Anil A. Thomas

Response of the primary tumor to neoadjuvant sunitinib in patients with advanced renal cell carcinoma.

PURPOSE We assessed the activity of neoadjuvant sunitinib on primary renal tumors in patients with advanced renal cell carcinoma as well as the feasibility and safety of subsequent surgical resection. METHODS A total of 19 patients with advanced renal cell carcinoma deemed unsuitable for initial nephrectomy due to locally advanced disease or extensive metastatic burden were treated with 50 mg sunitinib daily for 4 weeks on followed by 2 weeks off. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors every 2 cycles and the rate of conversion to resectable status was estimated. RESULTS Median patient age was 64 years and initial median radiographic renal tumor size was 10.5 cm. Clinical stage was N+ (10) and M+ (15). No patients experienced a complete response. Partial responses of the primary tumor were noted in 3 patients (16%), 7 (37%) had stable disease and 9 (47%) had disease progression in the primary tumor. Overall tumor response included 2 patients (11%) with partial response, 7 (37%) with stable disease and 10 (53%) with disease progression. At a median followup of 6 months (range 1 to 15) 4 patients (21%) had undergone nephrectomy and 5 died of disease progression. No unexpected surgical morbidity was encountered. Viable tumor was present in all 4 specimens. Sunitinib was associated with grade 3-4 toxicity in 7 patients (37%) and treatment was discontinued in 1 due to toxicity. CONCLUSIONS Administration of sunitinib in patients with advanced renal cell carcinoma with the primary tumor in place is feasible and can lead to a reduction in tumor burden that can facilitate subsequent surgical resection.

Emphysematous cystitis: a review of 135 cases

To review recently published data on emphysematous cystitis (EC), a potentially life‐threatening condition characterized by air within the bladder wall, and that most typically affects middle‐aged diabetic women.

Inadequacy of Biopsy for Diagnosis of Upper Tract Urothelial Carcinoma: Implications for Conservative Management

OBJECTIVE To report changes in grade and stage between initial diagnostic and repeat biopsies or resection for urothelial carcinoma (UTUC) and investigate the consequences for endoscopic management. Ureteroscopic management of upper tract UTUC is an alternative to nephroureterectomy, which is less invasive and preserves renal function. However, concerns about potential understaging, inaccurate grading, incomplete resection, lack of effective tertiary chemoprevention, and need for ureteroscopic surveillance limits it appeal. METHODS Clinicopathological records of patients with UTUC treated at our institution were reviewed. Fifty-six patients with a histologic diagnosis of UTUC and 2 or more consecutive biopsies or biopsy followed by surgical resection were included, resulting in 65 biopsy specimens. RESULTS The median interval between diagnostic biopsy and subsequent biopsy or resection was 6 weeks (range, 1 week to 60 months). Change in grade from the diagnostic biopsy occurred in 24 of 65 biopsies (37%), including 9 in which diagnosis changed from low to high grade. Change in the stage from the diagnostic biopsy occurred in 25 of 65 biopsies (38%). Overall, 24 (43%) patients were reclassified from low-grade, noninvasive disease to high-grade and/or invasive disease. CONCLUSION A change in grade and/or stage from the diagnostic biopsy occurred in more than one third of patients with UTUC managed conservatively. Because of the short median time interval between biopsies, this finding likely represents variability in tumor sampling on biopsy. Because of the concerns of undergrading and understaging, appropriate patient selection and vigilant endoscopic surveillance are mandatory for UTUC managed endoscopically.

Surgical Resection of Renal Cell Carcinoma After Targeted Therapy

PURPOSE The development of targeted agents for renal cell carcinoma has renewed interest in consolidative surgery due to the robust clinical responses seen with these agents. The integration of targeted therapy and surgery requires careful consideration due to the potential for increased perioperative morbidity. MATERIALS AND METHODS We retrospectively identified patients with renal cell carcinoma treated with sunitinib, sorafenib or bevacizumab plus interleukin-2 before tumor resection. RESULTS Between June 2005 and August 2008, 19 patients were treated with targeted therapy and subsequently underwent resection. Surgical extirpation involved an open and a laparoscopic approach in 18 and 3 cases, respectively, for locally advanced (8), locally recurrent (6) and metastatic disease (3). Two patients with extensive bilateral renal cell carcinoma were also treated to downsize the tumors to enable partial nephrectomy. Perioperative complications were noted in 16% of patients. One patient had a significant intraoperative hemorrhage and disseminated intravascular coagulopathy from a concomitant liver resection. An anastomotic bowel leak and abscess were noted postoperatively in another patient who underwent en bloc resection of a retroperitoneal recurrence and adjacent colon. Two patients (11%) had minor wound complications, including a wound seroma and a ventral hernia. Pathological analysis of 20 specimens revealed clear cell, chromophobe and unclassified renal cell carcinoma in 80%, 5% and 10% of cases, respectively. One patient (5%) had a pathological complete response. CONCLUSIONS Surgical resection of renal cell carcinoma after targeted therapy is feasible with low morbidity in most patients. However, significant complications can occur, raising concern for possible compromise of tissue and/or vascular integrity associated with surgery in this setting.

