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Done By Ehab Ahmed KAAU Outlines Epidemiology Risk factors Molecular pathway Pathology Presentation Diagnosis Chemoprevention Management Non-urothelial Bladder Cancer Epidemiology The most common malignancy affecting the Urinary System 80% in patients over 60 years of age M:F is 3.4:1 In some high incident regions, Bladder Cancer is associated with specific disease status or toxins exposures as in Balkan countries, Urinary Transitional Cell Carcinoma is associated with Balkan nephropathy Risk Factors Chemical carcinogenesis: o Aromatic Amines or its derivatives as 2- Naphthylamine, Benzidine, Azodyes, and 4-Aminobiphenyl Occupational : o Aluminum, Dye, Paint, Petroleum, Rubber o 20% Of cases Environmental : o Smoking : Increase by 6-10 folds Related to the extent of exposure, with long term o Analgesic abuse : Chemical structure similar to Analine dye Phenactin has been linked to CRD, Cancer of the Bladder, Renal Pelvis, and Ureters o Artificial sweeteners : Saccharin, and Cyclamates o Coffee consumption : Week association Reflect the confounding influence of Smoking o Upper tract cancer (TCC) o Pelvic radiation : Cervical, Ovarian, and Prostate cancers o Chronic infections : Cystitis, Schistosomiasis Mechanisms : 1. 2. 3. 4. Repeated chronic irritations can lead to metaplastic changes, then dysplasia, and finally carcinoma It predispose to obstructive uropathy, bacterial super infection, and production of Nitrosamines in the acidic urine environment Inflammatory cells are rich sources of reactive oxygen species Genetic variations in the genes involved in the inflammatory response alter their expression and function, potentially affecting the risk of developing cancer o Chemotherapy : Cyclophosphamide have up to 9 fold increase risk of Bladder Cancer o Others : Black foot disease Renal transplant recipient (prolong immunosuppressant) Molecular Pathways Metabolic activation of carcinogens : o arylamines require in vivo activation to acquire carcinogenic potential o Through P45 enzymes Detoxification of carcinogens : o Acetylation phenotype o Glutathione S transferase Pathology Pathologic tumor staging : o Lamina Propria Invasion o Muscularis Propria Invasion o Vascular Invasion Non-invasive Urothelial Neoplasm Flat lesions CIS Papillary lesions Dysplasia Urothelial Papilloma Inverted Papilloma PUNLMP LGPUC HGPUC Malignant Epithelial Tumors : o Transitional Cell Carcinoma : 90% of Bladder Cancer 75% Papillary and solid o Squamous Cell Carcinoma o Adenocarcinoma o Small Cell Carcinoma o Metastatic : 15% of cases Usually from Colon, Rectum, Prostate, and Cervix Less commonly from Melanoma, Stomach, Breast, and Lung Presentation Hematuria : o Intermittent, gross, painless, and total Pain : o Usually due to locally advanced or metastatic disease o Flank, Suprapubic, Bone, and Perineal pain Voiding symptoms : o Functional decrease in the bladder capacity, detrusor overactivity, invasion of the trigone, and obstruction o Irritative (more common), and Obstructive Constitutional symptoms : o Signs of advanced or metastatic diseases Staging Histological grade : o Based upon the degree of resemblance to the normal tissue architecture, and degree of nuclear anaplasia o Bladder tumors are now classified as either low or high grade. This replaces the previous system of classification in which tumors were designated as low (G1), intermediate (G2), or high (G3) grade o o o o o o Clinical staging (TNM) : Tx – Primary tumor cannot be assessed T0 – No evidence of primary tumor Ta – Non-invasive papillary carcinoma Tis – Carcinoma in situ T1 – Invade subepetheilial connective tissue T2 – Invade the muscles o T2a – Superficial muscle (inner half) o T2b – Deep muscle (outer half) o T3 – Invade perivesical tissue o T3a – Microscopically o T3b – Macroscopically (extravesical mass) o T4 – Invade other organs o T4a – Invade Prostate, Uterus, and Vagina o T4b – Invade Pelvic and Abdominal wall o o o o o o o o Nx - Regional lymph node cannot be assessed N0 - No lymph node metastasis N1 - Single lymph node, 2 cm or less N2 - Single lymph node 2-5 cm, or multiple lymph nodes less than 5 cm N3 - Lymph nodes more than 5 cm Mx - Distant metastasis cannot be assessed M0 - No distant metastasis M1 - Distant metastasis Stage T Stage grouping N M Stage 0a Ta N0 M0 Stage 0is Tis N0 M0 Stage 1 T1 N0 M0 Stage 2 Ta Tb N0 N0 M0 M0 T3a T3b T4a N0 N0 NO M0 M0 M0 T4b Any T Any T Ant T N0 N1 N2 N3 M0 M0 M0 M0 Stage 3 Stage 4 Diagnosis 1. 2. 