urinary bladder cancer

1. Carcinoma Urinary
Bladder
Pushpa Lal Bhadel
FCPS Resident
Department of Surgery
Kathmandu Model Hospital
Moderator
Dr. Ashok Kunwar

2. Anatomy of urinary bladder
Extraperitoneal structure located in true pelvis
Bladder divided into
oApex: pointing towards symphysis pubis, connected to
umbilicus by median umbilical ligament
oBody: between apex and fundus, above ureteral orifices
oFundus/Base: located posteriorly, triangular in shape, consist
of trigone and bladder neck
oNeck: formed by convergence of fundus and two inferolateral
surfaces, continuous with urethra
Primary function: reservoir of urine

5. Anatomy cont.
Lined by rough, trabeculated transitional cell
epithelium except at trigone
Urethra arise from neck of bladder
Surrounded by internal urethral sphincter
As bladder is filled it becomes ovoid in shape and
extends superiorly into abdominal cavity
Contraction is facilitated by detrusor muscle

6. Anatomy cont.
Relations:
Superior: parietal peritoneum
Anterior and lateral wall: pelvic fat, pubis
anteriorly
Superolateral: Sigmoid colon
Posterior:
oMale: rectum
oFemale: vagina and uterus

7. Support of bladder
At posterolateral bladder neck: condensation of fascia
join the prostatic fascia
Puboprostatic ligaments: condensation of anterior
endopelvic fascia from prostate to periosteum in pubis
bone
Median and lateral umbilical ligaments: urachus and
obliterated hypogastric arteries together with folds of
peritoneum

8. Blood supply
Arterial supply:
Superior vesical artery: upper
part in both males and females
Lower part:
oMales: Inferior vesical artery
oFemales: vaginal artery
All are branches of anterior
division of Internal iliac artery

9. Blood supply cont.
Venous drainage:
Male: vesical and prostatic venous plexus to internal
iliac veins and internal vertebral veins
Female: vesical and uterovaginal plexuses draining to
internal iliac vein

10. Lymphatics
External iliac lymph nodes: superolateral aspect of the
bladder
Internal iliac, sacral and common iliac nodes: the
neck and fundus of UB

11. Nerve supply
 Complex neurological control
 Sympathetic –
o Hypogastric nerve (T12 – L2).
o It causes relaxation of the detrusor muscle, promoting urine retention.
 Parasympathetic –
o Pelvic nerve (S2-S4).
o Increased signals from this nerve causes contraction of the detrusor muscle,
stimulating micturition.
 Somatic –
o Pudendal nerve (S2-4).
o Innervates the external urethral sphincter, providing voluntary control over
micturition

12. Nerve supply cont.

13. Introduction
Bladder cancer is a global disease
9th most common cancer worldwide 1
2nd after prostate cancer in GU system
Urothelial (previously known as transitional cell) carcinoma:
oUnited States and Western Europe
o90 % of bladder cancer
oCommon histological variant in Nepal 2
Non-urothelial histologies:
oMiddle East and other areas due to prevalence of schistosomiasis.
1 Ploeg M, Aben KK, Kiemeney LA. The present and future burden of urinary bladder cancer in the world. World J Urol. 2009;27(3):289-93.
2 Joshi HN, Makaju R, Karmacharya A, Karmacharya RM, Shrestha B, Shrestha R et.al. Urinary Bladder Carcinoma: Impact of Smoking, Age and its
Clinico-Pathological Ppectrum. Kathmandu Univ Med J 2013;44():292-295

14. Epidemiology
Incidence:
Europe: 118,000 cases and 52,00 deaths in 2012 1
US: approx. 80,000 new cases and 18,000 deaths every year 2
In developed regions such as North America and Europe,
bladder cancer is predominantly urothelial
2 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.
1 Marcos-gragera R, Mallone S, Kiemeney LA, et al. Urinary tract cancer survival in Europe 1999-2007: Results of the population-based study
EUROCARE-5. Eur J Cancer. 2015;51(15):2217-2230.

15. Epidemiology cont.
Incidence in Nepal:
Incidence of ca bladder in Nepal 1
oMale: 4.8%
oFemale: 1.4%
Acc. To WHO data published in 2018: 2
oBladder cancer deaths in Nepal: 309 or 0.19% of total deaths
oAge adjusted death rate: 1.62/100,000
oNepal ranks 118th in the world
2 https://www.worldlifeexpectancy.com/nepal-bladder-cancer
1 Poudel KK, Huang Z, Neupane PR, Steel R, Poudel JK. Hospital-Based Cancer Incidence in Nepal from 2010 to 2013. Nepal J Epidemiol.
2017;7(1):659-665.

