Noninvasive Papillary Urothelial Carcinoma of the Bladder: An Institutional Experience Focusing on Tumors With Borderline Features.

CONTEXT.­: Noninvasive papillary urothelial carcinomas (PUCs) comprise most urinary bladder tumors. Distinction between low-grade (LG-PUC) and high-grade (HG-PUC) PUCs is pivotal for determining prognosis and subsequent treatment. OBJECTIVE.­: To investigate the histologic characteristics of tumors with borderline features between LG-PUC and HG-PUC, focusing on the risk of recurrence and progression. DESIGN.­: We reviewed the clinicopathologic parameters of noninvasive PUC. Tumors with borderline features were subcategorized as follows: tumors that look like LG-PUC but have occasional pleomorphic nuclei (1-BORD-NUP) or elevated mitotic count (2-BORD-MIT), and tumors with side-by-side distinct LG-PUC and less than 50% HG-PUC (3-BORD-MIXED). Recurrence-free, total progression-free, and specific invasion-free survival curves were derived from the Kaplan-Meier method, and Cox regression analysis was performed. RESULTS.­: A total of 138 patients with noninvasive PUC were included, with the following distribution: LG-PUC (n = 52; 38%), HG-PUC (n = 34; 25%), BORD-NUP (n = 21; 15%), BORD-MIT (n = 14; 10%), and BORD-MIXED (n = 17; 12%). Median (interquartile range) follow-up was 44.2 months (29.9-73.1 months). Invasion-free survival was different between the 5 groups (P = .004), and pairwise comparison showed that HG-PUC had a worse prognosis compared with LG-PUC (P ≤ .001). On univariate Cox analysis, HG-PUC and BORD-NUP were 10.5 times (95% CI, 2.3-48.3; P = .003) and 5.9 times (95% CI, 1.1-31.9; P = .04) more likely to invade, respectively, when compared to LG-PUC. CONCLUSIONS.­: Our findings confirm a continuous spectrum of histologic changes in PUC. Approximately a third of noninvasive PUCs show borderline features between LG-PUC and HG-PUC. Compared with LG-PUC, BORD-NUP and HG-PUC were more likely to invade on follow-up. BORD-MIXED tumors did not statistically behave differently from LG-PUC.

Comparison of two core biopsy techniques before and after laparoscopic cryoablation of small renal cortical neoplasms.

INTRODUCTION: Cryoablation is an acceptable treatment option for small renal cortical neoplasms (RCN). Unlike extirpative interventions, intraoperative needle biopsy is the only pathologic data for ablated tumors. It is imperative that sampled tissue accurately captures pathology. We studied the optimal intraoperative needle core biopsy protocol for small RCN during laparoscopic renal cryoablation (LCA). METHODS: Patients with RCN<4cm underwent intraoperative biopsy during LCA. Four biopsy cores were taken per tumor, 2 before and 2 after LCA by using both a standard and modified technique. Standard technique: needle biopsy device was deployed after insertion into the renal tissue at a depth of 5mm. Modified technique: needle biopsy device was deployed 1mm outside of the renal tissue. Biopsies were examined and compared with reference standard pathology. Percentage agreement was calculated across biopsy types (standard vs. modified) and time points (pre- vs. postcryoablation). Logistic regression was used to identify factors impacting biopsy accuracy. RESULTS: Thirty patients with 33 RCNs underwent LCA. The mean patient age was 69.1±8.0yrs, and mean tumor size was 2.3±0.7cm. No significant bleeding resulted from biopsies. A definitive diagnosis was made in 31/33 RCNs (94.0%). Ten tumors (30.3%) were benign, 21 (63.7%) were malignant, and 2 (6.0%) were nondiagnostic. Biopsy length was significantly longer using the standard vs. modified technique with mean lengths of 9.3mm vs. 7.0mm, respectively (P=.02). Highest agreement was seen in preablation biopsies (90.3%). A significant association with agreement was seen for younger age (P=.05) and larger tumor size (P=.02). CONCLUSIONS: Younger age and larger tumor size were associated with improved accuracy. Preoperative sampling resulted in superior accuracy and the standard technique resulted in significantly longer cores. Use of preablation standard biopsy technique may result in the most accurate pathologic diagnosis for patients undergoing cryoablation for small RCNs.

Expression of PAX8 in normal and neoplastic renal tissues: an immunohistochemical study.

