Faculty Bibliography

PURPOSE/OBJECTIVE:To determine whether E-cadherin loss causes nonlobular cancers (NLCs) detected at mammographic screening to have different mammographic appearances than do NLCs with normal E-cadherin expression. MATERIALS AND METHODS/METHODS:This study design had hospital ethics committee approval; informed consent was waived. Membranous expression of E-cadherin was assessed immunohistochemically in patients younger than 70 years from a consecutive series of 1944 operable invasive breast cancers. Of those, 276 NLC cases (age range, 45-70 years) were common to a prospectively collected database of breast cancer detected at screening. The mammographic features of 131 NLCs with reduced E-cadherin expression were compared with those of 145 NLCs with normal E-cadherin expression. RESULTS:NLCs with E-cadherin loss were more likely to manifest as an ill-defined mass and less likely to manifest noncomedo microcalcifications at mammography than were NLCs with normal E-cadherin expression (47 [35.9%] of 131 vs 35 [24.1%] of 145, P = .03; and one [0.8%] of 131 versus 13 [9%] of 145, P = .001; respectively). NLCs with E-cadherin loss were significantly larger (>or=15 mm) than NLCs with normal E-cadherin expression (71 [54.2%] of 131 NLCs vs 57 [39.3%] of 145; P = .01). Both groups had a similar distribution of grade, tumor type, nodal metastases, and vascular invasion. CONCLUSION/CONCLUSIONS:Invasive NLCs with reduced E-cadherin expression detected at screening are more likely to appear as ill-defined masses and less likely to manifest noncomedo microcalcifications than are NLCs with normal E-cadherin expression. NLCs with reduced E-cadherin expression appear to have mammographic features that make them difficult to detect at small sizes.

PURPOSE/OBJECTIVE:Percutaneous biopsy of small renal tumors has not been historically performed because of concern about complications and accuracy. We reviewed our experience with percutaneous needle biopsy of small renal masses to assess the safety and accuracy of the procedure, the potential predictors of a diagnostic result and the role of biopsy in clinical decision making. MATERIALS AND METHODS/METHODS:A total of 100 percutaneous needle biopsies of renal masses less than 4 cm were performed between January 2000 and May 2007 with 18 gauge needles and a coaxial technique under ultrasound and/or computerized tomography guidance. A retrospective chart review was performed to document the complication rate and the ability to obtain sufficient tissue for diagnosis. Tumor size, tumor type (solid vs cystic), image guidance, biopsy number and core length were assessed for the ability to predict a diagnostic biopsy. RESULTS:No tumor seeding or significant bleeding was observed. Of the core biopsies 84 (84%) were diagnostic for a malignant (66) or a benign (18) tumor. Larger tumor size and a solid pattern were significant predictors of a diagnostic result. Histological subtyping and grading were possible on core biopsies in 93% and 68% of renal cell carcinomas, respectively. A total of 20 patients underwent surgery after a diagnostic biopsy. The histological concordance of biopsies and surgical specimens was 100%. CONCLUSIONS:Percutaneous needle biopsy of renal masses less than 4 cm is safe and provides adequate tissue for diagnosis in most cases. Larger tumor size and a solid pattern are significant predictors of a successful biopsy. Renal tumor biopsy decreases the rate of unnecessary surgery for benign tumors and can assist the clinician with treatment decision making, especially in elderly and unfit patients.

Breast needle core biopsy (NCB) is now a standard diagnostic procedure in the triple assessment of screen detected breast lesions. Therefore, it is important to provide robust and up-to-date data on the performance of NCB in the screening setting. However, previous studies of NCB have suffered from either limitation in the number of assessed cases or included a mix of symptomatic and screen detected breast lesions. In this study, we have evaluated the performance of a large series of uniformly assessed NCBs of screen detected lesions (20001 cases) over a period of 10 years (1997-2007). Our results showed a gradual increase in the number of NCBs and an improvement of their performance over the period of the study; absolute sensitivity increased from 84.9% to 96.4% and complete sensitivity increased from 90.9% to 99.7%. There was also a gradual reduction in the number of surgical interventions after benign (B2) and negative (B1) NCB diagnoses. Our study provides data showing variance from the suggested thresholds for the measures of performance of NCB in the United Kingdom which could be used to provide updated evidence-based thresholds for assessment of performance of NCB diagnosis use in the assessment of breast cancer screen detected lesions in the UK and elsewhere.

