Bladder and Urothelial Cancers – Flashcards
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Bladder Cancer Intro
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Most common malignancy in the urinary tract Urothelial/transitional cell carcinoma is the most predominant histologic type in developed regions (North America and Europe), accounting for 90% in the US Non-urothelial cell carcinomas more prevalent in other parts of the world Non-urothelial bladder cancers: Squamous cell carcinoma (SCC): 5% of cases in the US Adenocarcinoma: 2% of cases in the US Other: small cell carcinoma, sarcoma, bladder pheochromocytoma, bladder lymphoma Metastasis (secondary): melanoma, colon, prostate, lung, breast in order of incidence Urothelial cancer arises in the renal pelvis, ureter, and urethra less commonly
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Epidemiology
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9th most common cancer worldwide Approx 79,000 cases and 17,000 deaths yearly in the US Incidence increased by over 50% from 1985 to 2005 Many patients do not die from their disease, but do experience multiple recurrences Male > female (3:1) Median age of onset 69 years in men, 71 years in women. Younger onset in current smokers vs. never smokers. Rarely seen in children and young adults. When occurs, typically low grade, non-invasive. White males twice the incidence of African American and Hispanic men. Acetylator phenotypes: genetic polymorphism associated with decreased ability to acetylate aromatic amines Occupational differences among minorities that influence exposure to industrial carcinogens Although incidence is lower in women and African Americans, these groups have more advanced stage tumors at presentation compared with white men.
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Bladder CA risk factors
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-Cigarette smoke: most common cause of bladder cancer Increases risk 2-4 fold Risk returns to baseline 20-30 years after smoking cessation Quantify in pack years and if/when the patient quit Risk also present with second hand smoke -Chronic inflammation: increased risk of SCC Chronic UTI Indwelling bladder catheter Schistosoma infection Chronic bladder stones -Chemical exposure: most bladder carcinogens are aromatic amines. Occupational exposures Napthylamine Benzidine Aniline dyes 4-aminobiphenyl Coal Asphalt/tar exposure Rubber, dye, printing, and petroleum industries Cyclophosphamide: Caused by toxic metabolite, acrolein Latency period 6-13 years Radiation exposure
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SCC
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Schistosoma infection most common in East Africa and Middle East Otherwise, risk factors include: Urothelial irritants (as previously mentioned) Cyclophosphamide Intravesical BCG Smoking Radiation HPV infxn Squamous metaplasia Low rate of metastasis. Most deaths due to local progression. Primary management is surgical with or w/o radiation. No chemotherapeutic regimens have been effective. Poor prognosis Average survival of 1-3 years from diagnosis
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Adenocarcinoma
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Uncommon and often aggressive Poor prognosis Typically advanced at dx Risk fxs Chronic irritation, inflammation, infection Bladder exstrophy Schistosomiasis Treatment is surgical Chemo and radiation have not significantly improved survival
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Genetics and Epigenetics
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No clear hereditary causes identified Tumor suppressor p53 most commonly altered gene (associated with DNA repair and cell-cycle progression) NAT1 & NAT2 (N-acetyltransferase) GSTM1 (glutathione s-transferase mu-1)
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Aromatic amines and acetylation
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Acetylation is one of the conjugation pathways of Phase II liver detoxification. Eliminates excess histamine, serotonin, Sulfa drugs, PABA, sulphur amides, p-amino salicylic acid, aniline, hydrazines Many carcinogenic aromatic amines undergo catalysis by N-acetyltransferases Cigarette smoke 4-aminobiphenyl (ABP) β-napthylamine (BNA) SNPs in the genes for these enzymes associated with reduced ability to acetylate aromatic amines and other toxins. NAT1 & NAT2 polymorphisms: Slow vs rapid acetylators
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GSTM1
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One of the enzymes responsible for conjugation of glutathione for detoxification Null genotype prevalent in those with bladder cancer, suggesting decreased glutathione function
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Diet & Meds
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High fat diet has been associated with increased risk High coffee intake associated with increased risk Genistein is being studied as a chemopreventative agent Role of NSAIDS and Cox-2 inhibitors unclear Some evidence of risk REDUCTION pioglitazone/Actos Increased risk associated with 1 year or more of use Consumption of Aristolochia fangchi, a Chinese herb found in some weight loss formulas leads to bladder cancer due to aristocholic acid.
