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How to classify bladder tumors? [TU 2071]
Transitional Cell Carcinoma
Nontransitional Cell Carcinomas
- - Adenocarcinoma
- - Squamous cell carcinoma
- - Undifferentiated carcinomas
- - Mixed carcinoma
- - Rare Epithelial and Nonepithelial Cancers - villous adenomas, carcinoid tumors, carcinosarcomas, and melanoma
Etiology of squamous cell carcinoma?
Chronic infection, vesical calculi, or chronic catheter may also be associated with bilharzial infection owing to Schistosoma haematobium
Risk Factors for bladder cancer?
- Cigarette smoking -alpha- and betanaphthylamine, which are secreted into the urine of smokers
- Workers in the chemical, dye, rubber, petroleum, leather, and printing industries are at increased risk. Specific occupational carcinogens include benzidine, beta-naphthylamine, and 4-aminobiphenyl
- Exposure to arsenic in drinking water increases risk.
- Ingestion of artificial sweeteners
- Physical trauma to the urothelium induced by infection, instrumentation, and calculi increases the risk of malignancy
Definition of non-muscle-invasive bladder cancer?
- Papillary tumours confined to the mucosa and invading the lamina propria are classified as stage Ta and T1.
- Flat, high-grade tumours that are confined to the mucosa are classified as CIS (Tis).
- These tumours can be treated by transurethral resection of the bladder (TURB) and/or intravesical instillations and are therefore grouped under the heading of NMIBC for therapeutic purposes.
- However, molecular biology techniques and clinical experience have demonstrated the highly malignant potential of CIS and T1 lesions.
- The terms “NMIBC” and older one “superficial BC” are therefore suboptimal descriptions.
What are the layers of urinary bladder?
- Mucosa - Transitional epithelium and lamina propria
- Muscular layer
TNM staging of bladder carcinoma? [TU 2069/1 ,68/2]
- T - Primary tumour
- TX Primary tumour cannot be assessed
- T0 No evidence of primary tumour
- Ta Non-invasive papillary carcinoma
- Tis Non invasive ‘flat tumour’
- T1 Tumour invades subepithelial connective tissue
- T2 Tumour invades muscle
- T2a Tumour invades superficial muscle (inner half)
- T2b Tumour invades deep muscle (outer half)
- T3 Tumour invades perivesical tissue
- T3a Microscopically
- T3b Macroscopically (extravesical mass)
- T4 Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall
- T4a Tumour invades prostate, uterus or vagina
- T4b Tumour invades pelvic wall or abdominal wall
- N - Lymph nodes
- NX Regional lymph nodes cannot be assessed
- N0 No regional lymph node metastasis
- N1 Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, presacral or external iliac) [@ HOPE]
- N2 Metastasis in multiple lymph nodes in the true pelvis (hypogastric, obturator, external iliac, or presacral)
- N3 Metastasis in common iliac lymph node(s)
- M - Distant metastasis
- MX Distant metastasis cannot be assessed
- M0 No distant metastasis
- M1 Distant metastasis
Histological grading of bladder carcinoma?
- 1973 WHO grading
- Urothelial papilloma
- Grade 1: Well differentiated
- Grade 2: Moderately differentiated
- Grade 3: Poorly differentiated
- 2004 WHO grading system [papillary lesions]
- Urothelial papilloma (completely benign lesion)
- Papillary urothelial neoplasm of low malignant potential (PUNLMP)
- Low-grade (LG) papillary urothelial carcinoma
- High-grade (HG) papillary urothelial carcinoma
1973 WHO Grade 1 carcinomas have been reassigned to papillary urothelial neoplasm of low malignantpotential (PUNLMP) and low-grade (LG) carcinomas in 2004 WHO classification, and Grade 2 carcinomas to LGand high-grade (HG) carcinomas. All 1973 WHO Grade 3 carcinomas have been reassigned to HG carcinomas.
Histopathology of bladder carcinoma?