Cell-lineage-specific transcription factors are a group of regulatory proteins expressed in embryonic, differentiated, or neoplastic cells of the same lineage and represent a valuable repertoire of tissue-specific markers for the diagnosis of human tumors. Together with PAX2, PAX8 is a nephric-lineage transcription factor and is required for the establishment of renal-lineage cells and the formation of the kidney. In contrast to PAX2, little is known about the expression of PAX8 in adult kidney and renal tumors. In this study, we used immunohistochemistry to investigate the expression of PAX8 in adult human kidney and renal epithelial tumors. We report here that PAX8 was detected in renal epithelial cells in all segments of renal tubules from the proximal tubules to the renal papillae and in the parietal cells of Bowman's capsule in the adult kidney. PAX8 was also present in 98% of clear cell renal cell carcinomas (RCCs), 90% of papillary RCCs, and 95% of oncocytomas, similar to PAX2. In addition, PAX8 was found in 82% of chromophobe RCCs, 71% of sarcomatoid components of RCCs, and 100% (2/2) of renal medullary carcinomas. Overall, PAX8 was detected in 85% of metastatic renal tumors. Interestingly, expression of PAX8 was noted in some urothelial cells in the renal pelvis and ureters and approximately 23% of urothelial carcinomas of the renal pelvis, but not in the urothelium or urothelial carcinomas of the urinary bladder; this probably underlines the different embryonic origins of urothelial cells in the upper and lower urinary tracts. As shown in this study, PAX8 is widely expressed in normal and neoplastic renal tissues. PAX8 may be a useful additional marker for renal epithelial tumors; however, its specificity and sensitivity await further investigation.

A two-stage, p16(INK4A)- and p53-dependent keratinocyte senescence mechanism that limits replicative potential independent of telomere status.

With increasing frequency during serial passage in culture, primary human keratinocytes express p16(INK4A) (p16) and undergo senescence arrest. Keratinocytes engineered to express hTERT maintain long telomeres but typically are not immortalized unless, by mutation or other heritable event, they avoid or greatly reduce p16 expression. We have confirmed that keratinocytes undergo p16-related senescence during growth in culture, whether in the fibroblast feeder cell system or in the specialized K-sfm medium formulation, and that this mechanism can act as a barrier to immortalization following hTERT expression. We have characterized the p16-related arrest mechanism more precisely by interfering specifically with several regulators of cell cycle control. Epidermal, oral mucosal, corneal limbal, and conjunctival keratinocytes were transduced to express a p16-insensitive mutant cdk4 (cdk4(R24C)), to abolish p16 control, and/or a dominant negative mutant p53 (p53DD), to abolish p53 function. Expression of either cdk4(R24C) or p53DD alone had little effect on life span, but expression of both permitted cells to divide 25 to 43 population doublings (PD) beyond their normal limit. Keratinocytes from a p16(+/-) individual transduced to express p53DD alone displayed a 31-PD life span extension associated with selective growth of variants that had lost the wild-type p16 allele. Cells in which both p53 and p16 were nonfunctional divided rapidly during their extended life span but experienced telomere erosion and ultimately ceased growth with very short telomeres. Expression of hTERT in these cells immortalized them. Keratinocytes engineered to express cdk4(R24C) and hTERT but not p53DD did not exhibit an extended life span. Rare immortal variants exhibiting p53 pathway defects arose from them, however, indicating that the p53-dependent component of keratinocyte senescence is telomere independent. Mutational loss of p16 and p53 has been found to be a frequent early event in the development of squamous cell carcinoma. Our results suggest that such mutations endow keratinocytes with extended replicative potential which may serve to increase the probability of neoplastic progression.

Management of benign middle ear tumors: A series of 7 cases.

Benign middle ear tumors represent a rare group of neoplasms that vary widely in their pathology, anatomy, and clinical findings. These factors have made it difficult to establish guidelines for the resection of such tumors. Here we present 7 unique cases of these rare and diverse tumors and draw from our experience to recommend optimal surgical management. Based on our experience, a postauricular incision is necessary in nearly all cases. Mastoidectomy is required for tumors that extend into the mastoid cavity. Whenever exposure or hemostasis is believed to be inadequate with simple mastoidectomy, canal-wall-down mastoidectomy should be performed. Finally, disarticulation of the ossicular chain greatly facilitates tumor excision and should be performed early in the procedure.

Nonischemic laparoscopic partial nephrectomy using a novel wet monopolar device in a porcine model.

BACKGROUND AND PURPOSE: Laparoscopic partial nephrectomy (LPN) is the minimally invasive standard of care for the management of a cT(1a) renal mass. We evaluated a novel saline enhanced electrosurgical resection (SEER) device for performance of a nonischemic LPN. MATERIALS AND METHODS: Six pigs were used in a nonsurvival pilot study. Energy penetration was characterized by applying the SEER to the lower pole of each kidney for 30 seconds, 1 minute, and 3 minutes using pure cutting energy at 100W and a drip rate of 1 drip per second. Energy testing was performed with the hilum clamped in six kidneys and without clamping in six kidneys. Subsequently, a nonischemic upper pole LPN was performed with the SEER device, and the kidneys were harvested. The areas of necrosis were sectioned and stained with hematoxylin and eosin. Depth of necrosis was visualized grossly and microscopically for each time point. We also recorded time to perform LPN, estimated blood loss (EBL), and subjective severity of bleeding. RESULTS: The average operative time was 15.4 minutes. The mean EBL was 44.2 mL with nine (75%) cases classified as minimal, 2 (17%) moderate, and 1 (8%) severe bleeding. The mean depth of necrosis on the kidney remnants was 2.97 mm. The mean depth of necrosis for unclamped kidneys at 30 seconds, 1 minute, and 3 minutes was 0.38 mm, 0.88 mm, and 1.27 mm, respectively. The mean depths for the clamped kidneys were 2.73 mm, 3.23 mm, and 8.68 mm respectively. Depth of necrosis was significantly higher in the clamped kidneys at 3 minutes (P=0.0035). CONCLUSIONS: In the porcine model, the SEER transected parenchyma and collecting system with low resection times and minimal blood loss. Use of coagulation during resection is the main advantage of a monopolar resection compared with cold scissors. Testing performed for 3 minutes during hilar clamping demonstrated a significantly deeper level of necrosis.