OBJECTIVE:Basal phenotype has been found to be an independent poor prognostic factor for breast cancer. The aim of this study was to assess the mammographic appearance of screening-detected breast carcinoma with the basal phenotype. MATERIALS AND METHODS/METHODS:A series of 1,944 consecutively enrolled patients with operable invasive breast cancer underwent immunohistochemical analysis with cytokeratin 5/6 and cytokeratin 14 markers to identify tumors exhibiting basal phenotype characteristics. Among those patients, 356 women with breast cancer were common to a prospectively collected database of screening-detected cases of breast cancer. The predominant mammographic appearance and any associated features were reported by experienced image readers blinded to phenotype status. A chi-square test was used to assess difference between the mammographic appearances of a group of tumors with the basal phenotype and those of a group with the nonbasal phenotype. RESULTS:Forty-one (12%) of the screening-detected tumors had basal phenotypic expression, and these were compared with 309 (88%) nonbasal tumors. Basal-phenotype tumors were significantly more likely to manifest as an ill-defined mass (basal phenotype, 25 [61%] of 41 tumors; nonbasal phenotype, 75 [24%] of 309 tumors; p < 0.001) or with comedo calcification (basal phenotype, nine [22%] of 41 tumors; nonbasal phenotype, 30 [10%] of 309 tumors; p = 0.019). Nonbasal-phenotype tumors were more likely to manifest as a spiculated mass (nonbasal phenotype, 150 [49%] of 309 tumors; basal phenotype, eight [20%] of 41 tumors; p < 0.001). The low rate of spiculation in basal tumors was independent of histologic grade. CONCLUSION/CONCLUSIONS:Screening-detected breast tumors with a basal phenotype have a mammographic appearance different from that of nonbasal tumors. This finding may explain the good prognostic value of mammographic spiculation reported in previous studies.

Accurate Gleason score, pathologic stage, and surgical margin (SM) information is critical for the planning of post-radical prostatectomy management in patients with prostate cancer. Although interobserver variability for Gleason score among urologic pathologists has been well documented, such data for pathologic stage and SM assessment are limited. We report the first study to address interobserver variability in a group of expert pathologists concerning extraprostatic soft tissue (EPE) and SM interpretation for radical prostatectomy specimens. A panel of 3 urologic pathologists selected 6 groups of 10 slides designated as being positive, negative, or equivocal for either EPE or SM based on unanimous agreement. Twelve expert urologic pathologists, who were blinded to the panel diagnoses, reviewed 40x whole-slide scans and provided diagnoses for EPE and SM on each slide. On the basis of panel diagnoses, as the gold standard, specificity, sensitivity, and accuracy values were high for both EPE (87.5%, 95.0%, and 91.2%) and SM (97.5%, 83.3%, and 90.4%). Overall kappa values for all 60 slides were 0.74 for SM and 0.63 for EPE. The kappa values were higher for slides with definitive gold standard EPE (kappa=0.81) and SM (kappa=0.73) diagnoses when compared with the EPE (kappa=0.29) and SM (kappa=0.62) equivocal slides. This difference was markedly pronounced for EPE. Urologic pathologists show good to excellent agreement when evaluating EPE and SM. Interobserver variability for EPE and SM interpretation was principally related to the lack of a clearly definable prostatic capsule and crush/thermal artifact along the edge of the gland, respectively.

