Faculty Bibliography

PURPOSE/OBJECTIVE:To prospectively evaluate the magnetic resonance (MR) imaging appearance of the prostate and periprostatic tissues after vascular targeted photodynamic therapy (VTP) with palladium-bacteriopheophorbide for locally recurrent carcinoma after external beam radiation therapy. MATERIALS AND METHODS/METHODS:Informed consent was obtained from all patients, and approval was obtained from the ethics review boards of all participating institutions. Nonenhanced T2-weighted and dynamic gadolinium-enhanced T1-weighted MR imaging examinations were performed at baseline and 1 week, 4 weeks, and 6 months after VTP in 25 men (age range, 58-83 years; mean age, 73 years) as part of a prospective phase I/II trial. Percentage of MR-depicted necrosis was defined as the volume of nonenhancing prostatic tissue 1 week after VTP divided by the volume of the prostate. Patterns of intra- and extraprostatic necrosis were recorded. Pearson correlation coefficients were used to test correlations between necrosis and prostate-specific antigen level. RESULTS:Contrast material-enhanced T1-weighted MR images obtained 1 week after therapy showed necrosis in all patients. Treatment margins were irregular in 21 of 25 patients. T2-weighted images showed no clear treatment boundaries in any patient. Extraprostatic necrosis involved the puborectalis or levator ani muscles in 22, obturator internus muscle in 12, periprostatic veins in three, pubic bone marrow in four, and anterior rectal wall in nine of the 25 patients. The neurovascular bundle appeared to be spared in all patients. Percentage of MR-depicted intraprostatic necrosis was correlated with percentage decrease in prostate-specific antigen level (from baseline) at 4 weeks (r=0.41, P=.04) and 12 weeks (r=0.45, P=.02). CONCLUSION/CONCLUSIONS:Contrast-enhanced MR imaging depicts irregular margins of intraprostatic treatment effect. This finding suggests varied tissue sensitivities to VTP with palladium-bacteriopheophorbide.

OBJECTIVE:The objective of our study was to compare T2-weighted MRI alone and T2 combined with diffusion-weighted imaging (DWI) for the localization of prostate cancer. SUBJECTS AND METHODS/METHODS:T2-weighted imaging and DWI (b value = 600 s/mm2) were performed in 49 patients before radical prostatectomy using an endorectal coil at 1.5 T in this prospective trial. The peripheral zone of the prostate was divided into sextants and the transition zone into left and right halves. T2 images alone and then T2 images combined with apparent diffusion coefficient (ADC) maps (T2 + DWI) were scored for the likelihood of tumor and were compared with whole-mount histology results. Fixed window and level settings were used to display the ADC maps. Only tumors with an area of more than 0.13 cm2 (> 4 mm diameter) and a Gleason score of > or = 6 were considered significant. The area under the receiver operating characteristic curve (A(z)) was used to assess accuracy. RESULTS:In the peripheral zone, the A(z) value was significantly higher (p = 0.004) for T2 plus DWI (A(z) = 0.89) than for T2 imaging alone (A(z) = 0.81). Performance was poorer in the transition zone for both T2 plus DWI (A(z) = 0.78) and T2 (A(z) = 0.79). For the whole prostate, sensitivity was significantly higher (p < 0.001) with T2 plus DWI (81% [120/149]) than with T2 imaging alone (54% [81/149]), with T2 plus DWI showing only a slight loss in specificity compared with T2 imaging alone (84% [204/243] vs 91% [222/243], respectively). CONCLUSION/CONCLUSIONS:Combined T2 and DWI MRI is better than T2 imaging alone in the detection of significant cancer (Gleason score > or = 6 and diameter > 4 mm) within the peripheral zone of the prostate.

The loss of functional von Hippel-Lindau (VHL) tumor suppressor gene is associated with the development of clear-cell renal cell carcinoma (CC-RCC). Recently, VHL was shown to promote the transcription of E-cadherin, an adhesion molecule whose expression is inversely correlated with the aggressive phenotype of numerous epithelial cancers. Here, we performed immunohistochemistry on CC-RCC tissue microarrays to determine the prognostic value of E-cadherin and VHL with respect to Fuhrman grade and clinical prognosis. Low Fuhrman grade and good prognosis associated with positive VHL and E-cadherin immunoreactivity, whereas poor prognosis and high-grade tumors associated with a lack of E-cadherin and lower frequency of VHL staining. A significant portion of CC-RCC with positive VHL immunostaining correlated with nuclear localization of C-terminally cleaved E-cadherin. DNA sequencing revealed in a majority of nuclear E-cadherin-positive CC-RCC, subtle point mutations, deletions and insertions in VHL. Furthermore, nuclear E-cadherin was not observed in chromophobe or papillary RCC, as well as matched normal kidney tissue. In addition, nuclear E-cadherin localization was recapitulated in CC-RCC xenografts devoid of functional VHL or reconstituted with synthetic mutant VHL grown in SCID mice. These findings provide the first evidence of aberrant nuclear localization of E-cadherin in CC-RCC harboring VHL mutations, and suggest potential prognostic value of VHL and E-cadherin in CC-RCC.

