Superficial Bladder Tumors

1. Majed alharthi Superficial Bladder Tumors

3. Epidemiology Incidence bladder cancer is 3 time more common in men 2 times more common in white men than blacks 4th most common cancer in men (incidence) 6.6% after prostate, lung, colorectal, 9th most common cancer in women (incidence) 2.4%.

4. Epidemiology Mortality men have higher 5-year survival rates: white men 84%, black men 71%, white women 76%, black women 51% survival by stage at presentation more favourable for whites mortality higher in older people younger pepole have more favourable histology and prognosis

5. Etiology and Risk Factor Tumor Suppressor Genes p53 on chromosome 17p retinoblastoma gene (Rb) on chromosome 13q p19 and p16 on chromosome 9p, 9q

6. p53 a transcription factor that suppresses cell proliferation directs cells with damaged DNA towards apoptosis helps repair damaged DNA by inducing the production of nucleotides induces the expression of thrombospondin-1 (TSP-1) ? potent inhibitor of angiogenesis

7. retinoblastoma gene (Rb) pRb is normally complexed to E2F phosphorylated by cyclin-dependent kinases, which drives transitions of the cell cycle phosphorylated pRb dissociates from E2F, allowing uncomplexed E2F to induce transit from G1 to S phase

8. p19 and p16 p16 and p19 inhibit the cyclin-dependent kinases that phosphorylate E2F prevent transit from G1 to S phase

9. Etiology and Risk Factor Occupational exposure (20%) aniline dyes aromatic amines dietary nitrates and nitrites analgesic abuse (phenacetin) 5-15 kg over a 10 year period smoking (up to 4-fold risk) takes 20 years after quitting to return to non-smoker risk

10. Chronic Cystitis (paticularly SCC but increased risk of TCC too) infection Schistosoma haematobium long-term indwelling catheter (2-10% of paraplegics with long-term indwelling catheters develop bladder Ca (80% SCC) bladder stones

11. Radiation (2-4x risk). Cyclophosphamide (9x risk) acroline. Blackfoot disease (ingestion of arsenic from well water) ? endemic in South Taiwan Renal transplant recipient. Low amount of fluid ingestion.

12. Normal Urothelium normal urothelium is 3-7 layers thick basal cell layer with 1 or more layer of intermediate cells most superficial layer is composed of large, flat, umbrella cells The urothelial rest on lamina propria basement membrane

15. Epithelial Hyperplasia and Metaplasia epithelial hyperplasia increase in number of cell layers without nuclear or architectural abnormalities urothelial metaplasia non-transitional epithelial appearance, usually with epidermoid (squamous metaplasia) or glandular (adenomatous metaplasia) development

16. Cont �.. Von Brunn's nests islands of benign urothelium in the lamina propria cystitis cystica von Brunn's nests in which the central urothelium has undergone eosinophilic liquefaction cystitis glandularis similar to cystitis cystica, but transitional cells have undergone glandular metaplasia may be a precursor to adenocarcinoma

17. Urothelial Dysplasia Preneoplastic proliferative abnormalities: Atypical hyperplasia is similar to epithelial hyperplasia, except that there are also nuclear abnormalities and partial derangement of the umbrella cell layer Dysplasia epithelial changes that are intermediate between normal urothelium and carcinoma in situ (severe dysplasia). Dysplastic cells have large, round, notched, basally situated nuclei that do not exhibit the normal epithelial polarity. Dysplastic epithelium does not have an increased number of cell layers or mitotic figures

18. Inverted papilloma: benign proliferative lesion associated with chronic inflammation papillary fronds project into the fibrovascular stroma of the bladder rare malignant transformation coexists often with TCC elsewhere in the bladder Bez of overlying epithelium is normal.. Inverted Papilloma appeared as smaal raised nodules rather than papillary or frondlike tumors on endoscopic ispection