16. Epidemiology cont.
Gender, Racial and Age differences:
 Urothelial cancer is a disease of aging and environmental exposure
 Median age at diagnosis of 69 yrs. in men and 71 in women1
 Age specific incidence rates rise gradually around 50-54 yrs. in males
and females
 Sharper increase in males age 60-64 yrs.
 3/4th cases occur in males
oHigher incidence (9/100,000)
 Females (2.2/100,000)
1 Scosyrev E, Noyes K, Feng C, Messing E. Sex and racial differences in bladder cancer presentation and mortality in the US. Cancer. 2009;115(1):68-74.

17. Epidemiology cont.
Gender, Racial and Age differences:
Gender difference have been explained by difference in sex
steroid production and receptor expression
Women with: older age of menarche (≥15), parity, use of
estrogen or progesterone therapy have decreased risk
(Daugherty et al., 2013)
Women are likely to have more advanced and less favorable
prognosis

18. Epidemiology cont.
Gender, Racial and Age differences:
Common among Caucasian Americans
o1.5 x that of African-Americans
o2 x that of Hispanic Americans
o6 x that of Native Americans
African-American patients are more likely to have muscle-
invasive
African-American women have increased rate if non-urothelial
histology

19. Risk factors
Like skin and lungs, bladder comes in constant contact with
environment
Genetics:
 Genes associated :
oN-acetyltransferase 2 (NAT2)
oDeletion of glutathione S-transferase µ (GSTM1)
 Ability to metabolize aromatic amines found in cigarette smoke
 NAT2 detoxifies nitrosamines
 Activation of oncogenes: ras, c-erbB-1 and -2 and transcription factors
like E2F3
 Inactivation of tumor-suppressor genes: p53, p21, p16 and RB gene

20. Risk factors cont.
Hereditary:
 First degree relatives: 2 fold increased risk
 Not associated with Mendelian inheritance pattern
 Patient with Lynch syndrome: increased risk of developing urothelial
cancer
 Among mismatch repair gene, MSH2 mutation carriers (van der Post
et al., 2010)

21. Risk factors cont.
Smoking:
 30-40% of all urothelial carcinoma
 Aromatic amines are primary carcinogens
 Dietary beta carotene and vitamin supplementation (Vit-C,E and
folate) have protective role
 Smoking cessation for 1-3 yrs. have 2.6 RR
 1.1 RR among those having left smoking for 15 yrs.
 Survival benefit of quitting after diagnosis is controversial and
increases risk of second primary cancer

22. Risk factors cont.
Body mass index:
 Increasing BMI: major risk factor for bladder cancer development
(Choi et al., 2018; Koebnick et al., 2008; Sun et al., 2015; Zhao et al.,
2017)
 Strong association between smoking and obesity
 Obesity
oAttenuates prognosis
oIncreased risk of recurrence and shorter time interval of recurrence
 Mechanism: insulin resistance, chronic hyperinsulinemia, increased
bioavailability of steroid hormones and localized inflammation

23. Risk factors cont.
Occupational risk:
 Accounts for 5-10% of all bladder cancer
 Occupations directly related with aromatic amines like tobacco, dye
and rubber workers, hairdressers, painters and leather workers
 Works associated with polycyclic aromatic hydrocarbons like chimney
sweeps, nurses, waiters, alumni workers, petroleum workers and
seamen (Cumberbatch et al.,2015)

25. Risk factors cont.
Medical conditions:
 Potential to increase ca risk directly or indirectly
 Pt with neurogenic bladder and spinal cord injuries: chronic
indwelling catheters
oRisk of SCC bladder
 Bladder calculi, urinary outflow obstruction, recurrent UTIs and
inflammation: risk of development of keratinizing squamous
metaplasia (Ho et al., 2015; West et al. 1999)
 Malignant potential of bladder exstrophy (Rieder et al., 2006;
Smeulders and Woodhouse, 2001)