3. Urinalysis : o Microscopic, gross examinations, and dipstick chemical test Urine cytology : o 90% is sensitive for Cis o Limited sensitivity for upper tract TCC o Overall false negative rate is 65% o Specificity is 81-100% o Positive cytology considered poor prognostic factor Urine flow cytometry : o Evaluation of abnormal DNA ploidy may be more accurate than cytology for detecting the presence of exfoliated malignant cells 4. Urine immunocytochemistry and proteomocis assaays : o Immunocytochemistry : o More sensitive in detecting Low Grade Tumor than cytology NMP22 Proteomics assays : Analysis of protein expression in tissues, serum in order to identify tumors on the basis of unique protein expression pattern 5. Radiographic evaluation : IVP : o Cystogram phase detect 60-85% of large bladder cancer Ultrasound : o Can confirm Bladder mass but cannot determine depth of invasion, nodal involvement, and extravesical extension o Useful in evaluating upper tract CT Scan : o 80% accurate in differentiating locally advanced tumor form less invasive tumor o Advantages : Demonstrate extravesical extension, nodal involvement, visceral, pulmonary, or osseous metastasis o Disadvantages : Cannot differentiate depth of Bladder wall invasion, although thickened wall suggest muscle invasive disease Sensitivity for identification of nodal involvement is relatively low (false negative is 86%, and false positive is 16%) 6. Cystoscopy : o o Gold standard It begins with bimanual examination under anesthesia Abnormal areas should be sampled RGP should be done if upper tract cannot be visualized by IVP Cytology specimen should be taken if not previously done Should document the following : o o o o Tumor size, number, position, and growth pattern Mucosa Lower tract as urethra and prostate 7. Fluorescence cystoscopy : o o o Intravesical installation of a porphryin such as 5-aminolevulinic acid More effective than white light endoscope for the detection of multifocal tumors, thereby improving outcomes of TURBT Sensitivity is 87-97% Purpose Comparison between hexaminolevulinate fluorescence cystoscopy with white light cystoscopy for detecting Ta and T1 papillary lesions in patients with bladder cancer Methods A total of 311 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM HAL for 1 hour. The bladder was inspected using white light cystoscopy, followed by blue light (fluorescence) cystoscopy. Papillary lesions were mapped and resected for histological examination Conclusion HAL fluorescence cystoscopy detected at least 1 more Ta and T1 papillary tumor than white light cystoscopy in approximately a third of the patients with such tumors. Whether this would translate to improved patient outcomes has yet to be determined. University of Texas M.Grossman HB et al, July 2007 8. Metastatic work up : o Chest x-ray : o MRI o Non calcified densities Sensitive to detect Lymph Node metastasis Bone Scan In patients with invasive or locally advanced tumors, and other skeletal symptoms or unexplained elevation in serum Alkaline Phosphatase (ALP) Chemoprevention Use of various systemic agents to prevent or reverse changes in the urothelium Two types : 1. Primary chemoprevention : o 2. Block the formation of de novo Bladder Cancer in healthy individuals Secondary chemoprevention : o Avoiding formation of additional tumors in patients who have been treated for bladder cancer 1. 2. 3. 4. 5. 6. Agents : Retinoids (Vitamin A component) Pyridoxine (Vitamin B6) Vitamin C Alpha tocopherol (Vitamin E) Multivitamins Difluoromethylomithine Although some of the data supporting these agents is suggestive, NO role has been established for any of these agents in either primary or secondary chemoprevention Management Prognostic factors : o Stage Stage Ta, Tis, T1 o Grade o Multicentricity and frequency of recurrence : o Molecular markers Treatment options : o Endoscopic surgical management o Immunotherapy o Intravesical chemotherapy o Radical cystoectomy o Radiotherapy Risk stratification : Low Risk Patients High Risk Patients Initial presentation with superficial tumor Multiple superficial recurrence within sort time period Long interval between tumor recurrence >3 cm lesions, sessile, and on a thick stalk 3-4 Lesions, all of which are small (<3 cm) with a papillary appearance and on fine stalk Invasion of the lamina propria, poorly differentiated histology No lamina propria invasion, well differentiated histology Incomplete resection due to diffuse bladder involvement or unfavorable location Presence of diffuse Tis, or Tis in association with papillary tumors