19. nephrogenic adenoma lesion that resembles primitive renal collecting tubules is a metaplastic response to trauma, infection, or radiation associated w/ dysuria and frequency � vesical leukoplakia a response of the normal urothelium to noxious stimuli squamous metaplasia with marked keratinization, cellular atypia, and dysplasia premalignant lesion that may progress to SCC in 20%

20. Pseudosarcoma (post-op spindle cell nodule). Rare lesion resembling sarcoma of the bladder Reactive proliferation of spindle cells months after infection or LUT procedure Have been misinterpreted as malignant leading to inappropriate surgery

21. Urothelial carcinoma Carcinoma in situ may appear as a velvety patch of erythematous mucosa although quite often it is endoscopically invisible -consists of poorly differentiated TCC confined to the urothelium -may be asymptomatic or may produce severe symptoms of urinary frequency, urgency and dysuria cytology +ve in 80-90% pateints with CIS

22. CIS is present in 25% of pts with high-grade superficial TCC Between 40-80% progress to muscle-invasive cancer CIS is present in 20-75% of pts with muscle-invasive TCC ? direct relationship, is a precursor lesion to invasive bladder ca

23. Transitional bladder cancer Tumor Architecture -more than 90% of bladder cancers are urothelial cancers The WHO and the ISUP preferred to term �transitional� cell carcinoma as �urothelial� cancers. -urothelial cancer differ from urothelium by having increased numbers of epithelial cell layers with papillary foldings of the mucosa loss of cell polarity abnormal cell maturation from basal to superficial layers increased nuclear to cytoplasm (N:C) ratio prominent nucleoli clumping of chromatin increased number of mitoses

25. Tumor grading grade 0 (papilloma) papillary lesion with fine fibrovascular core covered with normal mucosa do not have more than 7 epithelial layers with no abnormalities in histology. Rare tumo Almost never recure after endoscopic resection

26. grade 1 (well-differentiated) papillary urothelial neoplasm of low maliginant potential ( PUNLMP ) thin fibrovascular stalk with thickened urothelium more than 7 cell layers only slight anaplasia and pleomorphism rare mitotic figures

27. grade 2 (moderately-differentiated) low-grade papillary urothelial carcinoma low-grade urothelial carcinoma wider fibrovascular core greater disturbance of base-to-surface cellular maturation loss of cell polarity N:C ratio is higher More nuclear pleomorphism More prominent nucleoli Mitotic figures are more frequent

28. grade 3 (poorly-differentiated) high-grade papillary urothelial carcinoma high-grade urothelial carcinoma do not differentiate as they progress from the basement membrane to the surface marked nuclear pleomorphism high N:C ratio mitotic figures may be frequent �

29. Sequmous cell carcinoma SCC accounts for 3-7% of bladder cancers in the US. 75% of bladder ca in Egypt. 80% of SCCs in Egypt are associated with S.hematobium infection. typically younger than patients with TCC Bilharzial cancers are exophytic, nodular, fungating lesions that are usually well-differentiated and have a relatively low incidence of lymph node involvement and distant mets

30. non-bilharzial SCCs are usually caused by chronic irritation from urinary calculi, long-term indwelling catheters, chronic UTI or bladder diverticuli.

31. Risk factor chronic infection with S. hematobium bladder stones long-term indwelling catheter paraplegia chronic UTI bladder diverticuli smoking male

32. SCC consists of keratinized islands that contain eccentric aggregates of cells called squamous pearls Urine cytology has limited utility in SCC diagnosis stage for stage, the prognosis of SCC is comparable to that of TCC SCC often have p16 and TP53 abnormalities

33. Adenocarcinoma � adenocarcinoma accounts for <2% of primary bladder cancers Most adenocarcinoma are poorly differentiated and invasive They are more commonly associated wiyh cystica glandularis tha eith carcinoma in situ Can be in ileal conduit or augmented, pouch, uretreosigmodstomies DIVIDE IN TO�. Primary vesical. Urachal. Metastatic.