Ninety-eight percent of all bladder cancers are epithelial malignancies, with the predominant majority being transitional cell carcinomas (TCCs). About 5% are adenocarcinomas or squamous cell carcinomas
What are the features of normal urothelium?
- The normal urothelium is composed of 3–7 layers of transitional cell epithelium resting on a basement membrane composed of extracellular matrix (collagen, adhesive glycoproteins, glycosaminoglycans).
- The epithelial cells vary in appearance:
- The basal cells are actively proliferating cells resting on the basement membrane; the luminal cells, perhaps the most important feature of normal bladder epithelium, are larger umbrella-like cells that are bound together by tight junctions
What is carcinoma in situ?
Carcinoma in situ (CIS) is a flat, high-grade, non-invasive urothelial carcinoma. The urothelium lacks the normal cellular polarity, and cells contain large, irregular hyperchromatic nuclei with prominent nucleoli It can be missed at cystoscopy or be considered as an inflammatory lesion if it is not biopsied. CIS is often multifocal and can occur in the bladder, but also in the upper urinary tract, prostatic ducts, and prostatic urethra.
- Classification of CIS into clinical type:
- • Primary: isolated CIS with no previous or concurrent papillary tumours and no previous CIS;
- • Secondary: CIS detected during follow-up of patients with a previous tumour that was not CIS;
- • Concurrent: CIS in the presence of any other urothelial tumour in the bladder.
Clinical features of Bladder carcinoma?
- Symptoms –
- Painless Hematuria is the most common presenting symptom
- Intermittent hematuria rather than constant.
- Symptoms of vesical irritability: frequency, urgency, and dysuria.
- Irritative voiding symptoms seem to be more common in patients with diffuse CIS.
- Ta, T1 tumours do not cause bladder pain and rarely present with lower urinary tract symptoms. CIS might be suspected in patients who do complain of these symptoms, particularly if they are refractory to symptomatic treatment.
- Signs –
- Patients with large-volume or invasive tumors may be found to have bladder wall thickening or a palpable mass—findings that may be detected on a careful bimanual examination under anesthasia.
- If the bladder is not mobile, that suggests fixation of tumor to adjacent structures by direct invasion.
- Hepatomegaly and supraclavicular lymphadenopathy are signs of metastatic disease.
- Lymphedema from occlusive pelvic lymphadenopathy may be seen occasionally. Patients may also present with back pain or pathologic fracture from bony metastases.
- On rare occasions, metastases can occur in unusual sites such as the skin presenting as painful nodules with ulceration
Laboratory finding in Urinary bladder carcinoma?
- Routine testing –
- The most common laboratory abnormality is hematuria. It may be accompanied by pyuria, which on occasion may result from concomitant urinary tract infection.
- Azotemia may be noted in patients with ureteral occlusion owing to the primary bladder tumor or lymphadenopathy.
- Anemia may be a presenting symptom owing to chronic blood loss, or replacement of the bone marrow with metastatic disease.
- Urinary cytology –
- Exfoliated cells from both normal and neoplastic urothelium can be readily identified in voided urine.
- Larger quantities of cells can be obtained by gently irrigating the bladder with isotonic saline solution through a catheter or cystoscope
Exfoliated urinary molecular markers for the detection of bladder cancer?
It is generally accepted that none of the tests can replace cystoscopy. However, urinary cytology or markers can be used as an adjunct to cystoscopy to detect invisible tumours, particularly CIS
- Bladder tumor antigen (BTA) stat test (Bard Diagnostic Sciences, Inc, Redmond, WA),
- BTA TRAK assay (Bard Diagnostic Sciences, Inc),
- Nuclear Matrix Protein (NMP22) assay, and the NMP22 BladderChek test,
- ImmunoCyt and UroVysion (FISH)
- Cytokeratins .
These tests have been demonstrated to enhance detection of bladder cancer when used either individually or in combination with cytology.
Guidelines for the primary assessment of NMIBC? (EAU Guidelines)
- Patient history should be taken.
