Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma.

The clinical behavior of renal cell carcinoma (RCC) cannot be predicted by histological and other markers. In this study, comparative genomic hybridization was used to evaluate whether the number of genomic aberrations has prognostic significance in 41 nonmetastatic clear cell RCC extending beyond the renal capsule. Losses were most prevalent at 3p (56%) and 9p and 13q (24% each). The number of DNA losses per tumor was associated with recurrence-free survival (P = 0.03). DNA gains most often involved chromosome 5q (17%) and chromosome 7 (15%). The number of DNA gains was not associated with clinical outcome. Loss of chromosome 9p was the only individual locus associated with recurrence (P = 0.04), suggesting that a tumor suppressor gene on chromosome 9p may play a role in RCC progression.

Allelic deletions in renal tumors: histopathological correlations.

Allelic loss on the short arm of chromosome 3 (3p) is considered to be one of the early detectable events in the pathogenesis of renal cell carcinoma (RCC). Conflicting reports, however, suggest that this event may be absent in some renal tumors. The present study attempts to further define subgroups of renal tumors associated with 3p deletions. In addition, we have also attempted to identify late genetic events associated with tumorigenesis and tumor progression. Eighty-two primary renal tumors (69 RCC and 13 oncocytic tumors) were analyzed by restriction fragment length polymorphism analysis directed at chromosomes 3, 11p, 17p, and 18q. Results were correlated with histopathological information. Deletions of 3p were seen in nonpapillary RCC of all cell types, but were absent in oncocytic and most papillary tumors. Among the 60 nonpapillary RCC, significant correlations were seen between deletion of 17p and tumor grade (P = 0.037), P stage (P = 0.027), and nodal metastases (P = 0.042). We therefore conclude that 3p deletions, although not specific to any cell type or histological pattern of RCC, are seen in a majority of clear cell nonpapillary RCC but are absent in oncocytic and most papillary tumors. Additional allelic losses on chromosome 17p are associated with advanced disease and, therefore, may be related to tumor progression. Further studies on larger series of patients with extended follow-up will be necessary to investigate the prognostic value of molecular genetic markers in RCC.

Molecular genetic alterations in superficial and locally advanced human bladder cancer.

We attempted to define the role of tumor suppressor genes in the pathogenesis of human bladder cancer through a combined molecular genetic and immunohistochemical approach. Thirty-four bladder tumors (1 Pis, 6 Pa, 5 P1, 3 P3a, 18 P3b, 1 P4; 8 low grade and 26 high grade tumors) have been analyzed. Restriction fragment length polymorphism analysis directed at 5 suspected or established tumor suppressor gene regions (3p21-25, 11p15, 13q14, 17p11-13, and 18q21) was combined with immunohistochemical using Rb-PMG3-245 monoclonal antibody directed at the retinoblastoma (Rb) gene product. Tumor grade correlated with deletions of 3p (P = 0.004) and 17p (P = 0.063). Tumor stage correlated with deletions of 3p (P = 0.010), 17p (P = 0.015) and altered Rb expression (P = 0.054). Vascular invasion correlated only with deletions of 17p (P = 0.038). No marker correlated with positive lymph nodes. Our results suggest that altered Rb expression occurs in all grades and stages of bladder cancer but is more commonly associated with invasive tumors. Genetic alterations of 3p, 11p, 17p, and 18q are rare events in low grade, superficial tumors, whereas they are more common in high grade and invasive bladder cancer. The role of these genetic alterations in the prognosis of bladder cancer will require additional follow-up and further studies.

Histopathological, cytogenetic, and molecular characterization of renal cortical tumors.

