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bladder cancer

Etiology: risk factors: 1) occupational exposure to aromatic amines a) used in synthesis of plastics, rubber, dyes, printing b) automobile workers, painters, truck drivers, machinists, miners, leather workers, workers in textile & paper manufacturing 2) tobacco smoking a) accounts for 1/3 of cases b) risk correlates with number of cigarettes smoked & years of smoking c) current smoking 2-fold risk relative to former smoker [6,23] d) second hand smoking also a risk factor 3) phenacetin-containing analgesics 4) cyclophosphamide, long-term use 5) recurrent UTI - especially with Schistosoma haematobium - common infection in Middle East 6) recurrent nephrolithiasis 7) proposed risks unconfirmed or disproven a) caffeine b) artificial sweeteners c) excess alcohol d) tryptophan metabolites Epidemiology: 1) most common urinary tract cancer 2) 78,000 cases/year [2] - 3% of all cancer deaths - 14,000 cancer-related deaths annually [2] 3) 2-3 times more common in men than women a) 4th leading cause of cancer among males - after lung cancer, colorectal carcinoma, prostate cancer b) 8th most common cancer in women 4) mean age of diagnosis: 67-70 5) more common in industrialized nations & urban areas Pathology: 1) morphology a) transitional cell carcinoma 90%, best prognosis b) squamous cell carcinoma 5% c) mixed cell cancer 5% d) adenocarcinoma is rare 2) second malignancies occur in about 10% of patients 3) metastases a) bone (26%) b) brain (7%) c) skin (5%) d) adrenal (35%) e) kidney (19%) 4) most bladder cancers are superficial & do not invade the underlying muscle [2] Genetics: 1) loss of part or all of chromosome 9 (55%)* FAM5A gene 2) 17p deletion, +/- p53 (40%) 3) 11p deletion (40%) 4) 13q deletion (20%) 5) down-regulation of BLCAP during progression 6) somatic mutations can constitutively activate FGFR3 7) S100A7 highly expressed in the urine of patients with squamous cell carcinoma of the bladder 8) other implicated genes ACRBP, PBOV1, SPANXC, SAGE1, FMR1NB, HDAC9 BAGE1, BAGE2, BAGE3, BAGE4, BAGE5, LENG4, HRAS, NAT2, MDM2, RB1, BAT2D1, EREG, ZNF225 * superficial recurrent carcinoma; other genetic aberrations associated with invasive carcinoma Clinical manifestations: 1) painless hematuria (75% of patients) - slightly rusty to bright red in color [City of Hope] 2) signs of bladder irritation (25% of patients) a) dysuria b) frequency c) urgency 3) signs/symptoms of advanced disease a) weight loss b) abdominal pain c) bone pain Laboratory: 1) urine cytology 2) urinary NMP22 (point of care test) lacks positive predictive value 3) serum chemistries (staging) 4) urine telomeric repeat amplification protocol (TRAP) sensitivity 90%, specificity 88-94% 5) urine telomerase reverse transcriptase promotor gene mutation (uTERTpm) 6) PD-L1 expression 7) see ARUP consult [7] Special laboratory: - cystoscopy with multiple biopsies Radiology: 1) intravenous pyelogram (IVP), now CT urogram a) ureteral obstruction b) hydronephrosis c) bladder filling defect d) lack of bladder distensibility 2) chest X-ray (staging) 3) CT of abdomen & pelvis (staging) 4) MRI generally no more useful than CT for staging Differential diagnosis: 1) renal carcinoma a) IVP b) cystoscopy c) painless hematuria may be seen with both conditions 2) nephrolithiasis a) generally painful hematuria b) IVP 3) urinary tract infection (UTI) a) pyuria b) positive urine culture 4) prostatitis Staging: - T1 neoplasms invade the submucosa - T2 neoplasms penetrate the muscular wall of the bladder - T3 tumor invades perivesical fat - T4 tumor invades prostate, uterus, vagina, pelvic wall or abdominal wall [13] * 60% of patients found to have non-invasive disease [2] Management: 1) depends upon staging - any aspirin use is associated with improved survival [27] 2) superficial disease (CIS - T1) (most common) a) endoscopic (transurethral) resection under anesthesia + - repeat transurethral resection & fulguration [34] prior to - intravesicular chemotherapy 