Initial Treatment Transurethral Resection (TURBT) : o Despite complete TURBT, up to 80% of patients with high risk tumors will recur within 12 month. So, adjuvant therapy is widely used Restaging TURBT : o Patients with high risk bladder cancer who are candidate for Intravesical therapy should undergo a repeat cystoscopy with biopsies of previous areas of involvement prior to therapy. This approach is important to detect previously under diagnosed disease and to reduce the tumor burden prior to therapy Random biopsies post-TURBT : o Any suspicious areas should be sampled o Not indicated in low-risk pt o 12.4% positive in high risk with normal cystoscopy o Prostatic urethral biopsy may be performed if neobladder creation is anticipated o ?tumor implantation Purpose evaluation of whether restaging transurethral resection (TUR) of superficial bladder cancer improves the early response to bacillus CalmetteGuerin (BCG) therapy Methods A total of 347 patients with high risk superficial bladder cancer (high grade Ta and T1 tumors associated with carcinoma in situ) underwent a single transurethral resection (TUR, 132 patients) or restaging TUR (215 patients) before receiving 6 weekly intravesical BCG treatments The patients were evaluated for response (presence or absence of tumor) at first follow up cystoscopy, at 6 and 12 months after treatment, and evaluated for disease stage progression within 3 years of follow up •Of the 132 patients who underwent a single TUR before BCG therapy, 75 (57%) had residual or recurrent tumor at the first cystoscopy and 45 (34%) later had progression •compared with 62 of 215 patients (29%) who had residual or recurrent tumors and 16 (7%) who had progression after undergoing restaging TUR (p = 0.001) Result Conclusion Restaging TUR of high risk superficial bladder cancer improves the initial response rate to BCG therapy, reduces the frequency of subsequent tumor recurrence and appears to delay early tumor progression Herr HW, Memorial SloanKettering Cancer Center, Dec 2005 Intravesical therapy : o Permits high local concentrations of a therapeutic agent within the bladder, potentially destroying viable tumor cells that remain following TURBT and preventing tumor implantation o Indications : 1. 2. 3. 4. 5. 6. Multiple, or large (>3cm) at presentation Recurrence within 1 year High grade Ta Any T1 Cis Positive cytology after resection of a visible tumor o Intravesical chemotherapy : ○ Metaanalysis of seven randomized trial has demonstrated that one immediate installation of chemotherapy after TUR decrease the relative risk of recurrence by 40 % ○ Up to 24 hours 1. o o o Intravesical BCG : Most common Live attenuated form of Mycobacterium Bovis The exact mechanism of action is UNKNOWN Antitumor mechanism Mononuclear cell infiltrate (CD4 T, Macrophages) Presence of Interferon gamma in the bladder Cytokines level are increased in the urine following treatment o Dose : Induction dose as Weekly injection for sex weeks Each dose consist of a vial of reconstituted theracys (81mg) or one 2 ml ampule of TICE BCG (50mg), plus 50 ml of sterile saline injected into the bladder through a catheter and retained for 2 hours o Maintenance therapy : Maintenance therapy consisted of intravesical BCG each week for 3 weeks given 3, 6, 12, 18, 24, 30 and 36 months from initiation of induction therapy Purpose The role of maintenance therapy, and its long-term effect on recurrence and progression Methods •All patients in the study had transitional cell carcinoma of the bladder with carcinoma in situ or an increased risk of recurrence. •The criteria for increased risk were 2 or more episodes of tumor within the most recent year, or 3 or more tumors within 6 months. At least 1 week following biopsy of carcinoma in situ and resection of any stage Ta or T1 transitional cell tumors 660 patients were started on a 6-week induction course of intravesical BCG • Three months following initiation of BCG induction therapy 550 consenting patients were stratified by purified protein derivative skin test and the presence of carcinoma in situ, and then randomized by central computer to receive BCG maintenance therapy (maintenance arm) or no BCG maintenance therapy (no maintenance arm). Result No toxicities above grade 3 were noted in the 243 maintenance arm patients. The policy of withholding maintenance BCG from patients with increased side effects may have diminished the opportunity to observe severe toxicity. Estimated median recurrence-free survival was 35.7 months in the no maintenance and 76.8 