We used cytogenetic and restriction fragment length polymorphism (RFLP) analysis methods to define genetic alterations and also correlate the changes with histopathology in renal cortical tumors. The study series is comprised of 50 renal tumors in 4 histological categories: (a) clear cell, nonpapillary, renal cell carcinoma (RCC) (n = 32); (b) nonclear cell, nonpapillary RCC (n = 10); (c) papillary RCC (n = 3); and (d) oncocytic tumors (n = 5). Successful karyotypes were obtained from 28 tumors (56%), of which 17 (61%) were abnormal. Abnormalities of chromosome 3p were seen in 9 tumors, which included unbalanced translocations and terminal or interstitial deletions. Abnormalities of chromosome 5 were identified in 11 tumors, 8 of which were due to unbalanced translocations between 3p and 5q, resulting in an extra copy for the region 5q22----ter. In addition, trisomy or tetrasomy of chromosome 17 was seen in 6 (5 with normal chromosome 3 and one with 3p deletion), trisomy or more copies of chromosome 7 in 8 (4 with 3p deletion, 2 with trisomy or tetrasomy 17, and 2 with trisomy alone), and trisomy 12 in 3 (all with trisomy 17) tumors. Furthermore, relative deficiency of chromosome 17p was seen in 3 (all with deletion 3p) and chromosome 18 in 4 (all with deletion 3p) tumors. RFLP analysis with four chromosome 3 specific probes detected 3p deletions in 19 tumors with the most common breakpoint located between 3p14-21. The 19 3p deletions detected by RFLP included tumors that also showed rearrangement of 3p by cytogenetics (n = 4) and those that showed normal karyotypes (n = 3) in addition to cytogenetic failures (n = 12). Deletions of 17p were seen in 5 of 31 informative cases. Thus, deletions of 3p were seen in a total of 24 tumors by cytogenetic and/or RFLP analysis, 21 of which were clear cell, nonpapillary RCC, whereas 3 had a minor clear-cell component. Oncocytic and nonclear, nonpapillary tumors, on the other hand, did not demonstrate 3p deletions by either technique, whereas trisomy 17 was seen in 3 of the 3 papillary tumors. The loss of alleles from chromosome 17p and 18 and an increased dosage of gene or genes on chromosomes 5q and 7 as seen in high-stage tumors of various histological subtypes may be associated with progression of disease.

Contemporary approach to the classification of renal epithelial tumors.

Our understanding of the morphologic and genetic features of renal epithelial neoplasia has brought about profound changes in the classification of these tumors. It is clear that they represent a heterogeneous group of tumors with distinct histopathologic, genetic, and clinical features ranging from benign to high-grade malignant. "Granular" and "sarcomatoid" carcinomas are not distinct entities, since tumors with granular or spindle cell features may be seen in many tumor-types. Using conventional pathologic tools such as hematoxylin and eosin staining, histochemistry, immunohistochemistry, and electron microscopy, we are able to properly classify the majority of these tumors. Nevertheless, approximately 6% to 7% of cases are impossible to classify in this fashion, thus requiring molecular genetic studies for proper characterization.

Late presentation of ureteral injury after laparoscopic surgery.

OBJECTIVE: To describe clinical presentation, etiology, and treatment of ureteral injuries recognized late in women who had gynecologic laparoscopies. METHODS: We reviewed the charts of 12 women who had delayed recognition of ureteral injuries between January 1991 and December 1998. RESULTS: Patients presented with fever, hematuria, flank pain, or peritonitis between 3 and 33 days postoperatively. The mechanism of ureteral injuries was electrocoagulation in seven women, laser ablation in one, and stapler ligation in four. The sites of injury were near the inferior margin of the sacroiliac joint on excretory urogram in eight women and near the ureterovesical junction in four. Three women initially treated with internal ureteral stents were subsequently treated with ureteroneocystostomy because of progression of urinary ascites in two and a delayed ureteral stricture in one. In nine patients, attempts at ureteral stenting were unsuccessful and immediate ureteral reconstruction was done. Outcomes were good in all cases. CONCLUSION: Delayed recognition of ureteral injury after gynecologic laparoscopy was associated with serious complications, and initial treatment with ureteral stenting was not useful. We advocate early open repair for those injuries.

Molecular genetic alterations of chromosome 17 and p53 nuclear overexpression in human bladder cancer.