PURPOSE/OBJECTIVE:To investigate differences in apparent diffusion coefficient (ADC) and T2 values between dense and sparse regions in prostate cancer. MATERIALS AND METHODS/METHODS:Eighteen patients (median age, 61 years; range, 44-72 years) gave informed consent for this retrospective Research Ethics Board-approved study. Prior to radical prostatectomy, ADC (b value, 600 sec/mm(2)) and T2 maps were obtained by using 1.5-T magnetic resonance (MR) imaging. Twenty-eight peripheral zone (PZ) tumors were reviewed by using whole-mount histologic findings, and regions assessed to contain primarily (>60%) normal PZ tissue were delineated. Tumors were categorized as "sparse" if more than 50% of their cross-sectional areas were these primarily normal PZ regions and were considered "dense" otherwise. Normal PZ tissue was outlined separately on the same section. Tumor and normal tissue outlines were transferred to corresponding ADC and T2 maps, and median values were calculated. Values were compared by using multiple regression analysis. Matched-pair tumor-to-normal tissue differences and log(2)-transformed ratios were assessed by using nonparametric tests. RESULTS:Thirty-six percent (10 of 28) of tumors were sparse; 64% (18 of 28) were dense. For both overall and intrapatient comparisons, dense tumors had significantly lower ADC and T2 values than normal PZ tissue (P < .05), but no significant differences were observed between sparse tumors and normal tissue. Log(2)-transformed tumor-to-normal tissue ratios were significantly less than zero for dense tumors for both ADC and T2 (P < .01) measurements but not for sparse tumors. Both matched-pair differences and log(2)-transformed ratios were significantly different between sparse and dense tumors (P < .01). ADC and T2 values were moderately correlated (Pearson correlation coefficient range, r = 0.770-0.804). CONCLUSION/CONCLUSIONS:Sparse prostate tumors have similar ADC and T2 values to those of normal PZ tissue. This may limit MR imaging detection and the assessment of tumor volume of some cancers.

The product of the von Hippel-Lindau gene (VHL) acts as the substrate-recognition component of an E3 ubiquitin ligase complex that ubiquitylates the catalytic alpha subunit of hypoxia-inducible factor (HIF) for oxygen-dependent destruction. Although emerging evidence supports the notion that deregulated accumulation of HIF upon the loss of VHL is crucial for the development of clear-cell renal cell carcinoma (CC-RCC), the molecular events downstream of HIF governing renal oncogenesis remain unclear. Here, we show that the expression of a homophilic adhesion molecule, E-cadherin, a major constituent of epithelial cell junctions whose loss is associated with the progression of epithelial cancers, is significantly down-regulated in primary CC-RCC and CC-RCC cell lines devoid of VHL. Reintroduction of wild-type VHL in CC-RCC (VHL(-/-)) cells markedly reduced the expression of E2 box-dependent E-cadherin-specific transcriptional repressors Snail and SIP1 and concomitantly restored E-cadherin expression. RNA interference-mediated knockdown of HIFalpha in CC-RCC (VHL(-/-)) cells likewise increased E-cadherin expression, while functional hypoxia or expression of VHL mutants incapable of promoting HIFalpha degradation attenuated E-cadherin expression, correlating with the disengagement of RNA polymerase II from the endogenous E-cadherin promoter/gene. These findings reveal a critical HIF-dependent molecular pathway connecting VHL, an established "gatekeeper" of the renal epithelium, with a major epithelial tumor suppressor, E-cadherin.