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Other smoking related illnesses:
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COPD Lung cancer
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Bladder CA
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Non-muscle invasive/superficial: 70% Muscle invasive Metastatic Pelvic lymph nodes, liver, lung, bone, adrenal gland
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Grading
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Grade 1: well differentiated Grade 2: moderately differentiated Grade 3-4: poorly differentiated or undifferentiated
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Staging
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TNM method (Tumor, Nodes, Metastasis) T (primary tumor) staging Ta: papillary, epithelium confined Tis: CIS (carcinoma in situ): noninvasive flat carcinoma T1: lamina propria invasion T2a: tumor has grown into the inner half of the muscle layer T2b: tumor has grown into the outer half of the muscle layer T3a: microscopic perivesical fat extension T3b: macroscopic perivesical fat extension T4a: invasion of pelvic viscera (prostatic stroma, rectum, uterus, and/or vagina) T4b: invasion extends to the pelvic sidewall, abdominal wall, or bony pelvis N (regional lymph node) staging NX: nodes cannot be assessed N0: no regional node spread N1: single node, 2, <5cm or multiple nodes 5cm M (distant metastasis) staging MX: cannot be determined M0: no metastasis M1: distant metastasis
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Stage grouping
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Stage grouping Stage 0is: Tis, N0, M0 Stage I: Ta-T1, N0, M0 Stage II: T2, N0, M0 Stage III: T3a-T4a, N0, M0 Stage IV: T4b, N0, M0 or any T, N 1,2,3, M0 or any T, any N, M1
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Imaging
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papillary tumor carcinoma in situ CIS
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Risk of recurrence
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CIS: 50-90% Ta low grade: 50-70% Ta high grade: 60% T1 high grade: 70-80% Risk of recurrence in upper tracts: 2-4%
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5 year survival by stage
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I: 85-96% II: 55-65% III: 38-59% IV: 15-27%
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Risk of progression
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CIS: >50% Ta low grade: 5-10% Ta high grade: 15-40% T1 high grade: 30-50%
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Bladder CA presentation
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Painless hematuria (gross or microscopic) is the classic initial presentation. Irritative voiding symptoms may also be presenting symptoms (dysuria, urgency, frequency) Symptoms are often intermittent Dx often delayed due to similarity of symptoms to benign disorders UTI IC (interstitial cystitis) Prostatitis Kidney stones Delays lead to worse prognosis due to more advanced stages Delayed dx has been shown to account for the poorer survival in women than men
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Hematuria
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Intermittent Gross Likelihood increases when gross vs microscopic Painless Present throughout micturition
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Pain
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Typically a painless presentation If present, usually the result of locally advanced or metastatic tumors
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Voiding symptoms
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Most common in patients with carcinoma in situ (CIS) May result from Functional decrease in bladder capacity Detrusor overactivity (OAB) Invasion of the trigone Obstruction of bladder neck or urethra Irritative Frequency (daytime or nocturnal) Urgency Dysuria Urge incontinence Obstructive Straining Intermittency Nocturia Weak force of stream (FOS) Sense of incomplete emptying
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Constitutional symptoms
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Fatigue Weight loss Anorexia
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PE
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Often unremarkable. Abnormalities more often in advanced cases. Abdominal exam Suprapubic region for masses Nodularity in periumbilical region in advanced lesions involving the dome of the bladder Perform digital rectal exam (DRE) in males and pelvic exam in females Pelvic mass: usually advanced disease Indurated prostate with prostatic invasion. Usu with bladder neck or prostatic urethra involvement. Attempt to palpate the base and lateral walls of the bladder for induration and/or fixation Examine urethra for frank bleeding Adenopathy Inguinal Para-aortic LN enlargement on abdominal exam with hepatic metastases