We set out to define the alterations of chromosome 17 in human bladder tumors and to correlate p53 nuclear over-expression with 17p deletions in those neoplasms. We studied 60 bladder tumors by restriction fragment-length polymorphism analysis directed at five different loci on chromosome 17. The same tumors were studied with a panel of mouse monoclonal antibodies (PAb1801, PAb240, and PAb1620) to mutant and wild-type p53 proteins using immunohistochemistry. Deletion of 17p correlated with grade (p = 0.039), stage (p = 0.004), and the presence of vascular invasion (p = 0.056). None of the pathologic parameters correlated with 17q deletions. p53 nuclear overexpression correlated with grade (p = 0.027), stage (p = 0.008), vascular invasion (p = 0.021), and the presence of nodal metastases (p = 0.007). In superficial (Ta) lesions, 17p was not deleted, whereas 55% of T1 and T2-T4 tumors showed a loss of heterozygosity. Mutations of p53 as detected by immunohistochemistry were seen in superficial as well as invasive tumors, whereas loss of heterozygosity was seen only in invasive tumors. A strong correlation was found between the presence of mutation and the loss of heterozygosity of the remaining allele (p = 0.0003). Additional follow-up and further studies are required to better define the role of p53 nuclear overexpression and 17p deletions as markers of tumor progression in human bladder cancer.

L-MYC allelotype in renal cell carcinoma.

The L-MYC restriction fragment-length polymorphism (RFLP) revealed by EcoR1 has been suggested to be of prognostic significance in lung, breast, and kidney cancer. The presence of the smaller allele, in either the homozygotic (S-S) or heterozygotic form (L-S), is felt to convey a worse prognosis than the homozygotic form for the larger allele (L-L). The significance of this relationship in lung cancer has been questioned recently. The objective of the present study was to test the prognostic significance of the L-MYC allelotype in a group of renal cell carcinoma (RCC) patients. Tumor and normal tissue were obtained from 59 patients who underwent radical nephrectomy for RCC between 1986 and 1990. EcoR1 restriction digests were performed on isolated DNA and hybridized with the L-MYC probe. Allelotypes were correlated with pathologic parameters and clinical outcome using the chi 2 test. The L-MYC alleolotype (L-L versus L-S and S-S) did not correlate with any pathologic parameter or likelihood of disease recurrence and does not offer any clinical utility in patients with RCC.

The role of the urologist in adjuvant chemotherapy trials for prostate cancer.

The urologist is ideally positioned to identify patients at high risk for relapse after radical prostatectomy. Several models have been proposed to help the urologist identify which patients are at risk and who should be considered for adjuvant therapy after radical prostatectomy. The appropriate initial trial design considered for this group of patients should be a randomized two-arm trial, without androgen deprivation, to assess more quickly the efficacy of selected agents.

Comparison of plicated and stapled continent ileocecal stoma.

Tapered terminal ileum and an intact ileocecal valve have been shown to be an effective efferent continence mechanism in patients with continent ileocecal urinary reservoirs. The terminal ileum can be tapered by simple suture plication or with linear gastrointestinal stapling devices. We used precise urodynamic techniques to study 21 continent urinary reservoirs constructed from ileocecal bowel segments: 14 with plicated segments and 7 with stapled segments. Mean contraction pressures tended to be higher in the latter (P = 0.054), although maximum contraction pressures were similar (P = 0.48). Terminal ileum tapered with the gastrointestinal stapling device and an intact ileocecal valve provide for an effective efferent continence mechanism that is easy to construct and catheterize.

Focal therapy for prostate cancer 1996: maximizing outcome.

OBJECTIVES: To summarize improvements in patient selection and the results of focal therapy for the management of localized prostate cancer. METHODS: A contemporary series of patients managed with wide surgical excision, radiation therapy (three-dimensional conformal radiation, interstitial radiation, and charged-particle or proton therapy), and cryo-therapy were reviewed. RESULTS: We used preoperative cancer grade, transrectal ultrasound, and serum prostate-specific antigen (PSA) in all patients, and cross-sectional imaging and bone scans in selected patients to allow for reasonably accurate cancer staging and selection of patients most likely to be cured by radical prostatectomy or radiation. In patients with extracapsular extension of prostate cancer, wide surgical excision and achievement of a clear surgical margin had therapeutic value. Newer radiation techniques resulted in a higher likelihood of prostate cancer control than previous techniques. Cryotherapy for patients with stages T1 through 3 prostate cancer was associated with a posttreatment undetectable PSA rate of 48% and a positive biopsy rate of 23%. CONCLUSIONS: Patients with organ-confined and, therefore, curable prostate cancer can be identified. Well-performed radical prostatectomy, radiation, and cryotherapy are alternative treatments for the management of localized prostate cancer.