- Renal and bladder US may be used during the initial work-up in patients with haematuria.
- At the time of the initial diagnosis of NMIBC, CT urography (or IVU) should be performed only in selected cases (e.g., tumours located in the trigone, multiple- or high-risk tumours).
- Cystoscopy is recommended in all patients with symptoms suggestive of BC. It cannot be replaced by cytology or by any other non-invasive test.
- Cystoscopy should describe all macroscopic features of the tumour (site, size, number and appearance) and mucosal abnormalities. A bladder diagram is recommended (Figure 5.1).
- Voided urine cytology is advocated to predict high-grade tumour before TURB.
- Cytology should be performed on fresh urine with adequate fixation. Morning urine is not suitable because of the frequent presence of cytolysis. However, negative cytology does not exclude a tumour
Role of Imaging in Bladder Carcinoma?
- Imaging is therefore used to evaluate the upper urinary tract and, when infiltrating bladder tumors are detected, to assess the depth of muscle wall infiltration and the presence of regional or distant metastases.
- Computed tomography (CT) urography is used to detect papillary tumours in the urinary tract, which can be seen as filling defects or indicated by hydronephrosis.
- Intravenous urography (IVU) can be an alternative if CT is not available
Fluorescent cystoscopy (photodynamic diagnosis) in Bladder carcinoma?
- It is the new method of tumor visualization.
- Photodynamic diagnosis (PDD) is performed using violet light after intravesical instillation of 5-aminolaevulinic acid (ALA) or hexaminolaevulinic acid (HAL).
- It has been confirmed that fluorescence-guided biopsy and resection are more sensitive than conventional procedures for detection of malignant tumours, particularly for CIS
- Cancer cells with accumulated porphyrin such as 5-aminolevulinic acid or hexaminolevulinate (HAL) are detected as glowing red under the fluorescent light.
Components of disease recurrence and progression score (EORTC GUCG Score)?
European Organization for Research and Treatment of Cancer (EORTC) Genito-Urinary Cancer Group (GUCG)
- Number of tumors
- Tumor diameter
- Prior recurrence rate
- Category - T1 or Ta
- Concurrent CIS
Total score - For recurrence 0-17, For Progression - 0-23
Risk Stratification of bladder carcinoma?
Based on available prognostic factors and particularly data from the EORTC risk tables, the assignment of patients to a specific risk catagory for recurrence or progression is considered crucial for facilitate treatment recommendations -
- Primary, solitary, Ta, G1* (PUNLMP, LG), < 3 cm, no CIS
- All tumours not defined in the two adjacent categories (between the category of low- and high-risk).
- Any of the following:
- • T1 tumour
- • G3** (HG) tumour
- • CIS
- • Multiple and recurrent and large (>3 cm) Ta G1G2 tumours (all conditions must be presented in this point)*
Discuss the various controversies in the management of superficial bladder carcinoma (TCC) having pT1 G III? [TU 2063/2]
Discuss recent management of PUGIII of bladder cancer. [TU 2060]
Management approach of superficial bladder cancer (TCC). [TU 2062/5]
Discuss the treatment of superficial bladder cancer. [TU 2071]
Outline the principles of management of bladder cancer. [TU 2056,64/5, 2063/12, 2061/5]
Discuss the recent trends in the management of pt with bladder carcinoma (TCC) [TU 2060/12]
- Tis - Complete TUR followed by intravesical BCG
- Ta (single, low-to-moderate grade, not recurrent) - Complete TUR
- Ta (large, multiple, high grade, or recurrent) - Complete TUR followed by intravesical chemo- or immunotherapy
- T1 - Complete TUR followed by intravesical chemo- or immunotherapy or radical cystectomy
- T2–T4 - Radical cystectomy, Neoadjuvant chemotherapy followed by radical cystectomy, Radical cystectomy followed by adjuvant chemotherapy, Concomitant chemotherapy and irradiation
- Any T, N+, M+ - Systemic chemotherapy followed by selective surgery or irradiation
Treatment recommendations in Ta, T1 tumours and CIS according to risk stratification?