Squamous Cell Carcinoma of the Bladder : A Clinicopathologic Analysis of 45 Cases

Squamous cell carcinoma of the bladder comprises less than 5% of all bladder cancers in the United States and its long-term prognosis has remained controversial. We examined a large series of patients who underwent radical and partial cystectomies for squamous cell carcinoma to identify associated histopathologic findings and clinical outcomes associated with these tumors. Patient age ranged from 46 to 83 years (average 68.5 y) with a male:female ratio of 3:2. Forty-three patients were white and 2 patients were African-American. No patient had a history of schistosomal infection and only 1 patient had a history of condyloma acuminatum. The majority of patients with reported signs and symptoms presented with hematuria (n=29/34), with the remainder presenting with lower urinary tract symptoms. Tumor size ranged from 0.8 to 6.4 cm (average 3.8 cm). Invasion was identified into the lamina propria (pT1, n=1/45), muscularis propria (pT2, n=14/45), perivesical fat (pT3, n=27/45), and adjacent structures (pT4, n=3/45). Concurrent metastases were identified in 11 of 45 patients (24%) to pelvic lymph nodes (n=9), perivesical lymph nodes (n=3), obturator lymph nodes (n=1), and bowel wall (n=1). Most tumors were moderately (n=29/45) or poorly (n=13/45) differentiated, whereas only 3 tumors were well differentiated (n=3/45). Keratinization was present in all cases within the invasive component and ranged from 5% to 95% of tumor bulk. Necrosis ranged from 0% to 60% and inversely correlated with tumor differentiation. Eighteen cases demonstrated a prominent giant cell reaction to keratin, and 30 tumors were associated with a desmoplastic reaction. Extensive perineural (n=11/45) and angiolymphatic invasion (n=7/45) were identified in a subset of tumors. The majority of cases demonstrated associated superficial lesions including keratinizing squamous metaplasia (n=28/45), nonkeratinizing squamous metaplasia (n=20/45), squamous cell carcinoma in situ (n=16/45), squamous metaplasia with dysplasia (n=4/45), verrucous squamous hyperplasia (n=3/45), and extensive condyloma acuminatum (n=1/45). Seven cases additionally demonstrated separate small foci of focal flat urothelial carcinoma in situ. Three cases demonstrated a markedly atypical squamous lining of the prostatic ducts at the prostatic urethra. Clinical follow-up was available on 35 patients (78%) and ranged from 1 to 175 months (average 33 mo, median 15 mo). Two patients developed recurrent local disease (n=2/35, 6%) and 13 patients developed subsequent metastatic disease (n=13/35, 37%). Ten patients were dead of disease (29%), with a time to death for most patients of less than 2 years (range 2 to 21 mo, average 10.5 mo). Thirty-seven percent of patients (n=13/35) were alive without disease. In conclusion, squamous cell carcinoma often presents at an advanced stage; however, radical cystectomy with lymph node dissection appears to offer a significant benefit in survival in a subset of patients.

Urethral Diverticula in 90 Female Patients: A Study With Emphasis on Neoplastic Alterations

PURPOSE Urethral diverticula are uncommon and occur predominantly in women. We examined a large series of female urethral diverticula to determine associated neoplastic alterations and subsequent clinical outcomes. MATERIALS AND METHODS All pathological evaluations of female urethral diverticulectomies performed at our institution between 1981 and 2007 were retrospectively reviewed and the clinicopathological features were correlated. RESULTS During this period 90 women underwent urethral diverticulectomy at our institution. Patient age was 24 to 78 years (mean 45). The most common clinical finding was urinary incontinence (29 of 78 women or 37%). Diverticular size was 0.3 to 5.0 cm (mean 1.7). Neoplastic alterations identified in 5 patients (6%) were glandular in nature, including 1 clear cell and 4 invasive adenocarcinomas. Superficial changes associated with invasive carcinoma included villous adenoma in 1 case, intestinal metaplasia in 2 and high grade dysplasia in 3. An additional 3 patients had extensive intestinal metaplasia. Of the 90 patients the remaining 82 demonstrated benign findings, including nephrogenic adenoma in 10 (11%). All 5 patients with invasive carcinoma underwent anterior pelvic exenteration with urinary diversion. In 2 patients with invasive adenocarcinoma metastatic disease subsequently developed, of which they died. CONCLUSIONS Although most cases of surgically resected diverticula demonstrate benign features, approximately 10% show atypical glandular findings, including invasive adenocarcinoma. Due to the risk of malignancy in a subset of patients careful clinical examination and followup are warranted in all patients to exclude neoplastic disease.