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Diagnosis
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The presence of otherwise unexplained hematuria is a urothelial cancer (esp if age >40) until proven otherwise. Goal of diagnostic evaluation is to determine the diagnosis, site, extent of cancer, and presence/absence of muscle invasive disease. Includes: Urinalysis with microscopy: looking for RBCs Renal function tests (BUN, creatinine): may indicate renal impairment secondary to obstruction Liver function tests: may be abn with metastasis Cystourethroscopy/cystoscopy Urine cytology (specimen typically collected at time of cysto): high specificity, more sensitive for high grade tumors or CIS (sensitivity 50%, specificity 96%) Upper tract imaging CT abdomen/pelvis with urography (w & w/o contrast) AKA CT urogram * Gold standard IVP (intravenous pyelography) PLUS nephrograms OR renal US (largely replaced by CT) Contrast MRI can be used in patients allergic to iodinated contrast
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Cystoscopy
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Gold standard for initial dx and staging In office procedure done with a flexible cystoscope Minimal risks include bleeding and infection Any visible tumor or suspicious lesion is either biopsied in office or resected transurethrally under anesthesia to determine histology and depth of invasion into submucosa and muscle layers
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CT urogram
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Abdomen & pelvis With and without contrast Includes delayed images to identify filling defects May demonstrate extravesical extension nodal involvement in pelvis or retroperitoneum visceral/pulmonary/osseous METS tumor involvement or obstruction of upper tract
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Treatment: surgical
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Primary tx for bladder cancer is surgical Transurethral resection of bladder tumor (TURBT) Bladder biopsy Can be both diagnostic and therapeutic (for non-muscle invasive tumors) Fulguration
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Surgical tx
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Radical cystectomy Initial therapy for muscle invasive tumors Involves removal of bladder and pelvic lymph nodes. prostate and seminal vesicles uterus, ovaries, fallopian tubes, and anterior vagina Sometimes spared in those wishing to preserve sexual or reproductive function Occasionally needed for recurrent T1 high grade tumors or CIS that has failed to respond to intravesical therapy Partial cystectomy Preserves bladder and maintains potency Survival similar to radical cystectomy (retrospective data) Tx of choice for bladder pheochromocytoma. May be indicated in urachal adenocarcinoma and non-urologic cancers invading the bladder by local extension
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Intervesical Tx
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Treatments instilled directly into the bladder via a catheter Indicated for stage Ta, T1, or CIS. Not effective for stage T2-T4 or non-urothelial tumors. 3 main indications Eradication of CIS with or without associated papillary tumor Eradication of residual tumor after incomplete resection To reduce recurrence and progression in completely resected tumors Types: Chemotherapy Mitomycin C Thiotepa Doxorubicin, etc. Immunotherapy BCG (Bacillus Calmette-Guerin) Interferon, etc.
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Comparison of chemotherapy vs BCG
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BCG reduces tumor recurrence and progression. Intravesical chemotherapy reduces recurrence, but does not alter progression. Maintenance BCG improves long term results, where maintenance chemotherapy offers no advantage. BCG is superior to intravesical chemo for treating CIS and high grade tumors. One dose of intravesical chemo may be used within 24 hours of TURBT in the absence of bladder perforation BCG should never be given within 2 weeks of TURBT BCG can be more toxic than chemo.
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Tx BCG
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Attenuated live bacillus vaccine (Mycobacterium bovis) MOA: stimulates the body's immune system to destroy tumor cells. May also have direct inhibitory effect on tumor cell invasion. Immune response peaks during 6th instillation of the initial course and during the 3rd instillation of subsequent courses.