Phase II study of neoadjuvant androgen deprivation followed by external-beam radiotherapy with 9 months of androgen deprivation for intermediate- to high-risk localized prostate cancer.

PURPOSE: To evaluate the toxicity and efficacy of individualized neoadjuvant androgen deprivation (AD) to maximal response followed by external beam radiotherapy (RT) with continued AD for a total of 9 months in a prospective phase II trial. PATIENTS AND METHODS: One hundred twenty-three patients received a total of 9 months of flutamide and luprolide combined with RT. RT initiation was individualized to begin after maximum response to AD as assessed by monthly digital rectal examination and prostate-specific antigen (PSA). The neoadjuvant phase was restricted to no more than 6 months. RESULTS: Median time to initiation of RT was 4.7 months. Indications to begin RT (and their rates) were undetectable PSA (28%), PSA unchanged from one month to the next (46%), PSA rising from one month to the next (10%), 6 months of AD (14%), and other (2%). Five-year outcomes were biochemical disease-free survival, (DFS) 63% +/- 7%; clinical DFS, 75% +/- 5%; cancer-specific survival, 99% +/- 1%; and overall survival, 89% +/- 3%. Patients initiating RT after 6 months of AD had significantly lower biochemical and clinical DFS. Those patients whose testosterone recovered to normal after completion of AD had a significantly superior survival rate. Of those patients potent before treatment, 65% remained so at last follow-up. CONCLUSION: The combination of 9 months of AD and RT, with initiation of RT individualized on the basis of maximum response to AD, achieves disease control rates comparable with past studies, while preserving potency in many patients. Further studies are warranted to determine the optimal combination of AD and RT in this patient population.

Intermediate-risk localized prostate cancer in the PSA era: radiotherapeutic alternatives.

OBJECTIVES: To retrospectively compare the biochemical disease-free survival (BDFS) of patients treated with standard dose external beam radiotherapy (SD-EBRT), SD-EBRT plus androgen deprivation (AD), and brachytherapy-based treatment (brachytherapy with or without EBRT with or without AD). METHODS: All 297 patients with intermediate-risk prostate cancer treated with these radiation-based treatments at our institution from August 1989 to June 2001 were included. Biochemical relapse was defined according to the American Society for Therapeutic Radiology and Oncology (ASTRO) definition, a prostate-specific antigen level of 1.5 ng/mL or greater and rising on two consecutive occasions (the "Bolla" definition), and the current prostate-specific antigen nadir plus 2 ng/mL with failure dated "at call" (the "Houston/Phoenix" definition). The number of patients treated with SD-EBRT, SD-EBRT plus AD, and brachytherapy-based treatment was 141, 84, and 72, respectively. The year of treatment was analyzed as a prognostic factor. The median follow-up was 32.3, 34.7, and 41.5 months for the ASTRO, Bolla, and Houston/Phoenix definitions, respectively. RESULTS: The brachytherapy-based treatment resulted in improved BDFS compared with SD-EBRT (ASTRO definition, 5-year BDFS rate 88% +/- 5% versus 49% +/- 5%, P <0.01; Bolla definition, 88% +/- 8% versus 49% +/- 5%, P <0.01; Houston/Phoenix definition, 81% +/- 10% versus 64% +/- 5%, P = 0.01). SD-EBRT plus AD was superior to SD-EBRT alone using the Bolla definition (5-year BDFS 76% +/- 7% versus 49% +/- 5%, P <0.01) and the Houston/Phoenix definition (85% +/- 6% versus 64% +/- 5%, P = 0.01), but not using the ASTRO definition (P = 0.17). Multivariate analysis, including prostate-specific antigen, clinical stage, Gleason score, and year of treatment, demonstrated improved biochemical outcomes for brachytherapy-based treatment versus SD-EBRT (ASTRO, P <0.01; Bolla, P <0.01; and a trend toward significance with Houston/Phoenix, P = 0.07) and for the addition of AD to SD-EBRT (Bolla, P <0.01 and Houston/Phoenix, P = 0.03). The year of treatment trended toward significance (P = 0.077) on multivariate analysis using the ASTRO definition. CONCLUSIONS: For patients with intermediate-risk prostate cancer, brachytherapy-based treatment and the addition of AD to SD-EBRT resulted in improved biochemical outcomes compared with the outcomes with SD-EBRT alone; however, these findings were dependent on the definition of biochemical failure used. The year of treatment may be an important prognostic factor in intermediate-risk prostate cancer.