1-6 treatments - intravesicular BCG for 6 treatments followed by periodic cystoscopy [2] - intravesicular BCG is associated with decreased mortality, & decreased decreased risk of Alzheimer's disease & related dementias [33] - nadofaragene firadenovec may be useful for BCG-resistant bladder cancer - doxorubicin, mitomycin, thiotepa, or BCG [2,13] b) laser surgery (not approved) c) 50-70% have superficial recurrences within 3 years d) 12% develop invasive or metastatic disease e) cystoscopy every 3 months for 2 years, then once a year f) recurrence of superficial disease: - may repeat transurethral resection + intravesicular chemotherapy once [2] - cystectomy without chemotherapy [2] 3) invasive disease (T2, T3) a) radical cystectomy with neoadjuvant chemotherapy [2] - gemcitabine + cisplatin is standard - methotrexate, vinblastine, doxorubicin + cisplatin (ddMVAC) may afford more complete response [21] - bladder-preserving treatment associated with increased risk of recurrence (36% vs 7%) but no difference in mortality b) removal of adjacent pelvic organs & regional lymph nodes - lymph node dissection associated with lower mortality than no lymph node dissection [13] - more extensive lymph node dissection might afford survival advantage [13] c) radiation - in conjunction with cystectomy - 40 Gray; 60 Gray with bladder-preserving treatment [13] - personalized strategy of dose-escalated radiotherapy - delivering radiotherapy to the bladder is challenging because it is a mobile & deformable organ [36] d) cisplatin-based combination adjuvant chemotherapy might diminish mortality, but evidence is not strong [13] - cisplatin, methotrexate, & vinblastine - methotrexate, vinblastine, doxorubicin, & cisplatin - gemcitabine & cisplatin is standard of care [14] - enfortumab vedotin (Padcev) + pembrolizumab (Keytruda) FDA approved for cisplatin-ineligible patients [32] - minimum of 3 cycles of chemotherapy [16] e) nivolumab may improve disease-free survival regardless of PD-L1 status [28,29] f) neoadjuvant atezolizumab with gemcitabine & cisplatin in patients with muscle- invasive bladder cancer downstages to non-muscle-invasive disease in > 2/3 [30] g) perioperative durvalumab with neoadjuvant cisplatin-based chemotherapy improves survival in muscle-invasive bladder cancer [35] h) 5 year survival is 40-50% regardless of mode of therapy i) surgical techniques that use small bowel as bladder reservoir 1] Kock's pouch 2] Indiana pouch 3] Mainz pouch 4) metastatic disease (T4, TxN) a) chemotherapy - methotrexate, vinblastine, doxorubicin, & cisplatin (MVAC) - gemcitabine & cisplatin is standard of care [14] - minimum of 3 cycles of chemotherapy [16] b) erythropoietin may alleviate myelosuppression during chemotherapy c) 30-70% of patients show initial response to therapy d) life expectancy is < 2 years (15 months) [2] e) atezolizumab after platinum-based chemotherapy [19] - PD-L1 expression > 5% [22] f) pembrolizumab may prolong survival 10.3 months vs 7.3 months for chemotherapy [17], PD-L1 expression essential [22] g) checkpoint inhibitors only for patients with PD-L1 expression [22] h) enfortumab vedotin for locally-advanced or metastatic bladder cancer failing platinum-based or PD-L1 inhibitor based therapy - enfortumab vedotin (Padcev) + pembrolizumab (Keytruda) FDA approved for cisplatin-ineligible patients [32] i) prognostic model includes: - performance status, liver metastasis, elevated platelet count, elevated neutrophil count/lymphocyte count, elevated serum lactate dehydrogenase, anemia [19] 5) screening a) may be useful in workers with history of exposure to aromatic amines b) urinalysis should not be used to screen for bladder cancer in asymptomatic patients [2] - not cost-effective in general population c) insufficient evidence to weight pros & cons [5]

Related

staging of bladder cancer

General

urologic malignancy (urologic cancer) bladder neoplasm

Database Correlations

OMIM 109800

References

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