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BCG complications
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Low grade side effects: cystitis, dysuria, hematuria, malaise, fatigue, low grade fever BCG sepsis Fever typically >102 Emergent situation
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Treatment: systemic chemotherapy
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Platinum based drug regimens Metastatic disease (stage IV) Neoadjuvant or adjuvant therapy for invasive disease (stage II/III) MVAC (mitomycin, vinblastine, adriamycin, cisplatin) Common s/e: mucositis, renal toxicity, myelosuppression, sepsis Overall response rate 40-50% Gemcitabine and cisplatin Common toxicity: myelosuppression Overall response rate similar to MVAC
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Monitoring
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Non muscle invasive Cysto q3mo x 2 years, then q6mo x 2 years, then annually Upper tract surveillance q1-2 years Muscle invasive LFT, creatinine, electrolytes, CXR q6-12mo Collective system imaging at baseline and q2 years Imaging of abdomen, pelvis, and upper tracts q3-6mo x 2 years, then as clinically indicated Cytology q6-12mo w or w/o urethral wash cytology
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ND treatment basics
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Reduce exposure to carcinogens Support detoxification pathways for enhanced elimination of carcinogens Glutathione Acetylation General emunctory support Provide antioxidant/anti-inflammatory/anti-cancer support
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Treatment: basics
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Urogenous contact hypothesis: increase in total fluid intake can dilute the urine concentration, increase frequency of urination, and reduce the contact time of potential carcinogens in urine with the bladder urothelium, leading to decreased risk of bladder cancer. Reduce carcinogenicity of urine: exposure to toxic chemicals in the environment are the biggest risk associated with bladder cancer Reduce urine exposure time to the bladder lining: the longer these carcinogens are in contact with the bladder epithelium, the higher the risk of developing cancer
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Smoking cessation
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STOP SMOKING Many protocols Individual or group counseling Telephone counseling and quitlines 1-800-QUIT-NOW or www.quitnow.net/oregon Habit replacement Chewing is self soothing: toothpicks, chewable herbs (dried citrus peel, pinch of mint) Ear seeds/auriculotherapy for cravings Acupuncture Botanicals Lobelia (10% of your formula) in a nervine tincture (things that promote GABA) California poppy Melissa Passionflower Mullein tea Bacopa: often used for addictions in Ayurveda. This herb is specific for changing patterns. Aromatherapy: black pepper, rosemary, peppermint, Roman chamomile, clary sage, vetiver, spikenard
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Hydration
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Increase water intake in order to dilute the urine and empty the bladder more frequently, reducing exposure to toxins
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Nutriton
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High intake of cruciferous vegetables has been shown to be protective against bladder CA A clinical study found that the risk of bladder CA increased by 37% with high fat intake, by 40% with low fruit consumption, and by 16% with diets low in vegetables Foods for liver detox: Brassicas (cabbage, broccoli, cauliflower, brussel sprouts) Sulfur containing foods (onion, garlic, leek) Citrus fruits H20 soluble fiber Artichoke, avocado, asparagus, red grapes, pomegranates, beets, turmeric, green tea, caraway, apples, tomatoes, peppers, berries, etc.