26. Risk factors cont.
Schistosomiasis:
Contributor for disease in tropical countries
Schistosomes are parasitic blood flukes having mammalian
hosts, freshwater snail as intermediate hosts
S. haematobium :
oLives in venules of human UB causing irritation and tissue fibrosis
oPromotes susceptibility to other bladder ca
oLinked to SCC bladder

27. Risk factors cont.
Indirect medical risk
factors:
Pioglitazone
Radiation
Chemotherapy
Environmental pollution
Diet:
Fluids
Food
Dietary supplements

28. WHO Classification
Non-Invasive urothelial neoplasia:
 Hyperplasia (flat and papillary) Reactive atypia
 Atypia of unknown significance
 Urothelial dysplasia (low-grade intraurothelial neoplasia)
 Urothelial carcinoma in situ (high-grade intraurothelial neoplasia)
 Urothelial papilloma
 Urothelial papilloma, inverted type
 Papillary urothelial neoplasm of low malignant potential
 Noninvasive low-grade papillary urothelial carcinoma
 Noninvasive high-grade papillary urothelial carcinoma
Invasive urothelial neoplasia:
 Lamina propria invasion
 Muscularis propria (detrusor muscle) invasion

29. Clinical features
Intermittent, gross, painless hematuria
Present throughout micturition
Incidence of malignancy:
oMicroscopic hematuria1: 2-5%
oGross hematuria2: 20.4%
Clot formation and clot urinary retention
1 Grossfeld GD, Litwin MS, Wolf JS, et al. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice
policy--part I: definition, detection, prevalence, and etiology. Urology. 2001;57(4):599-603.
2 Grossman HB, Messing E, Soloway M, et al. Detection of bladder cancer using a point-of-care proteomic assay. JAMA. 2005;293(7):810-6.

30. Clinical features cont.
 Constant pain: due to locally advanced metastatic tumors
 Flank pain: tumor obstructing the ureter
 Suprapubic pain: invading the peri vesical soft tissues and nerve or
causing BOO, urinary retention
 Hypogastric, rectal and perineal pain: invasion into obturator fossa,
perirectal fat, presacral nerves or urogenital diaphragm
 Bone pain: bone mets
 Persistent headache or disordered cognitive fxn: intracranial or
leptomeningeal mets

31. Clinical features cont.
Voiding symptoms: present in carcinoma insitu (CIS)
oIrritative symptoms: frequency, urgency, dysuria, urge incontinence
oObstructive symptoms: straining, intermittent stream, nocturia,
decreased force of stream, feeling of incomplete emptying
Constitutional symptoms: fatigue, weight loss, anorexia, failure
to thrive
Malignant cystitis: dysuria, suprapubic pain and frequency
oPresent in CIS

32. Clinical features cont.
Physical examination:
 Unremarkable in most patient
 Solid pelvic mass in advanced case
 DRE in men: induration of prostate gland
 Bimanual examination of vagina and rectum in women
 Nodularity in periumbilical region in advanced diseases
oAdenocarcinoma, urachal involvement

34. Investigation
Urinalysis :
 Urine dipstick for hematuria
oSensitivity: 91-100%, specificity: 65% (Liu et al., 2016)
 Specific gravity
 Urine cytology: 1
oEither by voiding or bladder wash at the time of cystoscopy
oPoor sensitivity 34% for low grade tumors
1 Lotan Y, Roehrborn CG. Sensitivity and specificity of commonly available bladder tumor markers versus cytology: results of a comprehensive literature
review and meta-analyses. Urology. 2003;61(1):109-18.

36. Investigation cont.
Urine based markers:
oNuclear matrix proteins (NMP22) or mini-chromosome
maintenance (MCM), micro RNA fragments
oSensitivity: 50-80%; specificity: 70-90% 1
oImmunocyt
oCxbladder
1 Chou R, Gore JL, Buckley D, et al. Urinary Biomarkers for Diagnosis of Bladder Cancer: A Systematic Review and Meta-analysis. Ann Intern Med.
2015;163(12):922-31.

37. Investigation cont.
Cystourethroscopy:
Gold standard for initial diagnosis and staging
Always to be performed in pt. 35 yrs. and older and hematuria
White light vs blue light
Approach:
oAny visible tumor or suspicious lesion: biopsied or resected
transurethrally to determine the histology and depth of invasion.
oPt. with a positive urine cytology & negative cystoscopic findings, biopsy
of apparently normal appearing urothelium, prostatic urethra, and
selective catheterization for urine specimens for cytology from the
upper tract.