Positive fraction of systematic biopsies predicts risk of relapse after radical prostatectomy.

OBJECTIVES: To determine whether the positive fraction of systematic sextant biopsies contributes to the prediction of serologic relapse after radical prostatectomy. METHODS: A retrospective review of patients who underwent transrectal ultrasound-guided systematic sextant biopsy and radical prostatectomy was performed. No patients received neoadjuvant or adjuvant therapy. The relationship between the positive fraction of systematic biopsies and risk of prostate-specific antigen recurrence was assessed with Kaplan-Meier and multivariate analyses. RESULTS: Patients with three or fewer positive sextant biopsies were at a significantly lower risk of relapse after radical prostatectomy than patients with four or more positive biopsies. Tumor grade and systematic biopsy results were the most powerful predictors of serologic relapse. CONCLUSIONS: The positive fraction of systematic biopsies contributes to the prediction of risk of relapse after radical prostatectomy.

Local recurrence after radical prostatectomy: characteristics in size, location, and relationship to prostate-specific antigen and surgical margins.

OBJECTIVES: To define the sonographic characteristics of local cancer recurrence after radical prostatectomy. METHODS: in 114 patients with an elevated prostate-specific antigen (PSA) and negative bone scan, 156 ultrasound-guided prostate fossa biopsies were carried out. RESULTS: in 53.5%, biopsy proved local recurrence. More than one ultrasound-guided biopsy session was required to make the diagnosis in 33% of patients. Local recurrence was seen on ultrasound at the anastomotic site (66%), the bladder neck (16%), and posterior to the trigone (13%). in 5% of patients there was a normal-appearing anastomotic site. Transrectal ultrasound was greater than 90% sensitive in detecting local recurrence, but lacked specificity. Examination of the radical prostatectomy specimens in patients with local recurrence showed positive surgical margins in 66% and organ-confined disease in 20%. CONCLUSIONS: Transrectal ultrasonography is a useful adjunct to PSA and digital rectal examination in the detection of local recurrences following radical prostatectomy.

Systematic sextant biopsies in the prediction of extracapsular extension at radical prostatectomy.

OBJECTIVES: To evaluate the clinical utility of transrectal ultrasound-guided systematic sextant needle biopsies in the prediction of extracapsular extension (ECE) at radical prostatectomy. METHODS: A retrospective analysis of 104 men who underwent systematic biopsy and radical prostatectomy at our institution was performed. All patients underwent preoperative staging by transrectal ultrasound and transrectal ultrasound-guided systematic sextant biopsy. The presence of pathologic ECE was correlated to the number of positive core biopsies on each side of the prostate by chi-square analysis. Sensitivity, specificity, positive and negative predictive values, and likelihood ratios (LRs) were calculated for both positive (two or three biopsies positive per side) and negative (no or one positive biopsy per side) test results. RESULTS: Forty-two (20.2%) of 208 sides demonstrated evidence of ECE at radical prostatectomy. Chi-square analysis demonstrated a significant correlation between the number of positive biopsies and the presence of ECE at radical prostatectomy (P = 0.001). Overall, the finding of multiple positive core biopsies (two or three per side) had predictive value with regard to the presence of ECE (sensitivity 62%, specificity 77%, positive predictive value 40%, negative predictive value 89%). The corresponding LRs were 2.5 for a positive and 0.5 for a negative test result. CONCLUSIONS: The probability of ECE at radical prostatectomy can be more accurately assessed preoperatively by the combined use of transrectal ultrasound and systematic sextant needle biopsies.