34. Primary Vesical. usually arise in bladder base or the dome -most common type of cancer in exstrophic bladders -stage for stage, the prognosis is comparable to TCC -patients� poor prognosis is probably due to advanced stage at diagnosis

35. Urachal Carcinoma . Extremely rare tumor that arised outside the bladder They may appear with a bloody or mucoid discharge from the umbilicus or mucocele as a palpable mass Mony of them have calcifications on Xray Tumor invading the bladder lumen may produce mucus in urine patients with urachal carcinomas have a worse prognosis than do those with a primary bladder adenocarcinoma -urachal carcinoma metastasize to iliac and inguinal lymph nodes, omentum, lung and bone �

36. Metastatic Adenocarcinoma From rectum, stomach, endometrium, breast, prostate, ovary.

37. most common sites of Mets with bladder are the pelvic lymph nodes : obturator nodes (74%) external iliac nodes (65%) presacral nodes (25%) extaregional common iliac nodes (20%) paravesical nodes (16%)

38. vascular mets. Liver (38%). Lung (36%). Bone (27%). Adrenal glands (21%). Intestine (13%).

39. The Important Prognostic Parameters in sup. bladder ca Grade Stage Presence of CIS Others lymphatic invasion, tumour size, papillary or solid tumour, multifocality, frequency of prior recurrence, DNA ploidy status, chromosomal factors (deletion of p53, 9, 13q

42. Tests are available to diagnose bladder cancer. Urine cytology. Flow cytometry. Quantitative fluorescent image analysis. Marker tests. Imaging excretory urography: indicated in all pts with suspected TCC. retrograde pyelography: if upper tracts not adequately visualized on IVP. CT abdo/pelvis: if suspect upper tract tumour Cystoscopy & Bimanual examination TURBT

46. Flow Cytometry requires large cell populations measures DNA content of cells whose nuclei are stained with DNA-binding fluorescent dye not more useful than cytology �

47. Quantitative fluorescent image analysis automated cytologic technique analyzes smears of cells on a microscope slide and measures DNA content in each cell can be performed with fluorescently labeled DNA probes to specific chromosomes of interest can demonstrate tumours with trisomy of chromosome 7, loss of chromosome 9, or 17p deletions

48. Tumors Markers. hyaluronic acid, hyluronidase nuclear matrix protein (BLCA4) telomerase Survivin FISH flursent cytology fluresence in situ hybridization

50. Cystscopy and TURBT The Gold standard Allows visualization of whole urethra and bladder. Permits biopsy of tumors and suspicious areas Invasive Sensitivity 73% specificity 68.5% (can be enhanced by fluorescence cystoscopy)

51. At initial diagnostic cystoscopy it is necessary to document: Tumor mapping: size, number, location, growth pattern (papillary or solid) Mucosa: normal, red areas or areas of irregular mucosa Lower tract: urethra, prostate Bimanual Examination under anesthesia (EUA ): Is there mass before resection ? Is there mass after resection ? Size and mobility of mass.

52. All visible tumor removed, then underlying muscle. Multiple biopsies taken from suspicious sites. Random biopsies from normal areas (controversial). Tumor encroaching the ureteral orifice: resection, no fulguration ,with D-J stent. Tumor in diverticulum: biopsy only- risk of perforation

53. Staging Test. Computed Tomography CT also provides information about the presence of pelvic and para-aortic lymphadenopathy and visceral metastases. CT is limited in accuracy because it can detect only gross extravesical tumor extension, lymph nodes that are quite enlarged, and liver metastases that are larger than 1 cm in diameter CT fails to detect nodal metastases in up to 40% to 70% of patients having them

54. Magnetic Resonance Imaging. MRI is not much more helpful than CT. With few exceptions the resolution of the pelvic and abdominal anatomy with traditional MRI has not been reported to be as good as that with CT MRI had a 75% sensitivity and a 96% specificity in detecting nodal metastases in patients with muscle-invasive bladder cancer who eventually underwent surgical staging

55. TNM STAGING

61. Nonurothelial bladder tumor Small cell carcinoma . (must evaluate for SCC of the lung or prostate) poor prognosis. Carcinosarcoma. contains malignant mesenchymal and epithelial elements poor prognosis even with cystectomy, rads and/or chemo Metastatic Carcinoma .

