Chapter 090. Bladder and Renal Cell Carcinomas (Part 2)

PathogenesisThe multicentric nature of the disease and high rate of recurrence has led to the hypothesis of a field defect in the urothelium that results in a predisposition to cancer. Molecular genetic analyses suggest that the superficial and invasive lesions develop along distinct molecular pathways in which primary tumorigenic aberrations precede secondary changes associated with progression to a more advanced stage. Low-grade papillary tumors that do not tend to invade or metastasize harbor constitutive activation of the receptor-tyrosine kinase-Ras signal transduction pathway and a high frequency of fibroblast growth factor receptor 3 (FGFR3) mutations. In contrast, CIS and invasive...
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Chapter 090. Bladder and Renal Cell Carcinomas (Part 2) Chapter 090. Bladder and Renal Cell Carcinomas (Part 2) Pathogenesis The multicentric nature of the disease and high rate of recurrence has led tothe hypothesis of a field defect in the urothelium that results in a predisposition tocancer. Molecular genetic analyses suggest that the superficial and invasivelesions develop along distinct molecular pathways in which primary tumorigenicaberrations precede secondary changes associated with progression to a moreadvanced stage. Low-grade papillary tumors that do not tend to invade ormetastasize harbor constitutive activation of the receptor-tyrosine kinase-Rassignal transduction pathway and a high frequency of fibroblast growth factorreceptor 3 (FGFR3) mutations. In contrast, CIS and invasive tumors have a higherfrequency of TP53 and RB gene alternations. Within all clinical stages, includingTis, T1, and T2 or greater lesions, tumors with alterations in p53, p21, and/or RBhave a higher probability of recurrence, metastasis, and death from disease. Clinical Presentation, Diagnosis, and Staging Hematuria occurs in 80–90% of patients and often reflects exophytictumors. The bladder is the most common source of gross hematuria (40%), butbenign cystitis (22%) is a more common cause than bladder cancer (15%) (Chap.45). Microscopic hematuria is more commonly of prostate origin (25%); only 2%of bladder cancers produce microscopic hematuria. Once hematuria isdocumented, a urinary cytology, visualization of the urothelial tract by CT orintravenous pyelogram, and cystoscopy are recommended if no other etiology isfound. Screening asymptomatic individuals for hematuria increases the diagnosisof tumors at an early stage but has not been shown to prolong life. Afterhematuria, irritative symptoms are the next most common presentation, which mayreflect in situ disease. Obstruction of the ureters may cause flank pain. Symptomsof metastatic disease are rarely the first presenting sign. The endoscopic evaluation includes an examination under anesthesia todetermine whether a palpable mass is present. A flexible endoscope is insertedinto the bladder, and bladder barbotage is performed. The visual inspectionincludes mapping the location, size, and number of lesions, as well as a descriptionof the growth pattern (solid vs. papillary). An intraoperative video is oftenrecorded. All visible tumors should be resected, and a sample of the muscleunderlying the tumor should be obtained to assess the depth of invasion. Normal-appearing areas are biopsied at random to ensure no field defect. A notation ismade as to whether a tumor was completely or incompletely resected. Selectivecatheterization and visualization of the upper tracts should be performed if thecytology is positive and no disease is visible in the bladder. Ultrasonography, CT,and/or MRI may help to determine whether a tumor extends to perivesical fat (T3)and to document nodal spread. Distant metastases are assessed by CT of the chestand abdomen, MRI, or radionuclide imaging of the skeleton. Bladder Cancer: Treatment Management depends on whether the tumor invades muscle and whether ithas spread to the regional lymph nodes and beyond. The probability of spreadincreases with increasing T stage. Superficial Disease At a minimum, the management of a superficial tumor is completeendoscopic resection with or without intravesical therapy. The decision torecommend intravesical therapy depends on the histologic subtype, number oflesions, depth of invasion, presence or absence of CIS, and antecedent history.Recurrences develop in upward of 50% of cases, of which 5–20% progress to amore advanced stage. In general, solitary papillary lesions are managed bytransurethral surgery alone. CIS and recurrent disease are treated by transurethralsurgery followed by intravesical therapy. Intravesical therapies are used in two general contexts: as an adjuvant to acomplete endoscopic resection to prevent recurrence or, less commonly, toeliminate disease that cannot be controlled by endoscopic resection alone.Intravesical treatments are advised for patients with recurrent disease, >40%involvement of the bladder surface by tumor, diffuse CIS, or T1 disease. Thestandard intravesical therapy, based on randomized comparisons, is bacillusCalmette-Guerin (BCG) in six weekly instillations, followed by monthlymaintenance administrations for ≥1 year. Other agents with activity includemitomycin-C, interferon (IFN), and gemcitabine. The side effects of intravesicaltherapies include dysuria, urinary frequency, and, depending on the drug,myelosuppression or contact dermatitis. Rarely, intravesical BCG may produc ...