Prospective evaluation of systematic sextant transition zone biopsies in large prostates for cancer detection.

OBJECTIVES: A prospective evaluation was performed to define the role of systematic transition zone (TZ) biopsies in prostates larger than 50 cc. METHODS: From August 1994 to July 1997, 213 consecutive patients referred because of an abnormal digital rectal examination or prostate-specific antigen greater than 4.0 ng/mL had a calculated prostate size greater than 50 cc by transrectal ultrasound (TRUS) measurement. These patients underwent TRUS-guided sextant biopsies of the peripheral zone (PZ) and TZ. RESULTS: The median calculated prostate size was 70 cc with a TZ size of 39 cc. Fifty-five cases of carcinoma of the prostate were found, giving a 26% detection rate. The TZ biopsies detected cancer in 30 of the 55 patients (55% sensitivity) compared with the 47 patients detected by the PZ biopsies (85% sensitivity). Seven cancers (13%) were detected only by the additional TZ biopsies. TZ biopsies revealed bilateral tumors when the PZ biopsies had shown unilateral disease in 2 cases. In 6 cases the TZ biopsies showed higher Gleason grade tumors than was found in the PZ. In the 30 cases with positive TZ biopsy, concordance between the PZ and TZ biopsies occurred in 74% (133 of 180) of the sectors. The PZ biopsy detected cancer in 43 of 66 corresponding sectors that had positive TZ biopsies, giving a sensitivity of 65% and a negative predictive value of 80%. CONCLUSIONS: Routine PZ biopsies missed detecting 13% of the cancers found with the addition of sextant TZ biopsies in patients with large prostates (greater than 50 cc). In addition, 14% of the patients with cancer had upgrading or detection of bilateral tumor with the added biopsies. Routine systematic sextant TZ biopsies should be considered in patients with prostates greater than 50 cc in size.

The role of transrectal ultrasound-guided biopsy-based staging, preoperative serum prostate-specific antigen, and biopsy Gleason score in prediction of final pathologic diagnosis in prostate cancer.

OBJECTIVES: To evaluate the role of ultra sound-guided systematic and lesion-directed biopsies, biopsy gleason score, preoperative serum prostate-specific antigen (PSA) as three objective and reproducible variables to provide a reliable combination in preoperative identification of risk of extraprostatic extension in patients with clinically localized prostate cancer. METHODS: The case records of 813 patients who underwent radical prostatectomy for clinically localized prostate cancer were analyzed. All had multiple systematic biopsies, two to three from each lobe, in addition to lesion-directed biopsies. Additionally, biopsies were done on seminal vesicles (SVs), if abnormal. Based on biopsy results, patients were classified as having stage B1 (T2a-T2b) or B2 (T2c) disease, depending on whether biopsies from one or both lobes were positive and stage C (T3) if there was evidence of SV involvement by biopsy of biopsies from areas of extracapsular extension as seen on transrectal ultrasound (TRUS) were positive. Logistic regression analyses with log likelihood chi-square test was used to define the correlation between individual as well as combination of preoperative variables and pathologic stage. RESULTS: On final pathologic examination, 473 (58%) patients had organ-confined disease, 188 (23%) had extracapsular extension (ECE), with or without positive surgical margins, and 72 (9%) had SV involvement. Eighty (10%) patients had pelvic lymph node metastases. Biopsy-based staging was superior to clinical staging in predicting final pathologic diagnosis. Logistic regression analyses revealed that the combination of biopsy-based stage, preoperative serum PSA, and biopsy Gleason score provided the best prediction of final pathologic stage. Probability plots constructed with these data can provide significant information on risk of extraprostatic extension in individual patients. CONCLUSIONS: This study demonstrates that TRUS-guided systematic biopsy in combination with preoperative serum PSA and biopsy Gleason score may provide a cost-effective approach for management decisions and prognostication in patients with prostate cancer.

Prediction of focal extracapsular extension at radical prostatectomy: Relative merit of transrectal ultrasound, endorectal magnetic resonance imaging, prostate specific antigen, prostate specific antigen density, and systematic biopsy.

