases (33%) and in 5 cases (9%), respectively. In 18 cases (33%), there was at least a moderate stromal reaction. A moderate or greater stromal reaction was seen in 48% (11/23) of the cases with Gleason score 8 or above compared with 22% (7/32) of the cases with Gleason score 7 (P=0.04). In 6 cases, there was a peculiar extensive desmoplastic reaction almost obscuring the carcinoma component, 5 of which were Gleason scores 4+4=8. Concurrent ordinary acinar nonfoamy adenocarcinoma was encountered in 26 of 55 cases (47%) with the following Gleason scores: Gleason 6 (27%); Gleason 7 (27%); and Gleason 8 to 10 (46%). Associated ordinary high-grade prostatic intraepithelial neoplasia and foamy gland variant of high-grade prostatic intraepithelial neoplasia/intraductal adenocarcinoma were seen in 13 cases (24%) and 11 cases (20%), respectively. Of the 19 cases with available immunohistochemical stains for high molecular weight cytokeratin, 7 (37%) showed nonspecific labeling of cancer cells in a nonbasal cell pattern. A similar finding was seen in 1 of the 7 (14%) cases with available stains for p63. Alpha-methyl-CoA racemase positivity was noted in all 9 cases stained. In summary, uncommonly foamy gland carcinoma consists of cribriform, fused/poorly formed glands, cords/single cells, and solid sheets typical of Gleason patterns 4 and 5. High-grade foamy gland cancer shares certain morphologic features with more typical lower-grade foamy gland cancer including relatively bland nuclei with more difficult to identify nucleoli and frequent intraluminal dense pink secretions. However, consistent with their higher architectural grade, high-grade foamy gland cancers had more prominent nucleoli and increased mitotic figures compared with lower-grade foamy gland cancer. A unique subset of high-grade foamy gland carcinoma poses particularly difficult diagnostic challenges, with scattered, scant, relatively bland foamy glands imbedded in an extensive densely sclerotic desmoplastic stroma.

Reduced growth and integrin expression of prostate cells cultured with lycopene, vitamin E and fish oil in vitro.

Integrins are transmembrane proteins that facilitate the interaction of cells with the extracellular environment. They have also been implicated in cancer progression. The effects of nutrients thought to be involved in the prevention of prostate cancer on integrin expression have not been determined. Prostate cancer cell lines representing a range of malignancy from normal (RWPE-1) to highly invasive phenotypes (22Rv1 < LNCaP < PC-3) were cultured with or without lycopene (10 nM), vitamin E (5 microm) or fish oil (100 microm) for 48 h. Growth and integrin (alpha2beta1, alphavbeta3 and alphavbeta5) expression were assessed using Trypan Blue exclusion and monoclonal antibodies combined with flow cytometry. Vitamin E enhanced (P < 0.001) whereas fish oil reduced the growth of all the cell lines tested (P < 0.001). Lycopene had no effect on growth. All the malignant cell lines exhibited lower expression of alpha2beta1 with the addition of lycopene to culture media. Supplemental fish oil reduced alpha2beta1 in most invasive cell lines (LNCaP and PC-3). Each nutrient at physiological levels reduced integrins alphavbeta3 and alphavbeta5 in most invasive cell lines (PC-3). The results suggest that integrins may represent an additional target of bioactive nutrients and that the effects of nutrients may be dependent on the type of cell line used.

Clinical assessment of the cancer diagnostic value of prostatic zinc: a comprehensive needle-biopsy study.

BACKGROUND: The correlation between Zinc concentration in the prostate's peripheral zone to the onset or presence of malignant process needs to be evaluated in detail. METHODS: Zinc concentration was measured in approximately 1-4 mm3 segments of fresh needle-biopsy cores, with X-ray fluorescence, and correlated with the histological findings of these tissue segments. RESULTS: Local Zinc concentration is correlated with the presence of cancer (PCa); the higher the Gleason score the greater the Local Zinc depletion. The Zinc value averaged over the entire extracted tissue is specific only to Gleason score 8-9 PCa. The results refer to patients avoiding Zinc-rich supplements since those show elevated prostatic Zinc concentration in identified cancer tissue. A computer simulation analysis of randomly located 0.03-3.3 cm3 lesions, with particular Gleason score and the measured Local Zinc concentration, revealed a potential diagnostic approach definitely superior to PSA, with sensitivity to the tumor grade and with excellent detection capability for Gleason score >6. Further clinical studies have been designed, both on full prostates after radical prostatectomy as well as on biopsy cores at higher resolution, to establish the accuracy of the method for Gleason score = 6. CONCLUSIONS: The PCa diagnostic potential of Local Zinc concentration is confirmed and there is indication that the amount of Zinc depletion could be used as a measure of the Gleason score of the tumor. Local Zinc concentration mapping has the potential to improve patient selection for biopsy, biopsy site selection and local therapy (e.g., Cryotherapy, Brachytherapy) site selection.