months in the maintenance arm (p<0.0001). Overall 5-year survival was 78% in the no maintenance compared to 83% in the maintenance arm Conclusion Compared to standard induction therapy maintenance BCG immunotherapy was beneficial in patients with carcinoma in situ and select patients with Ta, T1 bladder cancer. Median recurrence-free survival time was twice as long in the 3-week maintenance arm compared to the no maintenance arm, and patients had significantly longer worsening-free survival Lamm Dlet al, West Virginia University Medical Center,April 2000 o Efficacy : Delay tumor progression, decrease the need for subsequent cystectomy, and improve overall survival rate o Long term outcome : Studies showed that the survival rate at 4-5 years (70-86%) following BCG is similar to that achieved after Cystectomy o Complications : Cleavland Clinic approach for toxicity management Grade 1 Moderate symptoms less than 48 hours Presentation Mild to moderate irritative symptoms, mild hematuria, and fever <38.5 Assessment Urine culture to rule out UTI Management Anticholinergic, Antispasmodic, NSAID, Analgesia Grade 2 Severe symptoms and\or more than 48 hours Presentation Severe irritative symptoms, hematuria, or symptoms lasting more than 48 hours Assessment Urine culture, chest radiograph, and liver function Management Infectious consultation, treat culture result as appropriate Antimicrobial agents: INH 300 mg\day PO and Rifampin 600 mg\day PO Grade 3 Serious complications (hemodynamic instability, persistent high grade fever Presentation Allergic reaction (joint pain, rash) Assessment Urine culture, chest radiograph, and liver function Management INH 300 mg\day PO and Rifampin 600 mg\day PO for 3-6 month depend on the response Consider Prednisone 40 mg\day, when response is inadequate for septic shock (NEVER given without effective antibacterial therapy) o Contraindications : Absolute Contraindications Relative Contraindications Immunosuppressed patients UTI Personal history of BCG sepsis Liver disease Gross hematuria TB Traumatic catheterization Poor overall performance status Total incontinence Advanced age Immediately after TURBT, risk of intravasation o BCG Failure : Predictors of BCG Response skin testing and granuloma formation some studies have suggested that p53 status might provide a useful predictor for BCG response Llopis et fli showed that p53 expression analyzed at a cutoff of 20% positivity is a significant predictor of progression Sub classified to BCG Refractory BCG-Resistant BCG-Relapsing o Recommendations for the use of BCG : BCG is superior to chemotherapy for preventing recurrence Patients with intermediate risk and high risk tumors are suitable for BCG therapy BCG delay, prevent progression to muscle invasive disease Maintenance therapy is necessary for optimal therapy, but the optimal schedule and does have not yet been defined At least 1 year maintenance therapy is advised EUA 2007 2. Mitomycin C : o o o o 3. Alkylating agent that is minimally absorbed from the bladder circulation into the systemic circulation 20-60 mg Weekly for 6-8 weeks Side effects include chemical cystitis and skin reactions Anthracyclines : o o Epirubicin, Doxorubicin, and Valrubicin Approved for use in patients who have failed BCG, and in whom immediate cystectomy is either refused or contraindicated 4. Interferon : o o o o 5. 10-100 million units Weekly for sex weeks Side effects include Flu-like symptoms Still under trial Thiopeta : o o Seldom used High incidence of irritative voiding symptoms, myelosupression, and secondary leukemia Cystectomy : o Indications : 1. Muscle invasive disease 2. Failure to control symptoms (hemorrhage) with other parameters 3. Multiple tumors with unfavorable locations 4. Recurrent within short period of time despite use of Intravesical therapy 5. Superficial tumor of the prostatic urethra particularly if complete resection cannot be accomplished Adjuvent Treatment Papillary or solid Any Cis Papillary or Solid Ta,low grade chemotherapy into the bladder within 24 h of surgery Cystoscopy Q 3 m Ta, high grade or T1, low grade BCG •Cystoscopy, cytology Q3 month for 2 years, then Q6 month for 2 years, the each year •UT Q1-2 year T1, high grade T1, high grade : o Cystectomy and intravesical BCG therapy are both acceptable primary therapies For high-grade Tl disease and both options should be discussed o The ideal candidate for conservative treatment of Tl bladder cancer is ○ a patient with a solitary or at least completely resectable tumor, ○ a negative upper tract