The most prevalent mutations associated with the development of clear-cell renal cell carcinoma (CC-RCC) are the loss-of-function mutations of von Hippel-Lindau (VHL) tumor suppressor gene. These mutations invariably result in an inappropriate accumulation of HIF-alpha due to a failure of VHL as a substrate-recognition component of an E3 ubiquitin ligase complex to target HIFalpha for oxygen-dependent ubiquitin-mediated destruction. Stabilization of HIF-2alpha, but not HIF-1alpha, is the critical oncogenic event upon the functional loss of VHL in the development of CC-RCC. Here, we show that HIF-3alpha4, an alternatively spliced variant of human HIF-3alpha with similar domain structure as the murine inhibitory PAS protein (IPAS), forms an abortive transcriptional complex with HIF-2alpha and prevents the engagement of HIF-2 to the hypoxia-responsive elements (HREs) located in the promoter/ enhancer regions of hypoxia-inducible genes. In addition, the re-expression of HIF-3alpha4 in VHL-null 786-O CC-RCC cells via adenovirus decreases the endogenous expression of HIF-2-driven gene expression and suppresses the growth of 786-O tumor xenografts in SCID mice. These results suggest that HIF-3alpha4 is a naturally occurring dominant-negative HIF-3alpha splice isoform with tumor suppressive activity and support the targeted delivery of HIF-3alpha4 as a potential therapeutic option to curtail HIF-dependent tumor progression.

PURPOSE/OBJECTIVE:The incidence of renal cell carcinoma is increasing worldwide and there are new treatments for localized as well as metastatic tumors. The traditional role for percutaneous biopsy of renal masses has been limited, and so there is little general experience. There have been concerns about safety and accuracy. This review provides an update on the current techniques, indications and accuracy of needle biopsy of renal tumors. MATERIALS AND METHODS/METHODS:PubMed and MEDLINE were searched for English language reports of percutaneous needle core biopsy and fine needle aspiration of renal tumors that were published from 1977 to 2006. RESULTS:With the development of new biopsy techniques and wider experience with percutaneous probe ablation therapies the risk of tumor seeding appears negligible. Significant bleeding is unusual and almost always self-limiting. At centers with expertise needle core biopsy with or without fine needle aspiration appears to provide adequate specimens for an accurate diagnosis in more than 90% of renal masses. CONCLUSIONS:Percutaneous biopsy of renal masses appears to be safe and it carries minimal risk of tumor spread. Urologists should consider increasing the indications for renal biopsy of small renal masses that appear to be renal cell carcinoma, especially in elderly and unfit patients. With more experience and followup preoperative biopsy has the potential to decrease unnecessary treatment since up to a third of small renal masses are now reported to be benign at surgery. Percutaneous biopsy may also allow a better selection of renal tumors for active surveillance and minimally invasive ablative therapies. Finally, there is potential for stratifying initial therapy for metastatic renal cell carcinoma by histological subtype and in the future molecular characteristics.

OBJECTIVE:The aim of our study was to assess the effect of mammographic parenchymal pattern on patient survival, mammographic features, and pathologic features of breast cancer in a screened population. MATERIALS AND METHODS/METHODS:We classified the parenchymal pattern (according to BI-RADS) of 759 screened women who presented with a screening-detected (n = 455) or interval (n = 304) invasive breast cancer. Pathologic details (tumor size, histologic grade, lymph node stage, vascular invasion, and histologic type) and mammographic appearances were recorded. Breast cancer-specific survival was ascertained, with a median follow-up of 9.0 years. RESULTS:An excess of interval cancers was seen in women with dense breasts (p < 0.0001). Screening-detected (but not interval) tumors were significantly smaller in fatty breasts (p = 0.014). Tumor grade, lymph node stage, vascular invasion, and histologic type did not vary significantly with mammographic parenchymal pattern in screening-detected or interval cancers. Screening-detected cancers in fatty breasts were more likely to appear as indistinct (p = 0.003) or spiculated (p = 0.002) masses in contrast to cancers in dense breasts, which more commonly appeared as architectural distortions (p < 0.0001). No significant breast cancer-specific survival difference was seen by mammographic parenchymal pattern for screening-detected cancers (p = 0.75), interval cancers (p = 0.82), or both groups combined (p = 0.12). CONCLUSION/CONCLUSIONS:The prognosis of screened women presenting with breast cancer is unrelated to dense mammographic parenchymal pattern despite an excess of interval cancers and larger screening-detected tumors in this group. These data support the mammographic screening of women with dense parenchymal patterns.