- Low-risk tumours - One immediate instillation of chemotherapy.
- Intermediate-risk tumours - One immediate instillation of chemotherapy followed by further instillations, either chemotherapy (MMC) for a maximum of 1 year or 1-year full-dose BCG.
- High-risk tumours - Intravesical full-dose BCG instillations for 1-3 years or cystectomy (in highest-risk tumours).
- BCG failures - Radical cystectomy is recommended.
Instruments in TURBT?
- Resectoscope -
- Ellik Bladder evacuator - used to collect chips after TURP and TURBT.
Follow up cystoscopy after TURB?
First cystoscopy - 3 months after TURB in all patients with Ta, T1 tumours and CIS.
If negative, subsequent cystoscopy is advised 9 months later, and then yearly for 5 years in low risk tumors.
If negative for high risk tumors, subsequent cystoscopy and cytology should be repeated every 3 months for a period of 2 years, and every 6 months thereafter until 5 years, and then yearly.
Indication of second TURB?
- After incomplete initial TURB
- If there is no muscle in the specimen after initial resection, with the exception of TaG1 tumours and primary CIS;
- In all T1 tumours;
- In all G3 tumours, except primary CIS
If indicated, perform a second TURB within 2-6 weeks after initial resection. It should include resection of the primary tumour site.
Concomitant prostate cancer in Bladder cancer?
- Prostate cancer is found in 25-46% of patients undergoing cystectomy for BC.
- Take a biopsy of the prostatic urethra for cases of bladder neck tumour, when bladder CIS is present or suspected, when there is positive cytology without evidence of tumour in the bladder, or when abnormalities of the prostatic urethra are visible
Delivery of intravesical chemotherapy or immunotherapy.?
- Use // Timing // Goal
- Adjunctive // At TUR // Prevent implantation
- Prophylactic // After complete TUR // Prevent or delay recurrence or progression
- Therapeutic // After incomplete TUR // Cure residual disease
Agents used in intravesical chemotherapy?
- Mitomycin C,
- Thiotepa, and
- Bacillus Calmette-Guerin (BCG)
If intravesical chemotherapy is given, it is advised to use the drug at its optimal pH and to maintain the concentration of the drug by reducing fluid intake before and during instillation. The length of an individual instillation should be 1-2 hours.
What is Mitomycin C?
- Mitomycin C (MMC) is an antitumor, antibiotic, alkylating agent that inhibits DNA synthesis.
- With a molecular weight of 329, systemic absorption is minimal.
Dose of Mitomycin C?
- Third week onwards
- Dose - 40 mg in 40 cc of sterile water or saline given once a week for 6 weeks.
- The same dose is utilized for a single prophylactic instillation.
- Induction : 6 instillations, weekly for 6-weeks
- Maintenance : 4 instillations, monthly for next 4 months
Preparations before instillation of Intravesical Mitomycin C?
Restrict fluids for 8 hours before and during intravesical mitomycin C
- Oral doses of 1.3 g of sodium bicarbonate
- - Night before
- - Morning of and
- - 30 minutes before drug treatment
Empty the bladder by inserting foley catheter
The efficacy of Mitomycin C can be enhanced by administering it in a more concentrated solution of 40 mg in 20 cc of sterile water after alkalinizing the urine and with reduced fluid intake.
Side effects of Mitomycin?
Irritative voiding symptoms including urinary frequency, urgency, and dysuria. Unique to this drug is the appearance of a rash on the palms and genitalia, but this effect can be alleviated if patients wash their hands and genitalia at the time of voiding.
What is Thiotepa?
- Thiotepa is an alkylating agent with a molecular weight of 189.
- Although various doses have been used, 30 mg weekly seems to be sufficient.
- Up to 55% of patients respond completely.
- Cystitis is not uncommon after instillation but is usually mild and self-limited.