evaluation, and ○ no evidence of invasive disease in the prostatic urethra o Primary intravesical therapy should comprise induction BCG immunotherapy with 6 weekly instillations beginning no sooner than 2 weeks after tumor resection . o Cystoscopy with urinary cytology and possible biopsy should be done at 3 months to confirm the absence of recurrence or progression . o Maintenance therapy should be given . although comparison studies have not been done, the SWOG regimen of 3 weekly instillations at 3, 6, and every 6 months for 3 years is recommended o For patients with initial induction BCG therapy failure Who are unfit, refuse cystectomy, or have low- or .intermediategrade disease >>> an additional course of a BCGcontaining intravesical therapy is the preferred option o Cystectomy is indicated if salvage therapy fails, and it should be performed in a timely o Early cystectomy is recommended in diffuse high grade tumor who fail to response to Intravesical therapy Patients undergoing delayed cystectomy ( > 2 years) have a poorer prognosis than those undergoing more immediate cystectomy. Any Cis BCG Installation •Cystoscopy Q 3month for 2 years, then Q6 monthe for 2 years, the each year •Upper tract imaging Q12 year •Urinary biomarkers is optional Post Treatment Follow Up 1. 2. 3. Recurrent disease can develop any where in the genitourinary epithelium including Renal pelvis, Ureters, Urethra, and the Bladder Cystoscopy Urinary biomarkers Urethra (prostatic) 4. Upper urinary tract : o o o 3-20%, median time to discover of such tumors are 3-7 years IVP, CT Urography, RGP, and MRI Urogram Factors that may increase the risk of developing upper tract tumors are: Urethral involvement 2. VUR 3. Occupational exposure 4. Multiple tumor, Tis 1. o o Patients with negative cytology after TURBT, imaging of the upper tract every 1-2 years is recommended and should continued for 5 years in patients with low risk disease and for life in patients with high risk disease Patients with positive cytology and NO obvious intravesical tumor, carful periodic evaluation of the upper tract is important by CT Urography Treatment of Recurrent, Persistent Disease Cancer present on follow up cystoscopy: o TURBT o Adjuvant treatment according to the type and grade of the tumor o Follow up Q3 month for 2 years then Q6 month for 2 years then each year Positive cytology with Negative cystoscopy : Random biopsies of the bladder and prostate (in men) NO Cancer found Follow up, or BCG into the bladder Cancer found Cancer found BCG Complete response Incomplete response Different drug trial Maintenance BCG, Follow uo Persist Cystectomy Recurrent post 2 cycle of BCG, Mitomycin C treatment Complete response Maintenance BCG Recurrent as Tis, Ta Cystectomy or different drug into the bladder Recurrent as T1, high grade Cystectomy Non-urothelial Bladder Cancer The development of METAPLASIA and the presence of CHRONIC INFECTIONS are believed to be important factors in tumorgenesis Non-Schistosomal SCC Adenocarcinoma Schistosomal Bladder Cancer Non-epethilial Bladder Cancer Non-Schistosomal SCC : o 3-5% in North America and Europe, 75% in areas where Schistosoma Haematobium is endemic o Risk factors include chronic UTI, bladder stones, pelvic radiation, cyclophosphamide exposure, and smoking o Hematuria and irritative symptoms are present o Tumors are commonly bulky and locally invasive at diagnosis, but distant metastases are present in only 8 to 10 percent of cases at diagnosis o Treatment : Surgery Chemoresistant Adenocarcinoma : o 0.5-2%, 10% Urachal Adenocarcinoma o Non-urachal Adenocarcinoma : Low grade Treatment : Radical Cystectomy and lymph node dissection Chemotherapy for unrespectable tumor RT have been utilized by some centers with mixed results o Urachal Adenocarcinoma : Treated with surgical resection and resection of the Urachal ligament and Umbilicus No role for Chemotherapy or Radiotherapy Schistosomal Bladder Cancer : o 70% SCC, 20% TCC, and 5% Adenocarcinoma o Tumors are usually low- to moderate-grade. At diagnosis, lymph node metastases are present in about 20%, and distant metastases in 3%, possibly due to mural fibrosis causing delayed spread of the tumor o Treatment : Non-metastatic tumor treated with Radical Cystectomy and Lymph Node dissection Adjuvant Radiotherapy improve survival rate Neoadjuvent Chemotherapy improve survival rate ( 74% vs. 38% with cytectomy alone) Non-epithelial Bladder Cancer : o Sarcoma o Paraganglioma o Melanoma o Lymphoma o Lymphepithelioma-like carcinoma o Metastatic tumor Thank You