39. Investigation cont.
Urinary tract imaging:
 IVP:
oAppropriate choice for microscopic and
gross hematuria
oMore sensitive for smaller lesion of
ureter and renal pelvis
oOnly 60% of known bladder tumors
could be detected on IVU
Fig. Intravenous urography showing a filling defect in the
region of the right ureteric orifice.

40. Investigation cont.
Ultrasonography:
o Can confirm presence of a soft tissue
mass
o Cannot determine depth of invasion,
extravesical extension or nodal status
o Helpful in evaluating upper tract for
renal parenchymal diseases,
hydronephrosis
o Sensitivity: 93.24%, specificity: 100%,
positive predictive value: 100%, and
negative predictive value: 16.6% 1
Fig. Multiple transitional cell carcinomas of the bladder in
a 74-year-old man. Ultrasound of the bladder in
transverse plane shows multiple papillary tumors
(arrowheads) in the bladder.
1 Gharibvand MM, Kazemi M, Motamedfar A, Sametzadeh M, Sahraeizadeh A. The role of ultrasound in diagnosis and evaluation of bladder tumors. J Family Med Prim Care.
2017;6(4):840-843.

41. Investigation cont.
Computed tomography scan:
oCT with/without contrast for all bladder ca pts.
oCan demonstrate:
oExtravesical extension, nodal involvement in pelvis or retroperitoneum,
visceral, pulmonary or osseous mets and tumor involvement or
obstruction of upper urinary tract
oMay miss <1mm size tumors over trigone or dome
oCannot differentiate depth of bladder wall invasion (mucosal vs
lamina propria vs muscularis propria)
oSensitivity of 79-89.7%; specificity of 91–94.7% 1
1 Knox MK, Cowan NC, Rivers-Bowerman MD, Turney BW: Evaluation of multidetector computed tomography urography and ultrasonography for diagnosing bladder cancer. Clin
Radiol 2008;63:1317–1325

42. Fig. CT scan images of the abdomen (A) and pelvis (B) demonstrating a locally advanced
bladder tumor (arrows, right panels) and obstructing both ureters (arrowheads, left panel)

43. Investigation cont.
 Magnetic resonance imaging:
oFor staging of invasive or locally advanced disease
oEsp. at base and dome of bladder
oGadolinium-enhanced MRI superior to CT:
• To detect superficial and multiple tumors, extravesical tumor extension and surrounding
organ invasion
oAccuracy of MRI in overall staging of bladder cancer varies from 60 to 85%,
whereas that of local staging varies from 73 to 96% 1
oAccuracy of MRI in the staging of nodal metastases based on anatomic size
criteria ranges from 73 to 90% 2
1 Tekes A, Kamel IR, Imam K, Chan TY, Schoenberg MP, Bluemke DA: Dynamic MRI of bladder cancer: evaluation of staging accuracy. AJR Am J
Roentgenol 2005;184: 121–127
2 Barentsz JO, Jager GJ, Van Vierzen PB, Witjes JA, Strijk SP, Peters H: Staging urinary bladder cancer after transurethral biopsy: value of fast dynamic
contrast-enhanced MR imaging. Radiology 1996;201: 185–193.

44. Investigation cont.
Imaging for metastatic imaging:
oOnce diagnosis and clinical staging established
oRecommended imaging of chest either CxR or CT thorax
oBone scan and brain imaging for symptomatic patients
oPositron emission tomography (PET)/CT: suspicious LN
involvement

45. Investigation cont.
Other investigations:
Hemoglobin level
Serum electrolytes
Renal function test
Blood Grouping

46. Tumor staging and grading

47. Tumor staging and grading cont.

48. Tumor staging and grading cont.

49. Management

50. Management cont.
TURBT:
 Adequate resection with muscle specimen
 Muscle may be omitted in cases of documented low grade Ta disease
 In suspicious/known case:
 Bx adjacent to papillary tumor
 Consider prostate urethral Bx
 Papillary appearing tumor(non-muscle invasive):
• Early repeat TURBT (within 6 weeks):
o Incomplete resection
o No muscle in original specimen
o Large ≥3 cm or multifocal lesion
o Any T1 lesion