62. Nonepithelial bladder tumours (1-5%). neurofibroma pheochromocytoma partial cystectomy is treatment of choice TURBT is contraindicated primary lymphoma plasmacytoma sarcomas: angiosarcoma, hemangioma, leiomyosarcoma in adult , rhabdomyosarcoma in paediatrics

63. Superficial Bladder Cancer 70% of bladder tumors present as superficial lesions 10-20% of these progress to muscle-invasive lesions 70% of superficial lesions present as Ta 20% of superficial lesions present as T1 10% of superficial lesions present as CIS

64. Ta Stage Ta tumors are usually low grade. Only 6.9% are high grade. Recurrence is common---- Progression is rare. Their most important risk factor for progression is grade, not stage. So, high-grade Ta tumors should be followed as high risk.

65. T1 T1 tumors are usually papillary. Nodular or sessile appearance suggests deeper invasion. Increases the risk of recurrence and progression. Lymphovascular invasion increases the risk as well. There is significant potential for understaging in patients with non�muscle-invasive tumors, especially for those that appear to be stage T1 (understaging errors from 34% to 62% ).

66. CIS. Poorly differentiated, flat, urothelial carcinoma confined to the urothelium (no invasion of lamina propria). It is NOT �premalignant�.�it is highly malignant. Asymptomatic or severe symptoms (frequency, urgency, and dysuria) when diffuse. Urine cytology: positive in 80% to 90%. Cystoscopically: velvety patch of erythematous mucosa, or quite often invisible.

67. Present in 25% of patients with high-grade superficial tumors 40% to 83% progress to muscle-invasive. Present in 20% to 75% of high-grade muscle-invasive cancers. 20% of cystectomies for diffuse CIS have microscopic muscle-invading cancer. The majority in association with high-grade nodular tumors; only 3% -5% are isolated Tis disease. Patients with marked symptoms generally have shorter interval to muscle-invasion.

68. Depending upon cystoscopic and pathological findings, non-muscle invasive tumors can be stratified into low risk group or high risk group

71. Therapeutic Options. Endoscopic surgical management. Immunotherapy. Intavesical chemotherapy. Management of refractory disease. Surveillance.

72. Goals of Treatment Eradicating existing disease Preventing tumor recurrence Preventing tumor progression

73. Initial management is complete transurethral resection of bladder tumor (TURBT).

74. Repeat TURBT T1, high-grade Ta and if no muscle is identified on initial TUR: merit repeat resection. Nearly 40% will have disease at re-TUR With T1, repeat TUR can demonstrate worse prognostic findings in up to 25% of specimens If no muscle is identified on initial pathology, there is 64% risk of understaging T1

75. Re-TUR may change treatment plan in one third of cases.. Efficacy of BCG in preventing progression in high risk patients appears to be higher if re-TUR was performed before instillation of BCG. There is no consensus on timing of repeat TURBT, but usually1 to 4 weeks after the initial resection

76. Re-TURBT of high risk group improves the initial response to BCG therap reduces the frequency of recurrence ? delays early tumor progression ?improve survival

77. Complications of TURPT bladder perforation extraperitoneal vs. intraperitoneal clot retention ureteral orifice scarring

78. Low risk: usually TURBT alone + immediate intravesical chemothrapy High risk: intravesical therapy to decrease the risk of recurrence and progression

79. Immunotherapy Bacille Calmette Guerin. attenuated mycobacterium used as a vaccine for TB reconstituted in 50cc NS, administered 2-4 weeks post-TURBT, administer under gravity and remain for 2 hrs Always not given perioperative.