Clinicopathologic features and utility of immunohistochemical markers in signet-ring cell adenocarcinoma of the bladder

Signet-ring adenocarcinoma is an aggressive form of primary bladder adenocarcinoma that has been associated with poor outcomes. The utility of immunohistochemical markers in tumors with signet-ring morphology may vary from more typical adenocarcinomas arising at the same location, although this has not been examined in bladder adenocarcinoma. We examined a series of bladder adenocarcinomas to determine the impact of signet-ring cell features on clinical outcomes and immunohistochemical findings. We identified 25 patients with bladder adenocarcinoma, ranging in age from 28 to 78 years (mean, 57 years) and with a male-female ratio of 18:7. Six cases were urachal in origin. Signet-ring cells occurred in 19 of 25 bladder adenocarcinomas (76%) and ranged from 5% to 100% of tumor volume, with most tumors demonstrating more than 60% signet-ring cell differentiation (15/19), when present. Regional lymph node metastases were present in 8 of 19 patients (42%) who underwent cystectomy. The percentage of tumor containing signet-ring cells was significantly associated with the presence of adverse pathologic features (defined as unresectable primary tumor or regional lymph node metastasis, P = .013) and decreased overall survival (P = .034), and the latter remained significant in multivariable analysis after adjusting for positive soft tissue margins (P = .026). A comparison between immunohistochemical markers frequently used to analyze bladder adenocarcinoma demonstrated decreased expression of several markers in signet-ring (n = 9) versus colonic-type (n = 8) morphology, including CDX-2, beta-catenin, and E-cadherin, although these results did not reach statistical significance. In summary, the extent of signet-ring differentiation in bladder adenocarcinoma is associated with worsened survival and higher stage disease; the utility of immunohistochemical analysis in foci consisting of predominant signet-ring cells may be limited, although further studies that address this finding are needed.

Laparoscopic Transperitoneal Radical Prostatectomy in Renal Transplant Recipients: A Review of Three Cases

OBJECTIVES To report our experience with laparoscopic radical prostatectomy for the treatment of localized prostate carcinoma in 3 renal transplant recipients. METHODS We retrospectively identified all patients who had undergone laparoscopic prostatectomy for clinically localized prostate cancer between 1999 and 2006 at our institution (n = 1067). Of these patients, 3 were renal transplant recipients (dual cadaveric renal transplant, simultaneous pancreas kidney transplant, and a cadaveric renal transplant that had failed owing to chronic rejection by the time of surgery). We reviewed all available clinicopathological data. RESULTS All three patients underwent successful laparoscopic radical prostatectomy without major complications. The average operative time was 237 minutes (range, 180 to 290 minutes) with a mean estimated blood loss of 425 mL (range, 75 to 1000 mL). No changes in renal graft function, measured by serum creatinine, were noted. Pathological outcomes revealed negative surgical margins with organ-confined disease in each case. All three patients tolerated the procedure well and had an average hospital stay of 3.3 days (range, 2 to 5 days). CONCLUSIONS The data from our 3 patients suggest that laparoscopic radical prostatectomy is a technically feasible and safe treatment of localized prostate cancer in renal transplant recipients.

Optimizing Orthotopic Bladder Tumor Implantation in a Syngeneic Mouse Model

PURPOSE We established a reliable technique for orthotopically implanting bladder tumor cells in a syngeneic mouse model. MATERIALS AND METHODS MBT-2 murine bladder cancer cells were transurethrally implanted in the bladder of syngeneic C3H/He mice (Jackson Laboratory, Bar Harbor, Maine). Different chemical pretreatments were used before tumor implantation, including phosphate buffered saline (control), HCl, trypsin and poly-L-lysine. MBT-2 cells (1 x 10(6) or 2 x 10(6)) were instilled into the intravesical space after chemical pretreatment. Tumor take and bladder tumor volume were determined by micro ultrasound. Bladders were harvested at the end of the study to measure bladder weight and for histopathological examination. RESULTS Bladder pretreatment with HCl in 5 preparations was discontinued due to significant adverse reactions, resulting in death in 1 mouse, and severe bladder inflammation and hematuria 3 days after pretreatment in 2. Pretreatment with phosphate buffered saline, trypsin and poly-L-lysine in 6 animals each was tolerated well without significant adverse reactions or mortality. The tumor take rate in the control, trypsin and poly-L-lysine pretreatment groups was 33%, 83% and 83%, respectively. The take rate was higher in mice instilled with 2 x 10(6) cells than in those with 1 x 10(6) cells (93% vs 73%, p <0.05). CONCLUSIONS We report a reliable, feasible method of orthotopically implanting bladder tumor cells into a syngeneic mouse model. Poly-L-lysine and trypsin are useful adjunctive pretreatment agents to improve bladder tumor uptake. This model may be suitable to evaluate treatment paradigms for bladder cancer.

Acute kidney injury: novel biomarkers and potential utility for patient care in urology.

Urologists are integrally involved in the management of acute kidney injury (AKI), which is common after renal surgery or secondary to postrenal (obstructive) etiologies. The measurement of serum creatinine is a suboptimal indicator of AKI because it lags behind acute changes in renal function. Recent advances indicate that serum/urine biomarkers will prove useful for early detection of AKI, analogous to the use of cardiac enzymes for acute myocardial infarction. These serum/urine markers may guide future therapy, facilitate research efforts to reduce the severity of AKI, such as after partial nephrectomy, and allow for more accurate prognostication for patients with AKI.