We conducted a study to compare the relative merits of prostate specific antigen (PSA), PSA density (PSAD), transrectal ultrasound (TRUS), endorectal magnetic resonance imaging (MRI), and systematic biopsy in the prediction of focal extracapsular extension (ECE) at radical prostatectomy. A retrospective review of patients who underwent TRUS, endorectal MRI, and radical prostatectomy at our institution was performed. Patients with a diagnosis of prostate cancer who were thought to be surgical candidates by digital rectal examination and TRUS underwent endorectal MRI prior to radical prostatectomy. Imaging, PSA, PSAD, and systematic biopsy results (tumor grade and fraction of positive systematic biopsies) were correlated with step-sectioned, radical prostatectomy pathologic data. Data was analyzed for the entire prostate and on each individual side. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and likelihood ratios were calculated for each modality, and receiver operating characteristic (ROC) curves were generated. Stepwise logistic regression analysis was used to weigh the relative contributions of preoperative parameters in predicting ECE. Data was collected from 54 patients who had sextant systematic biopsy, imaging, and radical prostatectomy. A total of 24 sides demonstrated ECE (19 patients, 5 with bilateral ECE). When assessed for the dominant prostate side and on a side-for-side basis, MRI had the highest sensitivity and NPV for detecting focal ECE. MRI also had the highest PPV, and TRUS had the highest specificity for side-for-side analysis. For the dominant prostate side, PSA had the highest specificity and PPV for detecting focal ECE. Of note, significant overlap was demonstrated in the 95% confidence intervals of all modalities with each other for all analyses. ROC analyses found MRI and Gleason sum to be superior for the dominant prostate side assessment and MRI and the fraction of positive systematic biopsies to be superior for a side-for-side analysis. Optimal likelihood ratios for positive test results were seen for PSA (dominant prostate side) and MRI (side-for-side), and for negative test results for MRI. Logistic regression demonstrated MRI and Gleason sum to be powerful predictors of ECE. Thus, we would conclude that endorectal MRI and tumor grade provide unique information in the prediction of focal ECE in select patients.

Comparison of systematic sextant and lesion directed biopsies in prostate cancer detection.

This study was designed to determine the value of performing separate lesion directed biopsies in addition to systematic random sextant biopsies for the detection, grading, and assessment of bilaterality of prostate cancer. A prospective study of 82 consecutive patients who had peripheral zone hypoechoic regions visualized on transrectal ultrasound was performed. All patients had either an abnormal prostate-specific antigen or an abnormal digital rectal examination and underwent random systematic and lesion directed biopsies. Cancer detection, laterality, and histologic grade of lesion directed biopsies were compared with those from systematic random biopsies. Prostate cancer was detected in 35 (40%) of 82 patients who had a hypoechoic lesion visualized. Three (9%) cancers would have been missed if only systematic biopsies had been performed, while nine (26%) cancers would have been missed if only lesion directed biopsies had been performed. In all but one patient, the Gleason score of the lesion directed biopsy was equal to or within one grade of the highest Gleason score determined from systematic biopsy. Systematic random biopsies detected cancer on the opposite side of a positive lesion directed biopsy in 48% of patients. In no case did a lesion directed biopsy add to the detection of bilateral disease. In conclusion, lesion directed biopsies increase the detection of prostate cancer when performed in addition to systematic random sextant biopsies. However, lesion directed biopsies alone would result in a substantial miss rate of prostate cancer. They do not add to the determination of bilateral disease, nor do they add to the pathologic grading of the detected cancer.

Imaging and management of atypical testicular masses.

Most testicular masses are germ cell malignancies and require radical orchiectomy. There are other causes of testicular masses, however, some of which have characteristic imaging and clinical features. A presumptive diagnosis may be possible for some of these atypical testicular masses. This may result in testis-preserving surgery or nonoperative management.

Fertility and testis cancer.

Patients with testicular cancer may demonstrate impaired spermatogenesis because of the disease process or as a direct consequence of treatment. For some patients, impaired spermatogenesis may resolve spontaneously, while in others, treatable etiologies may be identified and corrected.