80. The contraindications for BCG administration Absolute gross hematuria bacterial infection traumatic catheterization (if traumatic catheterization, treatment should be delayed for several days) immunosuppression and immunocompromised patients/ recent TURBT (<2 weeks) Relative poor overall performance status advanced age prior hx of TB previous severe reaction to BCG pregnancy

81. BCG work in patient with CIS initial tumour-free RR 76% 50% durable response for median period of 4 years 30% tumour-free over 10 years (most recur within the 1st 5 years)

82. The Indications For BCG primary treatment of CIS treatment of residual papillary lesion when resection not possible(60% response) prophylaxis for T1 and high-grade/multiple/recurrent Ta lesions (decreased recurrence by 40% vs. TUR alone) carcinoma of the mucosa or superficial ducts of the prostate

84. The side effects of BCG and how are they treated Local LUTS, dysuria: treated with anticholinergics, acetaminophen, phenazopyridine Hematuria (30%): hold BCG granulomatous prostatitis (20-30%) symptomatic in 1% may increase PSA may progress to testicular involvement: traeated with orchiectomy if untreated bladder contracture (<0.5%) �

85. Systemic arthralgias pruritis fever/malaise if T > 38.5 for 24 hrs or T > 39.5, tx w/ INH 300mg PO OD x 3 months add pyridoxine if treating with INH) systemic BCGosis: treated with INH-RIF for 6 mo, add ethambutol if acutely ill manifests as pulmonary or hepatic disease BCG sepsis (0-4%): treated with standard life support + triple drug therapy Prednisone is effective as adjunct to triple drug therapy in animal models Quinolones are preferable to cycloserine in multidrug treatment of BCG sepsis

86. patients after BCG should be considered for cystectomy Those who have recurrent T1 lesion at 3 months after 6 week course of BCG Those who have persistent Cis after 2 x 6week courses of BCG These pts are more likely to progress to muscle invasive cancer

87. work in prophylaxis after TURBT decrease in recurrence of 40% overall T1G3 lesions: recurrence 16-40%, progression in 5-40% evidence of delayed progression SWOG comparison of doxorubicin and BCG: progression in 37% doxo vs. 15% of BCG delay in interval progression of BCG pts vs. TUR controls: Herr (1988) cystectomy rate for CIS was decreased with BCG (11% vs. 55% TUR alone)

88. Interferon Interferon as a solitary agent is more expensive and less effective than BCG or chemotherapy in eradication residual disease preventing recurrence of pappillary disease and treating CIS may be combined with BCG some evidence for improved efficacy

89. Conclusion Higher efficacy against CIS and disease reccurrence than intravesical chemotherapy Most evidence suggest that the BCG is superior for the intial management of high grade Ta and T1 BCG is the only agent shown to delay or reduce high-grade tumor progression Interferon-a has not been shown to have benefit compared with BCG for primary treatment but appears to work well in combination with BCG, especially for salvage.

90. BCG maintenance therapy significantly reduces recurrence and progression compared with chemotherapy or induction BCG alone. The SWOG maintenance schedule appears to be significantly better than other regimens

91. Intravesical chemotherapy Potentially destroying viable tumor cells that remain following TURBT Preventing tumor implantation

92. Indications: Multiple, or large (>3cm) at presentation Recurrence within 1 year High grade Ta Any T1 Cis Positive cytology after TUR of a visible tumor

93. Regimens: Single Immediate Peri-operative Chemotherapy Induction Course

94. Single Immediate Peri-Operative Chemotherapy Decreases the relative risk of recurrence by 40% Recommended for all types of papillary superficial tumors Mitomycin C (MMC) appears to be the most effective agent perioperatively. Within 24 hours ( better within 6 hs) No perforation or extensive muscle resection. Local irritative symptoms are common complications, but serious sequelae are rare

95. Mitomycin C mitomycin C. cross-linking agent that inhibits DNA synthesis sensitive in G1 phase, overall non-cell-cycle specific How is mitomycin C delivered instilled weekly for 6-8 weeks at 20-60mg � How effective is mitomycin C average benefit 15% in 5 papers, w/ only 2/5 demonstrating statistical significance no significant benefit of mitomycin C over TUR on progression

96. The side effects of mitomycin C chemical cystitis (40%) decreased bladder capacity palmar desquamation skin rash leukopenia bladder contraction (0.05%)