51. Fig. A) Broad-based papillary lesion.
B) Resection of lesion with loop electrocautery.
C) Depth of resection to detrusor muscle.
A B C

52. Management cont.
Transurethral resection for sessile or invasive
appearing tumor (likely muscle invasive)
• Repeat TURBT if
oPrior resection did not include muscle
oAny T1 lesion
oFirst resection does not allow adequate staging
oIncomplete resection

53. Complications
TURBT:
oMinor bleeding
oIrritative symptoms
oUncontrolled hematuria
oClinical bladder perforation
oTUR syndrome
oUO obstruction

54. Management cont.

55. Management cont.
Intravesical chemotherapy:
All patient undergoing TURBT
Within 6 hrs. of surgery: decrease recurrence by 35%
Agents commonly used: Mitomycin C, bacille Calmette-
Guérin(BCG), Gemcitabine
Other agents: Epirubicin, Valrubicin, Docetaxel, Gemcitabine,
Interferon
Newer immunotherapeutic agents:
oKeyhole-limpet hemocyanin (KLH) , Bropirimine, Mycobacterial cell wall
DNA extract, Thiosulfinate extracts of garlic, IL-12

56. Management cont.

57. Management cont.

58. Management cont.
Neoadjuvant chemotherapy :
 MVAC (Methotrexate, Vinblastine, doxorubicin(Adriamycin), Cisplatin)
and GC (Gemcitabine and Cisplatin)
 Improves overall survival by 5%-7%.

59. Management cont.
Partial cystectomy:
 cT2 muscle invasive disease with solitary lesion
 Tumor away from ureteral orifices
 No CIS as determined by random biopsies
 Should be given with neoadjuvant cisplatin based combination
chemotherapy
 Bilateral pelvic lymphadenectomy should be performed and include
common, internal iliac, external iliac and obturator nodes

60. Management cont.
Radical cystectomy/cystoprostatectomy
 In non-muscle invasive disease: reserved for high grade cT1
 Cystectomy should be done within 3 mths if diagnosis if no therapy is
intended
 Primary treatment: cT2, cT3 and cT4a disease
 Highly selective in patient with cT4b
 Should be given with neoadjuvant cisplatin based combination chemotherapy
for cT2-cT4a disease
 Bilateral pelvic lymphadenectomy should be performed and include common,
internal iliac, external iliac and obturator nodes

61. Management cont.
Urinary diversion:
 Conduit urinary diversion
 Continent cutaneous reservoir
oIleocecal valve (Indiana)
oFlap valve (Penn, Lahey)
oIntussuscepted nipple valve (Koch)
 Orthotopic neobladder

62. Types of Urinary Diversion
ILEAL CONDUIT
(incontinent
diversion to
skin)
CONTINENT
CUTANEOUS
RESERVOIR
(continent
diversion to
skin)
ORTHOTOPIC
NEOBLADDER
(continent
diversion to
urethra)
Figures from www.clevelandclinic.org/health/health-info/docs

63. Complications
Cystectomy:
 Septic complications from urine
leak or bowel leak
 Wound dehiscence
 Pulmonary embolism
 Hemorrhage
 Electrolyte abnormalities
 Bone demineralization
 Mucus production
 Stone formation
 Chronic infection
 Diarrhea
 Vitamin B-12 def.
 Increased rectal cancer

64. Management cont.

65. Management cont.

66. Management cont.

67. Management cont.

68. Management cont.

69. Management cont.
Radiation therapy:
 EBRT given at 60 Gy over 4- to 6-week period
 EBRT has very good response in short term for pTa or pT1
 Not effective in long run for Ta and CIS:
 90% recurrence in 5yrs
 No studied extensively in NMI cancer

70. Follow-up

71. Follow-up cont.

72. Prognosis
 Depends on type and stage of bladder cancer
 5-year survival rate for bladder cancer not spread beyond the inner layer of
bladder: 96%
 5-year survival rate for invasive disease limited to bladder: 70%
 5-year survival rate for disease extending to LN or organs: 36%
 5-year survival rate for patient with distant metastasis: 5%

73. References
 Sabiston Textbook pf Surgery, 20th edition
 Schwartz’s Principles of Surgery. 10th edition
 Bailey & Love’s Short practice of Surgery, 27th edition
 Campbell-Walsh-Wein Urology, 12th edition
 https://www.nccn.org/professionals/physician_gls/default.aspx