- Myelosuppression manifested as leukopenia and thrombocytopenia occurs in up to 9% of patients owing to systemic absorption. A complete blood count should be obtained in all patients before successive instillations.
What is BCG?
- BCG is an attenuated strain of Mycobacterium bovis.
- The exact mechanism by which BCG exerts its antitumor effect is unknown, but it seems to be immunologically mediated.
- Mucosal ulceration and granuloma formation are commonly seen after intravesical instillation.
- Activated helper T lymphocytes can be identified in the granulomas, and interleukin-2 reportedly can be detected in the urine of treated patients.
- It appears to be the most efficacious intravesical agent for the management of CIS.
Dose of intravesical BCG?
Third week onwards
Dose : 80mg in 50ml NS (2hour)
Induction : 6 instillations, weekly for 6-weeks followed by a period of 6 weeks where no BCG is given
Maintenance therapy should be considered in high-risk patients. One instillation every week for 3 consecutive weeks at 3, 6, 12, 18, 24, 30 and 36 month
- High risk of tumour recurrence – 2 years
- High risk of tumour progression – 3 years
Side effects of BCG?
Side effects of intravesical BCG administration are relatively common, although severe complications are uncommon. Most patients experience some degree of urinary frequency and urgency. Hemorrhagic cystitis occurs in approximately 7% of patients, and evidence of distant infection is found in <2%.
- 1. Mild systemic or moderate local symptoms
- - Treated with isoniazid (300 mg daily) and pyridoxine (vita-min B6 50 mg/day)
- - Dosage of BCG should be reduced.
- - Isoniazid is continued while symptoms persist and stopped 1 day before the next instillation.
- 2. Severe systemic symptoms
- - Stop instillations.
- - Patients with prolonged high fever (>103°F), symptomatic granulomatous prostatitis, or evidence of systemic infection require treatment with isoniazid and rifampin (600 mg daily).
- 3. BCG sepsis (eg, high fever, chills, confusion, hypotension, respiratory failure, jaundice)
- - treated with isoniazid, rifampin, and ethambutol (1200 mg).
- - addition of cycloserine (500 mg twice daily) or prednisolone (40 mg daily) increases survival rates.
Absolute contraindications of BCG intravesical instillation?
- • during the first 2 weeks after TURB;
- • in patients with visible haematuria;
- • after traumatic catheterisation;
- • in patients with symptomatic urinary tract infection.
Investigation work up for muscle invasive bladder carcinoma?
- MDCT Urography + CT Chest (Chest X-Ray + IVU)
- MRI with fast dynamic contrast-enhancement (Alternative)
- Bone and brain metastasis (MRI) only for symptomatic cases
Types of muscle invasive bladder carcinoma?
- 1. Localized (Organ confined) Muscle invasive Bladder CA (T2, N0-Nx, M0)
- 2. Locally advanced (Operable) Muscle invasive Bladder CA (T3-T4a, N0-Nx, M0)
- 3. Locally advanced (Inoperable) Muscle invasive Bladder CA (T4b, N0-Nx, M0)
- 4. Metastatic Bladder CA (T-any, N-any, M+)
Management of Localized (Organ confined) Muscle invasive Bladder Cancer?
- Consider the following factors
- - Age (Radical cystectomy not advised >80 yrs due to high post op mortality)
- - Patient’s compliance
- - Performance Score
- - Renal status
1. If fit for surgery (Criteria fullfilled) - go for RC. If patient is not fit for surgery, Neoadjuvant chemotherapy followed by RC.
2. If Patient not willing for cystectomy, go for bladder preservation Strategy: TUR + Concomitant Chemotherapy & Radiotherapy. If the patient is not fit for Chemotherapy - TUR +RT
Chemotherapy regimen for bladder carcinoma?
- M-VAC (28 days cycle: 2-3 cycles) - Methotrexate, Vinblastine, Adriamycin, Cisplatin
- GC (Gemcitabine)
Management of Locally advanced (Operable) Muscle invasive Bladder Carcinoma?