Neuroendocrine (NE) differentiation in prostate cancer is typically detected by immunohistochemistry as single cells in conventional adenocarcinoma. Prostatic NE tumors, such as carcinoid or small cell carcinoma, are rare and large cell NE carcinoma (LCNEC) is described only in case reports. We identified 7 cases of LCNEC and compiled their clinicopathologic characteristics. In 6 cases, there was a history of adenocarcinoma treated with hormone therapy for a mean of 2.4 years (range: 2 to 3 y). The remaining case was de novo LCNEC. LCNEC was incidentally diagnosed in palliative transurethral resection specimens in 5 cases. The mean patient age at diagnosis with LCNEC was 67 years (range: 43 to 81 y). LCNEC comprised solid sheets and ribbons of cells with abundant pale to amphophilic cytoplasm, large nuclei with coarse chromatin and prominent nucleoli along with brisk mitotic activity and foci of necrosis. In 6 cases, there were foci of admixed adenocarcinoma, 4 of which showed hormone therapy effects. LCNEC was strongly positive for CD56, CD57, chromogranin A, synaptophysin, and P504S/alpha methylacyl CoA racemase. There was strong bcl-2 overexpression, expression of MIB1, and p53 in >50% of nuclei, focally positive staining for prostate specific antigen and prostatic acid phosphatase and negative androgen receptor staining. Follow-up was available for 6 patients, all of who died with metastatic disease at mean of 7 months (range: 3 to 12 mo) after platinum-based chemotherapy. LCNEC of prostate is a distinct clinicopathologic entity that typically manifests after long-term hormonal therapy for prostatic adenocarcinoma and likely arises through clonal progression under the selection pressure of therapy.

The recent description of novel recurrent gene fusions in approximately 80% of prostate cancer (PCa) cases has generated increased interest in the search for new translocations in other epithelial cancers and emphasizes the importance of understanding the origins and biologic implications of these genomic rearrangements. Analysis of 15 PCa cases by reverse transcription-polymerase chain reaction was used to detect six ERG-related gene fusion transcripts with TMPRSS2. No TMPRSS2/ETV1 chimeric fusion was detected in this series. Three-color fluorescence in situ hybridization confirms that TMPRSS2/ERG fusion may be accompanied by a small hemizygous sequence deletion on chromosome 21 between ERG and TMPRSS2 genes. Analysis of genomic architecture in the region of genomic rearrangement suggests that tracts of microhomology could facilitate TMPRSS2/ERG fusion events.

Prostate cancer (CaP) is characterized by the accumulation of both genetic and epigenetic alterations that transform premalignant lesions to invasive carcinoma. However, the molecular events underlying this critical transition are poorly understood. One of the important genes that might play a role in CaP development is the PTEN gene. At the present time, there has been no systematic analysis of the incidence of genomic PTEN deletion by fluorescence in situ hybridization (FISH) in CaP and associated preneoplastic histologic lesions. This study assesses the frequency of PTEN deletion by interphase FISH analysis in CaP and prostatic intra-epithelial neoplasia (PIN). Dual-color FISH was performed using DNA probes for bands 10q23.3 (PTEN locus) and chromosome 10 centromere using 35 radical prostatectomy specimens. PTEN deletions were not found in 3/3 of stroma, 6/6 samples of benign glandular epithelium, and 12/12 samples of low-grade PIN. However, PTEN deletions were found in 3/13 (23%) of high-grade PIN and 24/35 (68%) of CaP. Concordance was observed between PTEN deletion status and the overall cellular PTEN protein expression levels, as assessed by immunohistochemistry. The high frequency of PTEN deletion observed in CaP versus precursor lesions implicates a pivotal role for PTEN haploinsufficiency in the transition from preneoplastic PIN to CaP. Moreover, this observation is an important consideration for novel therapeutic trials in CaP in which biologic efficacy is influenced by the activity level of PTEN. These findings draw attention to the usefulness of this relatively simple FISH assay for future applications in clinical laboratories.