97. doxorubicin doxorubicin anthracycline antibiotic binds DNA base pairs, inhibiting topoisomerase II and inhibiting protein synthesis How well does doxorubicin work? 13-17% improvement over TUR in preventing recurrence no advantage in preventing progression

98. The side effects of doxorubicin chemical cystitis � main s/e (50%) decreased bladder capacity GI or allergic reactions

99. Epirubicin derivative of doxorubicin 50-80 mg/ml over 8 weeks decreased recurrence vs. TUR alone (12% vs. 15%) unavailable in US

100. Thiotepa Only agent approved by FDA for intravesical treatment of papillary bladder Ca non cell-cycle specific alkylating agent decreases tumour recurrence by 16% no effect on tumour progression the side effects of thiotepa. myelosuppression (leukopenia) (8-55%) thrombocytopenia (3-31%) LUTS (12-69%)

101. valrubicin semisynthetic analogue of doxorubicin causes cell-cycle arrest in G2 phase and inhibits topoisomerase II the role of valrubicin is to treats BCG refractory CIS who cannot tolerate cystectomy

102. Ethoglucid triethyleneglycol diglycidyl ether podophyllin derivative alkylating agent decreased RR and increased time to 1st recurrence no improvement in tumor progression

103. TUR alone < 1 immediate dose mitomycin C (within 6 hours of TUR) < mitomycin C immediate and x 5 weeks q3 month

104. conclusion In general, side effects of chemotherapy tend to less common and less severe than those for BCG, so consensus is that these agents should be used preferentially over BCG for low-risk disease Prevernt early recurrenace No long term benefit Dose not prevernt tumor progression Single perioperative instillation - Most effective treatement strategy for low risk patients

105. Induction course

106. Cystectomy Cystectomy should be considered for initial therapy in select patients. Risk of initially understaged muscle invasive disease. Risk of progression even after intravesical therapy. High cure rate associated with cystectomy. Factors associated with increased risk of progression are large tumor, high-grade, site poorly accessible to complete resection, diffuse disease, CIS, infiltration of lymphatic or vascular spaces, and prostatic urethral involvement. Cystectomy, however, is not without complications and morbidity.

107. Cystectomy Strongly considered for patients with high grade and invading deeply into lamina propria, exhibit lymphovascular invasion, or associated with diffuse CIS, or in diverticula. Patients with CIS or high-grade papillary disease refractory to two courses of intravesical BCG (80% risk of failure or progression), in that setting, cystectomy is the standard of care and should not be considered early

108. surveillance The most common approach: /3 months x 2 yrs /6 months x 2 yrs /Annually

109. Follow-up involves: History (voiding symptoms and hematuria) Urinalysis Urine cytology Cystoscopy Periodic upper tract imaging (especially for high-risk patients) Tumor markers (investigational)

110. Cystoscopy is the hallmark of surveillance. The optimum schedule is controversial but may be individualized based on risk. �� ?��� Patients with solitary low-grade Ta lesions whose initial 3-month surveillance cystoscopy is normal and who have negative cytology can have surveillance on a less aggressive schedule. Annual cystoscopy is probably reasonable, and cessation may be considered in 5 years. �� ?��� Patients with high-grade tumors (including CIS) warrant quarterly cystoscopy for 1 to 2 years, semiannual cystoscopy for 1 to 2 years, and annual cystoscopic evaluation for life. ��

111. ��� Upper tract imaging is not necessary for low-grade tumors but should be performed at diagnosis and every 1 to 2 years for high-grade tumors. � � ?��� Cytology is usually performed at the time of each cystoscopy. Its specificity is very high, but its sensitivity is suboptimal and a negative cytology does not assure the absence of any grade bladder cancer. �� ?��� A number of tumor markers have shown the ability to improve upon the sensitivity of cytology, but specificity is lower for most. �� ?��� Increased fluids, smoking cessation, and a low-fat diet are recommended

113. T h a n k s��.