- Neoadjuvant Chemotherapy followed by RC, or
- Neoadjuvant Chemotherapy (M-VAC 2 cycle) followed by concomitant chemotherapy (4 more cycle) and RT. External beam irradiation (5000-7000 cGy) is used in fractions over 5-8 weeks
Management of locally advanced (Inoperable) Muscle invasive Bladder carcinoma?
Systemic Chemotherapy followed by Palliative Cystectomy (Symptomatic relief), or
Systemic Chemotherapy followed by concomitant chemo-radiotherapy
Management of Metastatic Bladder Carcinoma?
Systemic Chemotherapy + RT – Symptomatic relief
Surgery for bladder cancer?
TUR - Patients with single, low-grade, noninvasive tumors may be treated with TUR alone. those with superficial disease but high-risk features should be treated with TUR followed by selective use of intravesical therapy,
Partial cystectomy - Patients with solitary, infiltrating tumors (T1–T3) localized along the posterior lateral wall or dome of the bladder are candidates for partial cystectomy.
Radical cystectomy – muscle invasive bladder cancer. External beam irradiation (5000–7000 cGy), delivered in fractions over a 5- to 8-week period, is an alternative to radical cystectomy in well-selected patients with deeply infiltrating bladder cancers.
What is Radical cystectomy?
- In men, standard RC includes removal of the bladder, prostate, seminal vesicles, distal ureters, and regional lymph nodes. Prostate-sparing cystectomy is an option in a subset of carefully selected patients with BC without involvement of the prostatic urethra and without prostate cancer.
- In women, standard RC includes removal of the bladder, entire urethra and adjacent vagina, uterus, distal ureters, and regional lymph nodes.
- Standard lymphadenectomy in BC patients involves removal of nodal tissue cranially up to the common iliac bifurcation, with the ureter being the medial border, and including the internal iliac, presacral, obturator fossa and external iliac nodes.
- Do not delay cystectomy for > three months as it increases the risk of progression and cancer-specific mortality
Sexual function-preserving cystectomy (SPC)?
- 1. Prostate sparing cystectomy: part or the whole prostate is preserved including seminal vesicles, vas deferens and neurovascular bundles.
- 2. Capsule sparing cystectomy: the capsule or peripheral part of the prostate is preserved with adenoma (including prostatic urethra) removed by TURP or en bloc with bladder. Seminal vesicles, vas deferens and neurovascular bundles are also preserved.
- 3. Seminal sparing cystectomy: seminal vesicles, vas deferens and neurovascular bundles are preserved
- 4. Nerve sparing cystectomy: the neurovascular bundles are the only tissue left in place.
Urinary diversion after radical cystectomy?
• Abdominal diversion - ureterocutaneostomy, ileal or colonic conduit, and various forms of a continent pouch
• Urethral diversion - various forms of gastrointestinal pouches attached to the urethra as a continent, orthotopic urinary diversion (neobladder, orthotopic bladder substitution)
• Rectosigmoid diversions - uretero- (ileo-)rectostomy.
What is ileal conduit?
- 20 cm of vascularised distal ileum (30 cm from IC valve) is prepared.
- Ureters are re-implanted over the ileum. Other end of ileum is brought out as a 3 cm stoma in right iliac fossa.
- Patient has to wear a bag over it.
Obturator reflex in TURB?
The obturator nerve passes in close proximity to the inferolateral bladder wall, bladder neck and lateral prostatic urethra. The obturator reflex can occur when the obturator nerve is directly stimulated by the electrical current transmitted by the resectoscope, especially when the tumor is localized at the lateral wall of the bladder, where the obturator nerve runs in close proximity during its intrapelvic course.
Clinical importance - bladder injury due to obturator reflex
Enlist the causes of postoperative oligouria. Discuss the principle of its management. [TU 2057,60]
Discuss the pre-operative staging importance in malignancy with example. 2060