OBJECTIVE:The aim of this study was to review the prognostic significance of pathologic and radiologic factors for screening-detected invasive breast cancers of any size. MATERIALS AND METHODS/METHODS:The patient group was a consecutive series of 470 screening-detected invasive breast cancers that were diagnosed between 1988 and 1998. Data regarding tumor type, grade, maximum invasive diameter, lymph node status, and the presence or absence of vascular invasion were recorded, as were the mammographic features of the lesion. Survival was ascertained from hospital records and a cancer registry. Differences in survival were assessed using Kaplan-Meier survival curves with a log-rank test for difference. The significance of any correlations was assessed using the chi-square test and the chi-square test for trend. Multivariate analysis used a Cox proportional hazards model. RESULTS:At univariate analysis, large invasive size, the presence of definite vascular invasion, high histologic grade, and nodal involvement were associated with poorer breast-cancer-specific survival. Mammographic spiculation (the presence of either a spiculated mass or distortion) was associated with more prolonged breast-cancer-specific survival. The presence or absence of mammographic comedo calcification did not influence breast-cancer-specific survival. In a Cox multivariate analysis that included those factors significant in univariate analysis, size, grade, nodal stage, and mammographic spiculation maintained their prognostic significance. CONCLUSION/CONCLUSIONS:Mammographic spiculation is an independent, good prognostic factor for screening-detected invasive breast cancer. The mechanism of how mammographic spiculation confers a beneficial prognostic effect is not clear.

The differential diagnosis of mucin-producing adenocarcinoma of the prostate includes conventional prostatic adenocarcinoma with mucin production, secondary adenocarcinoma usually of colorectal origin and, very rarely, urothelial-type adenocarcinoma arising from either the prostatic urethra or proximal ducts. Conventional prostatic adenocarcinoma with mucin production is readily identified by routine microscopy and immunohistochemistry. The distinction between secondary adenocarcinoma and urothelial-type adenocarcinoma, however, can present a significant diagnostic challenge. In addition, documented examples of the latter in the prostate are exceptionally rare. A transurethral resection of prostate specimen and prostatic needle biopsies from two patients showing urothelial-type adenocarcinoma of the prostate were identified in our consultation files. One of the patients subsequently underwent a radical prostatectomy. Both patients had negative gastrointestinal endoscopic workups. Transurethral resection of prostate material from two patients with clinically confirmed secondary adenocarcinoma of colonic origin involving the prostate and a prostatectomy specimen with mucinous conventional prostatic adenocarcinoma were also identified for comparison purposes. Formalin-fixed, paraffin-embedded sections were stained for prostate-specific antigen (PSA), prostatic acid phosphatase, carcinoembryonic antigen, cytokeratin 7, cytokeratin 20 and high molecular weight cytokeratin 34betaE12. The urothelial-type adenocarcinoma cases were diffusely positive for cytokeratin 7 and focally positive for 34betaE12 and cytokeratin 20, consistent with an origin from the urothelium of the prostatic urethra or proximal prostatic ducts. In contrast, the secondary adenocarcinoma of colonic origin cases were diffusely cytokeratin 20 positive and either negative or focally positive for cytokeratin 7 and negative for 34betaE12. The mucinous conventional prostatic adenocarcinoma was positive for PSA and prostatic acid phosphatase and negative for cytokeratin 7, cytokeratin 20 and 34betaE12. All tumors were positive for carcinoembryonic antigen.

A universal response to changes in cellular oxygen tension is governed by a family of heterodimeric transcription factors called hypoxia-inducible factor (HIF). Tumor hypoxia, as well as various cancer-causing mutations, has been shown to elevate the level of HIF-1alpha, signifying a critical role of the HIF pathway in cancer development. The recently identified third member of the human HIF-alpha family, HIF-3alpha, produces multiple splice variants that contain extra DNA binding elements and protein-protein interaction motifs not found in HIF-1alpha or HIF-2alpha. Here we report the molecular cloning of the alternatively spliced human HIF-3alpha variant HIF-3alpha4 and show that it attenuates the ability of HIF-1 to bind hypoxia-responsive elements located within the enhancer/promoter of HIF target genes. The overexpression of HIF-3alpha4 suppresses the transcriptional activity of HIF-1 and siRNA-mediated knockdown of the endogenous HIF-3alpha4 increases transcription by hypoxia-inducible genes. HIF-3alpha4 itself is oxygen-regulated, suggesting a novel feedback mechanism of controlling HIF-1 activity. Furthermore, the expression of HIF-3alpha4 is dramatically down-regulated in the majority of primary renal carcinomas. These results demonstrate an important dominant-negative regulation of HIF-1-mediated gene transcription by HIF-3alpha4 in vivo and underscore its potential significance in renal epithelial oncogenesis.