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Tx basics
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Identify other exposures in the home or workplace Occupation risks as mentioned in previous slide. Follow safety protocols. Chlorinated tap water associated with bladder cancer risk High arsenic levels in drinking water are associated with increased risk
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ND Tx
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Support detoxification pathways Acetylation support: Cofactors: B1, B5, Vitamin C Deficiencies associated: B2, B5, and Vitamin C Glutathione support: NAC (N-acetyl cysteine): 600mg BID to TID Glutathione injections or liposomal oral preparations Milk thistle seeds Lipotropic nutrients: choline, methionine, betaine, B6, folic acid, B12 Selenium Mitochondria support (smoking!) CoQ10 L-carnitine Probiotics Lactobacillus casei: decreases in excretion of mutagens in the urine: 5 billion CFU daily Honey Anti-proliferative, anti-metastatic, activates mitochondrial pathway, induces mitochondrial outer membrane permeability (enhances cytotoxicity), modulates oxidative stress, anti-inflammatory, inhibits angiogenesis
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Nutrient/vitamin support
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Supplementation with a combo of vitamins and zinc decreased tumor recurrence in pts with TCC of the bladder Vitamin A: 40,000 IU B6: 100mg Vit C: 2g --Antioxidant, increases glutathione Vitamin E: 400 IU Zinc: 90mg (supplement with Cu appropriately with this high of a dose Selenium 200mcg daily Antioxidant Promotes glutathione Vitamin D Correct deficiency Worse prognosis and more aggressive forms with lower levels
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Botanicals
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Curcumin Antitumor, antiinflammatory, apoptotic, antioxidant Shown to potentiate the apoptotic and antiproliferative effects of BCG in bladder cancer cells 500-1000mg BID Rhodiola rosea Improvement in cell characteristics; no statistically significant reduction in recurrence Variable doses have been used. 100-300mg TID Cordyceps sinensis and militaris Anti-tumor, anti-inflammatory, immunomodulating Dose: 3-9g daily of aqueous extract Green tea/EGCG Anti-cancer, anti-inflammatory Some conflicting evidence with bladder CA Dose: 3 or more cups per day, 200mg TID of catechins in extract Vaccinium macrocarpon (cranberry) High in polyphenols, quercitin
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Nature Cure
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Detoxification treatments/Emunctory support Sauna/Sweating Hydrotherapy Dry skin brushing Castor oil packs Deep breathing exercises
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Urothelial carcinoma of the ureter and renal pelvis - Epidemiology
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5-10% of renal pelvis tumors 2-5% of urothelial tumors occur in the upper urinary tract Mean age at presentation is 65 yo Incidence is increasing Male > female (3:1) Caucasian > African American (2:1)
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Urothelial carcinoma of the ureter and renal pelvis - risk factors
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Bladder TCC (2-4% lifetime risk of UUT TCC) Stage, grade, multiplicity, ureteral reflux, recurrent CIS after BCG, TCC close to ureteral orifice Contralateral UUT TCC Risk fx shared with bladder CA Cigarette smoking (>/= 3x the risk); only partly declines with smoking cessation Occupational exposure (>/= 4x the risk) Cyclophosphamide Risk factors specific to UUT TCC Balkan nephropathy (100-200x the risk) Analgesic abuse (3.6x the risk) Phenacetin, aspirin, acetominophen, codeine Papillary necrosis (6.9x the risk) 20x the risk with concomitant analgesic abuse Aristocholia fangchi use Lynch II syndrome
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UUT TCC Symptoms
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Often asymptomatic Gross hematuria Dull flank pain Acute renal colic Bone pain
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UUT TCC
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Commonly associated conditions Bladder CA Balkan nephropathy: interstitial nephritis endemic to Balkan countries Lynch II syndrome: familial syndrome predisposing to GI, endometrial, and UUT neoplasms
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UUT TTC PE
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Often unremarkable Weight loss/anorexia CVA tenderness Flank or abdominal mass Labs and Imaging as discussed for Bladder CA
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DDx for filling defects
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SCC, RCC Air (iatrogenic/infectious) blood clot fibroepithelial polyp fungus ball Hemangioma inflammatory lesions (granuloma, malakoplakia, TB) Inverted papilloma Radiolucent calculus Benign tumors (leiomyoma, neurofibroma, cholesteatoma Renal papilla Sloughed papilla More..
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Prognosis
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5 year survival based on grade Grade 1-2: 40-87% Grade 3: 0-33% 5 year survival based on stage Ta, T1, Tis: 60-90% T2: 43-75% T3: 16-33% T4: 0-5%
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Treatment
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Nephroureterectomy is gold standard Topical therapy (BCG, Mitomycin C, thiotepa) Instilled via percutaneous nephrostomy, external ureteral catheter, or into bladder with indwelling ureteral stent Typically given for large, multifocal, or residual tumor burden Benefit has not been consistently demonstrated
